Survival Benefit of Stereotactic Radiotherapy in the Complex Management of Metastatic Melanoma.

BACKGROUND/AIM: Targeted therapy and immunotherapy, with additional stereotactic radiation therapy (SRT) have revolutionized the management of metastatic malignant melanoma (mMM). We aimed to analyze the effectiveness and safety of SRT and determine its role in the complex management of mMM. PATIENTS AND METHODS: We treated 24 patients with solitary metastasis, 15 with oligometastatic disease and one with multiple metastases. The primary endpoint was to investigate the possible effect of stereotactic radiotherapy for metastatic lesions on patients' survival taking the systemic therapy into consideration. RESULTS: The median overall survival (OS) for the entire group was 30.07 months; 50% of them received immunotherapy, 32% received targeted therapy. Complete remission of the irradiated lesions was observed in six patients, partial tumor response was achieved in 13, while stable disease was detected in 10; tumor progression occurred in four cases. Compartmental recurrence (recurrence in the brain in a not previously irradiated region) developed in seven patients. OS was significantly longer in those with extracranial metastases treated with stereotactic body radiotherapy in comparison to brain SRT. We found a strong correlation between tumor response and mean OS (42.5 months after complete or partial remission versus 11.8 months in those with stable or progressive disease). No OS difference was observed according to the number of irradiated lesions or type of systemic therapy before SRT (no therapy: 43.6 months, with therapy: 25.7 months). Significant OS advantage was shown when immunotherapy was administered post-SRT (mean OS: with immunotherapy: 39.6 months, no immunotherapy: 18.5 months). CONCLUSION: In the case of oligometastatic MM, SRT can be used safely and with good efficiency in addition to targeted therapy/anti-programmed cell death protein 1 therapy. Improved survival warrants including SRT in the complex management of mMM, however, further studies are needed for SRT optimization.

Predictive Potential of RNA Polymerase B (II) Subunit 1 (RPB1) Cytoplasmic Aggregation for Neoadjuvant Chemotherapy Failure.

We aimed to investigate the contribution of co-translational protein aggregation to the chemotherapy resistance of tumor cells. Increased co-translational protein aggregation reflects altered translation regulation that may have the potential to buffer transcription under genotoxic stress. As an indicator for such an event, we followed the cytoplasmic aggregation of RPB1, the aggregation-prone largest subunit of RNA polymerase II, in biopsy samples taken from patients with invasive carcinoma of no special type. RPB1 frequently aggregates co-translationally in the absence of proper HSP90 chaperone function or in ribosome mutant cells as revealed formerly in yeast. We found that cytoplasmic foci of RPB1 occur in larger sizes in tumors that showed no regression after therapy. Based on these results, we propose that monitoring the cytoplasmic aggregation of RPB1 may be suitable for determining-from biopsy samples taken before treatment-the effectiveness of neoadjuvant chemotherapy.

Magnetic Resonance Imaging-Based Delineation of Organs at Risk in the Head and Neck Region.

Purpose: The aim of this article is to establish a comprehensive contouring guideline for treatment planning using only magnetic resonance images through an up-to-date set of organs at risk (OARs), recommended organ boundaries, and relevant suggestions for the magnetic resonance imaging (MRI)-based delineation of OARs in the head and neck (H&N) region. Methods and Materials: After a detailed review of the literature, MRI data were collected from the H&N region of healthy volunteers. OARs were delineated in the axial, coronal, and sagittal planes on T2-weighted sequences. Every contour defined was revised by 4 radiation oncologists and subsequently by 2 independent senior experts (H&N radiation oncologist and radiologist). After revision, the final structures were presented to the consortium partners. Results: A definitive consensus was reached after multi-institutional review. On that basis, we provided a detailed anatomic and functional description and specific MRI characteristics of the OARs. Conclusions: In the era of precision radiation therapy, the need for well-built, straightforward contouring guidelines is on the rise. Precise, uniform, delineation-based, automated OAR segmentation on MRI may lead to increased accuracy in terms of organ boundaries and analysis of dose-dependent sequelae for an adequate definition of normal tissue complication probability.

Clinical considerations of bleomycin based electrochemotherapy with variable electrode geometry electrodes for inoperable, deep-seated soft tissue sarcomas.

The aim of the current prospective pilot study exclusively for deep-seated soft tissue sarcomas (STS) was to evaluate efficacy and safety of bleomycin-based ECT using VEG (variable electrode geometry) electrodes. During a 2-year period, seven surgically inoperable STSs were treated at the University of Szeged, Department of Surgery in Hungary. Electrode placement was determined by software planning using preoperative imaging (CT/MRI) and intraoperative ultrasound. Intravenous bleomycin (15.000 IU/m2) was administered 8 min before first pulse generation which lasted up to 40 min. Tumour response was evaluated through CT/MRI 2 months after treatment as per RECIST v.1.1. Five male- and 2 female patients were treated with fibromyxoid sarcoma (n = 2), epitheloid sarcoma (n = 3), liposarcoma (n = 1) and myofibroblastic sarcoma (n = 1) with median age of 54 years (49-88). Median tumour diameter, tumour volume and tumour depth was 5.9 cm (3.7-22.5), 131.13 cm3 (35.6-2456.22) and 6.18 cm (3.74-18.18), respectively. Median operative time was 75 min (35-180), median hospital stay 2 days (2-20). Two month follow-up confirmed partial response in 5 patients, while stable disease in 1 patient, and progressive disease in 1 case as per RECIST v.1.1. Grade 2 ulceration was experienced in four cases, and a transient left musculus quadriceps femoris plegia occured in one patient. Local control of deep-seated STSs with BLM-based VEG ECT holds a promising perspective and our results may serve as a practical guide for further investigation and treatment planning.

Predictive role of neostromal CD10 expression in breast cancer patients treated with neoadjuvant chemotherapy.

Background: The therapeutic strategy of invasive breast cancer is based on routine histopathological markers (estrogen-, progesterone receptor, HER2, Ki67) routinely evaluated in tumor cells. However, the assessment of cancer stroma could influence therapeutic strategies. Studies have shown that stromal expression of CD10, a zinc-dependent metalloproteinase, is associated with biological aggressiveness of the tumor. In the present retrospective study, we aimed to evaluate stromal CD10 expression and association between CD10 expression and response to neoadjuvant chemotherapy in invasive breast cancer. Methods: CD10 immunohistochemistry was performed on core biopsies taken before the neoadjuvant therapy. Stromal CD10 expression was determined and compared with well-known predictive and prognostic tissue markers as well as with the following groups defined according to the degree of tumor response: no regression, partial regression, and complete regression. Results: A total of 60 locally advanced invasive breast carcinomas of "no special type" were included. The proportion of CD10 positive tumors was significantly higher in the "no regression" group compared to "complete regression" group (p = 0.000). Stromal CD10 expression was found to be significantly associated with decrease in response to neoadjuvant chemotherapy. According to CD10 expression we did not find any difference in hormone receptor status, Ki67, tumor grade or neostromal area. Conclusion: Our data suggest that CD10 expression can serve as a predictive marker of the effect of neoadjuvant chemotherapy in breast cancer patients. Therefore, its inclusion into the routine assessment of biopsies to tailor tumor-specific therapeutic strategies merits consideration.

Deep-inspirational breath-hold (DIBH) technique in left-sided breast cancer: various aspects of clinical utility.

BACKGROUND: Studying the clinical utility of deep-inspirational breath-hold (DIBH) in left breast cancer radiotherapy (RT) was aimed at focusing on dosimetry and feasibility aspects. METHODS: In this prospective trial all enrolled patients went through planning CT in supine position under both DIBH and free breathing (FB); in whole breast irradiation (WBI) cases prone CT was also taken. In 3-dimensional conformal radiotherapy (3DCRT) plans heart, left anterior descending coronary artery (LAD), ipsilateral lung and contralateral breast doses were analyzed. The acceptance of DIBH technique as reported by the patients and the staff was analyzed; post-RT side-effects including radiation lung changes (visual scores and lung density measurements) were collected. RESULTS: Among 130 enrolled patients 26 were not suitable for the technique while in 16, heart or LAD dose constraints were not met in the DIBH plans. Among 54 and 34 patients receiving WBI and postmastectomy/nodal RT, respectively with DIBH, mean heart dose (MHD) was reduced to < 50%, the heart V25 Gy to < 20%, the LAD mean dose to < 40% and the LAD maximum dose to about 50% as compared to that under FB; the magnitude of benefit was related to the relative increase of the ipsilateral lung volume at DIBH. Nevertheless, heart and LAD dose differences (DIBH vs. FB) individually varied. Among the WBI cases at least one heart/LAD dose parameter was more favorable in the prone or in the supine FB plan in 15 and 4 cases, respectively; differences were numerically small. All DIBH patients completed the RT, inter-fraction repositioning accuracy and radiation side-effects were similar to that of other breast RT techniques. Both the patients and radiographers were satisfied with the technique. CONCLUSIONS: DIBH is an excellent heart sparing technique in breast RT, but about one-third of the patients do not benefit from that otherwise laborious procedure or benefit less than from an alternative method. TRIAL REGISTRATION: retrospectively registered under ISRCTN14360721 (February 12, 2021).

Individually selected teletherapy technique for accelerated partial breast irradiation.

BACKGROUND: The aim of the study was to individualize accelerated partial breast irradiation based on optimal dose distribution, protect risk organ and predict most advantageous technique. MATERIALS AND METHODS: 138 breast cancer patients receiving postoperative APBI were enrolled. APBI plans were generated using 3D-conformal (3D-CRT), sliding window intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT). In the case of superficial tumours, additional plans were developed by adding electron beam. To planning target volume (PTV) 37.5 Gy/10 fractions, 1 fraction/day was prescribed. A novel plan quality index (PQI) served as the basis for comparisons. RESULTS: IMRT was the most advantageous technique regarding homogeneity. VMAT provided best conformity, 3D-CR T - the lowest lung and heart exposure. PQI was the best in 45 (32.61%) VMAT, 13 (9.42%) IMRT, 9 (6.52%) 3D-CRT plans. In 71 cases (51.45%) no difference was detected. In patients with large PTV, 3D-CRT was the most favourable. Additional electron beam improved PQI of 3D-CRT plans but had no meaningful effect on IMRT or VMAT. IMRT was superior to VMAT if the tumour was superficial (p < 0.001), situated in the medial (p = 0.032) or upper quadrant (p = 0.046). CONCLUSIONS: In half of all cases, individually selected teletherapy techniques provide superior results over others; relevance of a certain technique may be predicted by volume and PTV localization.

Examination of Tumor Regression Grading Systems in Breast Cancer Patients Who Received Neoadjuvant Therapy.

Neoadjuvant therapy is a common form of treatment in locally advanced breast cancer (LABC) patients. Besides some guidelines for grading regression, a standardized general scheme is not yet available. The aim of our study was to compare the prognostic impact of different regression grading systems, namely the TR/NR, Chevallier, Sataloff, Denkert-Sinn, Miller-Payne, NSABP-B18, Residual Disease in Breast and Nodes and Residual Cancer Burden (RCB) on disease-free (DFS) and overall survival (OS). Data of 746 breast cancer patients treated in neoadjuvant setting between 1999 and 2019 have been included. The different regression grades and follow-up data were collected from medical charts. Statistical analysis included the Kaplan-Meier method, log-rank test and multivariate Cox regression. The average patient age was 55 years. The DFS and OS estimates of patients with complete pathological regression and residual in situ carcinoma have been significantly more favorable than those having partial regression or no signs of regression (pDFS<0.001, pOS < 0.001). Significant differences were found between DFS estimates of classes with partial regression and without regression defined by RCB. Concerning DFS estimates, the RCB classification (p = 0.019), while regarding OS data the y-stage (p = 0.011) and the nodal status (ypN; p = 0.045) were significant prognosticators by multivariate Cox regression. Regression grading systems help the evaluation of regression in LABC patients treated with neoadjuvant therapy. Of the several grading systems compared, the RCB classification makes the best distinction between the outcomes of the different classes, therefore we recommend the inclusion of RCB into the histopathological findings.

Influence of mutagenic versus non-mutagenic pre-operative chemotherapy on the immune infiltration of residual breast cancer.

Background: Chemotherapeutic agents are often mutagenic. Induction of mutation associated neo-epitopes is one of the mechanisms by which chemotherapy is thought to increase the number of tumor-infiltrating lymphocytes. It is not known, however, whether treatment with various chemotherapeutic agents with different mutagenic capacity induce a significantly different number of stromal tumor-infiltrating lymphocytes (StrTIL) in residual cancer.Methods: One hundred and twenty breast carcinoma cases with residual disease that were treated with one of three types of pre-operative chemotherapy regimens were selected for the study. The percentage of StrTIL was evaluated in pretreatment core biopsies (pre-StrTIL) and post-treatment surgical tumor samples (post-StrTIL). TIL changes (ΔStrTIL) were calculated from the difference between post-StrTIL and pre-StrTIL.Results: When analyzing the pre-StrTIL and post-StrTIL among the three treatment groups, we detected significant StrTIL increase independently of the treatment applied. Based on distant metastases-free survival analysis, both post-StrTIL and ΔStrTIL was found to be independent prognostic factor in HR negative cases. Conclusions: Significant increase of StrTIL in the residual disease was observed in patients treated with the highly (platinum), moderately (cyclophosphamide) and marginally mutagenic chemotherapeutic agents (taxane, anthracycline). Increase in StrTIL in residual cancer compared to pretreatment tumor tissue is associated with improved distant metastasis-free survival in cases with HR negative breast carcinoma.

Prone Positioning on a Belly Board Decreases Rectal and Bowel Doses in Pelvic Intensity-Modulated Radiation Therapy (IMRT) for Prostate Cancer.

The presence of normal tissues in the irradiated volume limits dose escalation during pelvic radiotherapy (RT) for prostate cancer. Supine and prone positions on a belly board were compared by analyzing the exposure of organs at risk (OARs) using intensity modulated RT (IMRT). The prospective trial included 55 high risk, localized or locally advanced prostate cancer patients, receiving definitive image-guided RT. Computed tomography scanning for irradiation planning was carried out in both positions. Gross tumor volume, clinical and planning target volumes (PTV) and OARs were delineated, defining subprostatic and periprostatic rectal subsegments. At the height of the largest antero-posterior (AP) diameter of the prostate, rectal diameters and distance from the posterior prostate wall were measured. IMRT plans were generated. Normal tissue exposure and structure volumes were compared between supine and prone plans using paired t-test. In the volumes of the prostate, PTV, colon and small bowel, no significant differences were found. In prone position, all rectal volumes, diameters, and rectum-prostate distance were significantly higher, the irradiated colon and small bowel volume was lower in dose ranges of 20-40 Gy, and the exposure to all rectal segments was more favorable in 40-75 Gy dose ranges. No significant difference was found in the exposure of other OARs. Prone positioning on a belly board is an appropriate positioning method aiming rectum and bowel protection during pelvic IMRT of prostate cancer. The relative reduction in rectal exposure might be a consequence of the slight departure between the prostate and rectal wall.

Clinical benefit of fulvestrant monotherapy in the multimodal treatment of hormone receptor and HER2 positive advanced breast cancer: a case series.

Fulvestrant is a pure estrogen receptor (ER) antagonist approved for the treatment of metastatic ER positive breast cancer in postmenopausal women with disease progression following antiestrogen therapy. The clinical results of fulvestrant demonstrated encouraging activity in tumors in spite of HER2 positivity, but data about its use after progression on anti-HER2 agents are limited. Partial responses and durations of response of 12, 25, and 38 months in three cases with multiple metastases of ER positive and HER2 positive breast cancer were observed; all patients had been treated with 1-4 regimens of an anti-HER2 agent in combination with chemotherapy or an aromatase inhibitor before the initiation of fulvestrant. Fulvestrant is a valuable option with limited toxicity and durable response in metastatic HER2 and ER positive breast cancer after progression on anti-HER2 agents as well. Therapeutic benefit even in extensive skin metastases and (irradiated) brain metastases may be expected. Further investigations are warranted to establish where it fits into the multimodal management of ER and HER positive breast cancer.

Daily Setup Accuracy, Side-effects and Quality of Life During and After Prone Positioned Prostate Radiotherapy.

BACKGROUND/AIM: Exposure of organs at risk with prostate radiotherapy (RT) is lower in the prone position. This study is a prospective evaluation of setup accuracy, side-effects, and quality of life (QOL) during and after prone positioned RT. PATIENTS AND METHODS: Image-guided (IG) intensity-modulated (IM) RT was administered in prone position on belly-board to 55 high-risk prostate cancer (PC) patients. Rectum diameters were measured in two areas of the symphysis at the beginning of RT and during it. Side-effects, QOL, and prostate specific symptoms (PSS) were evaluated. RESULTS: Setup accuracy was similar to that reported in the literature. In the upper area of symphysis rectal diameters were significantly changed during treatment, but in the prostate region, no difference was detected. No change was detected in patients' QOL and PSS during treatment, but after RT, they improved. CONCLUSION: Prone positioned IG-IMRT is feasible with tolerable side-effects for high-risk PC patients. Changes in QOL and PSS are insignificant during RT, while improvement after RT suggests a rapid recovery.

Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma.

BACKGROUND: In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study. METHODS: From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively. RESULTS: The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%. CONCLUSIONS: Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is safe and improves outcome. Dose escalation in 12.5 mg steps may be recommended for properly educated patients.

A simple clinical method for predicting the benefit of prone vs. supine positioning in reducing heart exposure during left breast radiotherapy.

BACKGROUND AND PURPOSE: The benefit of reduced radiation heart exposure in the prone vs. supine position individually differs. In this prospective cohort study, the goal was to develop a simple method for the operation of a validated model for the prediction of preferable treatment position during left breast radiotherapy. MATERIAL AND METHODS: In 100 cases, a single CT slice was utilized for the collection of the needed patient-specific data (in addition to body mass index, the distance of the LAD from the chest wall and the area of the heart included in the radiation fields at the middle of the heart in the supine position). Outcome was analyzed in relation to the full CT series acquired in both positions and dosimetric data. RESULTS: Great consistency was found between the tested and original method regarding sensitivity and specificity. The prioritization of LAD dose, and the use of heart dose and position-specific dose constraints as safety measures ensure sensitivity and specificity values of 82.8% and 87.3%, respectively. In an additional "routine clinical practice" series of 60 patients the new method seemed feasible in routine clinical practice. External testing on a 28-case series indicated similar accuracy. CONCLUSION: We consider this simple clinical tool appropriate for assisting individual positioning aiming at maximum heart protection during left breast irradiation.

Capecitabine in Combination with Docetaxel in First Line in HER2-Negative Metastatic Breast Cancer: an Observational Study.

Due to the limited experience with capecitabine plus docetaxel (XT) combination in the first-line treatment of metastatic breast cancer in Hungary, the main objective of the study was to analyze the effectiveness and tolerability of XT therapy. A prospective, open-label, non-randomized, single-arm, multicenter, observational study was designed. All female patients were eligible whose metastatic breast cancer could be treated with the XT protocol according to the summary of product characteristics of the drugs. The median progression free survival was 9.9 ± 3.0 months. Time to treatment failure was 4.6 ± 5.1 months on average. The overall response rate was 28.9 %, the clinical benefit rate was 73.3 %. The treatment was discontinued in 35.6 % of patients due to disease progression and in 20.0 % due to adverse events (AE). 33 patients with a total of 73 AEs have been reported, and 13 of them had serious adverse events (SAE). The efficacy and the safety profile of XT chemotherapy proven in the study are consistent with the results demonstrated in randomized trials. First-line XT chemotherapy effectively improves the PFS in metastatic breast cancer.

Cardiac Surveillance Findings During Adjuvant and Palliative Trastuzumab Therapy in Patients with Breast Cancer.

BACKGROUND/AIM: Trastuzumab therapy, the standard treatment for human epidermal growth factor receptor type-2 (HER2)-positive breast cancer, is associated with possible cardiotoxicity. We set out to retrospectively analyze the cardiac follow-up data of patients with breast cancer receiving trastuzumab treatment. PATIENTS AND METHODS: The study involved 47 and 31 patients receiving adjuvant or palliative chemotherapy plus trastuzumab, respectively. Cardiovascular system assessments including echocardiography were regularly performed. RESULTS: A significant heart abnormality was detected in 44.7% of the operable and 41.9% of metastatic cases. In the adjuvant setting, left ventricular ejection fraction changes occurred mostly during treatment and less frequently after its completion (40.4% vs. 19.4%), while in the palliative setting, 35.5% and 40% in the first and the second year of therapy. An asymptomatic atrial septum aneurysm was detected in 8.5% and 13% of the patients in the two groups. CONCLUSION: Trastuzumab-related cardiotoxicity is mostly manifested in an asymptomatic decrease in left ventricular ejection fraction; hypertension, a high body mass index and left-sided irradiation are its predictors.