Ablative dose stereotactic body radiation therapy for oligometastatic disease: a prospective single institution study.

Localized, metastasis-directed stereotactic body radiation therapy (SBRT) of oligometastatic disease (OD) is currently rapidly evolving standard of care in many institutions. Further reports of outcomes are required to strengthen the level of evidence in the absence of comparative trials evaluating different practical procedures. The aim of this prospective single institutional study is to analyse, in unselected cohort of patients from real-world clinical practice, the long-term survival, tumor control outcomes and safety of SBRT in OD (radical ablative radiotherapy with biological equivalent dose BED10>100 Gy). In addition to standard toxicity and survival parameters, we report unique outcomes as FFWD - Freedom from widespread dissemination, FFNT - Freedom from the need of subsequent treatment and functional survival with Karnofsky performance status higher than 70%. A total of 110 patients were prospectively evaluated, 60% and 40% were treated for lung and liver oligometastatic disease, respectively. No grade 3 or 4 acute toxicities (CTCAE) were reported. With median follow up of 22.2 months and 2-year overall survival of 88.3%, four patients (6.1%) experienced local progression in the lung SBRT cohort. In the liver SBRT cohort, median follow up was 33 months, 2-year overall survival was 68.5% and 11 patients (25%) experienced local and 36 (81.8%) distal progression. Higher BED10 of 150-170 Gy compared to 100-150 Gy was an independent positive prognostic factor for local progression-free survival for all patients with hazard ratio 0.25. This confirms SBRT ablative radiobiology effects to be independent of OD primary histology and location. The best outcomes in terms of FFNT were observed in the multivariable analysis of patients with 1-2 lung OD compared to both the liver OD cohort and patients with more than 2 lung metastases. Better FFNT in the liver SBRT cohort was observed in patients with 1-2 liver metastases and in patients whose liver OD was irradiated by higher BED10. In conclusion, SBRT is a suitable option for patients who are not surgical candidates; with approximately 30% of patients not requiring subsequent treatment 2 years after SBRT. We believe that this treatment represents a safe and effective option for oligometastatic involvement in patients with various primary tumors.

Effect of Tumor Size and p16 Status on Treatment Outcomes - Achievement of Complete Remission in Prospectively Followed Patients with Oropharyngeal Tumors.

BACKGROUND: Oropharyngeal squamous cell tumors associated with human papillomavirus infection (p16 positive tumors) have better prognosis than p16 negative tumors regardless of the more advanced stage of the disease. Tumor volume (GTVt+n) is generally an important factor affecting treatment results of ionizing radiation. The aim of this prospective non-randomized study is to evaluate the effect of tumor volume on the (chemo)radiation treatment results in a group of patients with p16 negative and p16 positive oropharyngeal tumors. PATIENTS AND METHODS: Patients with confirmed squamous cell tumor of the oropharynx of stages III and IV, according to the 7th version of the TNM (tumor-nodes-metastases) classification, were eligible for this study. The main exclusion criteria were palliative treatment, neoadjuvant chemotherapy or planned concomitant therapy with cetuximab. Patients were treated according to standardized protocols with curative intent. Primary tumor volume (GTVt) and involved nodes volume (GTVn) were obtained from radiotherapy planning system for further statistical analysis. The differences in tumor volumes between the groups according to p16 expression were assessed with subsequent testing of probability to achieve complete remission (CR) of the disease in both groups. RESULTS: In total, 49 patients - 84% men, median age 60.5 years, 25 (51%) patients p16 positive, 40 (82%) underwent concomitant chemoradiotherapy. Median of GTVt in the whole patients group is 40.2 ccm, GTVn 11.78 ccm and median volume of the whole tumor burden (GTVt+n) 70.21 ccm (range 11.05-249). Median of GTVn was greater in the p16 positive cohort (p = 0.041). In the entire group, the median time to reach CR was 91 days (95% CI 86-107 days) from the end of radiotherapy. In the group of p16 negative patients, 14 achieved CR (61%) out of 23 patients, in p16 positive group 20 (80%) out of 25 patients (p = 0.111). P16 negative patients had a longer time to CR (p = 0.196, HR 1.58, 95% CI 0.79-3.18). None of the independently assessed volumetric parameters of the tumor (GTVt, GTVn, GTVt+n) affected CR in the p16 positive patients group, while there was a significant impact of the whole tumor burden (GTVt+n) in the p16 negative cohort (median 58.1 ccm in CR patients vs. 101.9 ccm, p = 0.018). CONCLUSION: We have showed less GTVt+n dependence to achieve CR in p16 positive tumors in comparison with p16 negative tumors. Thus, p16 positive oropharyngeal squamous cell cancers should not be withdrawn from the curative treatment intent based on the greater GTVt+n. Key words oropharyngeal neoplasms - p16 status - treatment outcome - tumor burden - complete remission This work was supported by grant of the Ministry of Health of the Czech Republic AZV 15-31627A and by grant of the Ministry of Health of the Czech Republic - Conceptual development of a research organization (MMCI 00209805). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 2. 11. 2018 Accepted: 11. 11. 2018.

Patterns of failure after brain metastases radiotherapy: reflections on the importance for treatment and clinical trials reporting.

In many ongoing clinical trials, new strategies for radiotherapy of brain metastases are currently being investigated. A post surgical focal cavity stereotactic radiosurgery and the developing role of a hippocampal-sparing whole brain radiotherapy are of the highest importance. The evaluation of spatial patterns of metastases failure after radiotherapy is a powerful tool for assessing the potential benefit of new different radiotherapy approaches, which enables to identify possible directions leading to better radiotherapy techniques and to modify general management for newly diagnosed brain metastases. The purpose of this article is to present a mix between trial data and philosophical point of view for discussion about the importance of systematic evaluation of spatial patterns of failure in all ongoing trials investigating new approaches in local brain metastases treatment.

Utilization of Prognostic Indexes for Patients with Brain Metastases in Daily Radiotherapy Routine -  is the Complexity and Intricacy Still an Issue?

BACKGROUND: Many prognostic indexes are available for patients with brain metastases in order to estimate remaining lifetime before selection of appropriate treatment including palliative radiotherapy. Their routine utilization is often deprecated for their complexity. We developed a practical tool based on widely available spreadsheet editors for facilitation of daily clinical use of selected indexes (RPA, GPA and WBRT 30) and evaluated its usage for retrospective single institutional survival analysis of patients irradiated for brain metastases. PATIENTS AND METHODS: Spreadsheet platform was prepared and adjusted for automatic calculation of selected prognostic indexes after input of the relevant parameters. The consecutive series of newly diagnosed patients referred during 2011 to the palliative brain radiotherapy were analyzed, and real calculated survival parameters of individual subgroups of RPA, GPA and WBRT 30 were compared with estimated ones. Correlation of radiotherapy technique and estimated survival at the time of treatment indication was evaluated. RESULTS: Total of 121 patients (61% with multiple metastases) were irradiated with the majority undergoing whole brain radiotherapy. Median overall survival from the time of radiotherapy indication was 3.13 months. Non balanced distribution into individual scoring systems subgroups was observed with 8 (7%), 89 (73%) and 24 (20%) patients assigned to RPA 1, 2 and 3 subgroup, 3 (3%), 9 (7%), 57 (47%) and 52 (43%) patients assigned to GPA 3.5- 4, GPA 3.0, GPA 1.5- 2.5 and GPA 0- 1.0 subgroup and 10 (8%), 88 (73%) and 23 (19%) patients assigned to WBRT 30 subgroup D, B and A. Entire differences in overall survival between subgroups are significant among all three scoring systems. CONCLUSION: Routine calculation of available prognostic indexes is useful in decision making regarding the best radiotherapy of brain metastases, and their calculation is greatly facilitated by properly prepared widely available spreadsheet tools.

Toxicity and survival outcomes of adjuvant chemoradiation for gastric and gastroesophageal junction cancer patients treated in period 2006-2009: an institutional experience.

Surgical resection is the mainstay of gastric or gastroesophageal junction cancer treatment and has curative potential for patients with early-stage disease. In order to improve the poor survival rates, there are two complementary treatment strategies used at most - perioperative chemotherapy based on UK Magic trial or adjuvant chemoradiation based on INT-0116 trial. Daily treatment decision making should be led also by institutional experiences with toxicity evaluation. We evaluated survival and toxicity outcomes of 47 consecutive patients who underwent adjuvant chemoradiation in our institution in the years 2006-2009. 45Gy in 5 weeks with concurrent two cycles of FUFA Mayo regimen chemotherapy were administrated as part of combined treatment. The acute toxicity was relatively mild (CTCAE scale): grade 2 nausea in 26%, vomiting in 13%, and diarrhoea grade 1 in 15% and general abdominal discomfort in 57% of patients. Grade 3 haematological and infectious complications in 6% and 2% respectively. Late adverse events were as follows: grade 1 esophageal toxicity in 17%, signs of mild chronic esophageal ulceration and esophageal stenosis in 9% of patients (50% of them had tracheoesophageal fistula). The Kaplan- Meier estimate of the median overall survival was 30.5 months with median 25.7 months disease free survival. The overall survival was statistically significantly affected by the amount of removed positive lymph nodes. For the proper evaluation of radiotherapy role in multimodal treatment approach, results of other clinical trials investigating role of concurrent radiotherapy in administration of perioperative chemotherapy will be necessary. Meanwhile, two equally approaches are possible, all having their pros and cons. Institutional toxicity evaluation is recommended in order to provide the best care possible.

Toxicity and survival outcomes of adjuvant chemoradiation for gastric and gastroesophageal junction cancer patients treated in period 2006-2009: an institutional experience.

Surgical resection is the mainstay of gastric or gastroesophageal junction cancer treatment and has curative potential for patients with early-stage disease. In order to improve the poor survival rates, there are two complementary treatment strategies used at most - perioperative chemotherapy based on UK Magic trial or adjuvant chemoradiation based on INT-0116 trial. Daily treatment decision making should be led also by institutional experiences with toxicity evaluation. We evaluated survival and toxicity outcomes of 47 consecutive patients who underwent adjuvant chemoradiation in our institution in the years 2006-2009. 45Gy in 5 weeks with concurrent two cycles of FUFA Mayo regimen chemotherapy were administrated as part of combined treatment. The acute toxicity was relatively mild (CTCAE scale): grade 2 nausea in 26%, vomiting in 13%, and diarrhoea grade 1 in 15% and general abdominal discomfort in 57% of patients. Grade 3 haematological and infectious complications in 6% and 2% respectively. Late adverse events were as follows: grade 1 esophageal toxicity in 17%, signs of mild chronic esophageal ulceration and esophageal stenosis in 9% of patients (50% of them had tracheoesophageal fistula). The Kaplan- Meier estimate of the median overall survival was 30.5 months with median 25.7 months disease free survival. The overall survival was statistically significantly affected by the amount of removed positive lymph nodes. For the proper evaluation of radiotherapy role in multimodal treatment approach, results of other clinical trials investigating role of concurrent radiotherapy in administration of perioperative chemotherapy will be necessary. Meanwhile, two equally approaches are possible, all having their pros and cons. Institutional toxicity evaluation is recommended in order to provide the best care possible. Keywords: adjuvant chemoradiation, gastric cancer, early toxicity, late toxicity, survival outcomes.

Stereotactic body radiation therapy for colorectal cancer liver metastases; early results.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is well feasible and effective method for treatment of colorectal cancer liver metastases. MATERIALS AND METHODS: From September 2009 to December 2011, 11 patients with 15 inoperable liver metastases of colorectal cancer were treated by SBRT using Varian Clinac iX linear accelerator. We treated 6 men and 5 women of age from 51 to 81 years (median 68). SBRT doses ranged from 40 to 56 Gy (median 54 Gy) and were administered in 3 to 8 fractions. RESULTS: Local control rates at 2, 4, 6, 9 and 12 months after completion of SBRT were 100%, 91%, 91%, 67% and 50%, respectively. Disease progression-free survival rates at 2, 4, 6, 9 and 12 months were 82%, 82%, 64%, 50% and 50%, respectively. Median follow-up was 15 months. No severe side effects were attributed to the therapy. CONCLUSION: Our study assessed the feasibility of SBRT in selected group of patients with 1 to 3 colorectal cancer liver metastases with no other treatment option. We achieved excellent local control and very moderate acute and late side effects. Distant metastases were the most common recurrence form after SBRT. SBRT demonstrated excellent local control and resulted in occasional long-term survivors without any serious side effects of therapy.

Adjuvant accelerated partial-breast irradiation of early-stage breast cancer using stereotactic approach - methodology, technical challenges and early results of prospective randomized trial.

BACKGROUND: The adjuvant radiotherapy (RT) of the early-stage breast cancer patients as local treatment aims to eliminate potential microscopic residual disease in the surgery bed or satellites in its neighborhood. Based on published studies, accelerated partial breast irradiation (APBI) is recommended for strictly selected patients. The aim of this single-institution prospective randomized study was to compare the targeted APBI delivered by stereotactic approach with the currently more commonly used accelerated whole breast irradiation with the boost to the tumor bed in terms of feasibility, safety, tolerance, and cosmetic effects. MATERIALS AND METHODS: Early-stage breast cancer patients after partial mastectomy were screened for eligibility. The inclusion criteria were age > 50 years, non-lobular carcinoma histology, size 2cm, negative margins 2mm, L0, ER-positive, BRCA negative. Enrolled patients were equally randomized into two arms according to radiotherapeutic regiment - external APBI (5× 6 Gy) and accelerated whole breast irradiation with the boost (15× 2,67 Gy + 5× 2 Gy). These preliminary results of the ongoing study evaluated the first 57 from 84 planned patients. RESULTS: The median age was 65 years. The tumors were of grade 1 in 60 % of patients, the median size of 9mm and 70 % were classified as invasive ductal carcinoma. Statistical significant differences between the groups in baseline characteristics were not observed. A total of 29 patients was enrolled in the APBI group by the end of 2020. All enrolled patients were evaluated one month after RT. A total of 40 (70,2 %) a 33 (58 %) had examinations 3 and 6 months after RT, respectively. Toxicity evaluation showed statistically significantly fewer acute adverse events in the APBI group in terms of skin erythema, desquamation, skin tenderness, dryness, edema, pigmentation, breast pain and fatigue. Late toxicity evaluated in 3 and 6 months after RT was significantly higher in the control group. The cosmetic effect (independently evaluated by a physician, nurse and patient) was more favorable to the APBI group. CONCLUSION: The technique using the principles of targeted radiotherapy turned out to be a less toxic and easier feasible approach for adjuvant radiation of early-stage breast cancer patients. Consequently, the presented study increases the level of evidence for RT-indicated patients to the establishment of external APBI into daily clinical practice.

[Opportunistic infections in patients after complex therapy of cancer]. / Oportunní infekce mozku u pacientu po komplexní terapii nádorového onemocnení.

BACKGROUNDS: An opportunistic infection is an infection caused by pathogens, such as Toxoplasma gondii, that usually are not pathogenic in a healthy host but may cause an infection in immunocompromised patients. Although the most frequent cause of an opportunistic infection is immunodeficiency due to HIV infection, the immunodeficiency induced by anticancer treatment cannot be ignored. DESIGN: A 56-year old female patient after a comprehensive treatment of breast cancer underwent a stereotactic biopsy of MR-verified multiple brain lesions suspected to be of metastatic aetiology. The histology report unexpectedly concluded that the lesion was brain toxoplasmosis confirmed by detection of IgM specific antibody in cerebrospinal fluid. Immunology examination has proven a deficit of cell-mediated immunity. The symptoms (cephalea, cerebellar symptomatology with vertigo) and MR findings disappeared following 6-month treatment with a combination of pyrimethamin, sulfadiazin and leucovorin. CONCLUSION: Since neoplastic duplicities and brain lesions of non-neoplastic aetiology are found in about 11% of oncology patients, histological verification of aetiology of intracranial lesions is essential for targeted therapy of these patients. Our case of brain toxoplasmosis documents the role of opportunistic infections in differential diagnosis of brain lesions in patients who underwent anticancer treatment.

[New therapeutic options in therapy of glioblastoma multiforme]. / Nové moznosti I lécby glioblastoma multiforme.

Glioblastoma multiforme is one of the most aggressive malignant brain tumours with limited therapeutics options. Standard therapy is maximal surgical resection and adjuvant concurrent chemo-radiotherapy and maintenance therapy with temozolomide. This approach improves median and 5-year survival in comparison with postsurgical radiotherapy alone. Additional predictive and prognostic biomarkers are necessary, especially due to the development of targeted therapy--antibodies and tyrosine kinase inhibitors. These new therapeutic approaches are under intensive investigation. The most promising data currently available are for anti-angiogenic therapies, such as bevacizumab and cediranib. This review presents a summary of the possible role of targeted therapy in the treatment of glioblastoma multiforme.

Stereotactic Body Radiotherapy - Current Indications.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is used to treat localized tumor lesions and consists of applying high doses of radiation to a small number of fractions using specially equipped linear accelerators, modern immobilization devices, and imaging methods, which are considered special, advanced techniques in modern day radiotherapy. SBRT is a very well tolerated, non-invasive, short-term treatment that does not require hospitalization or any complicated preparation. Compared to standard radiotherapy techniques, SBRT allows, due to its precision, significantly higher doses to be applied to the target with less damage to surrounding healthy tissues. If dose constraints are not exceeded, the risk of damage to tissues and organs around the irradiated volume is reduced to minimum. The principle of SBRT is the application of ablative doses of radiation that cause necrosis of the irradiated tissue. PURPOSE: The aim of this review is to provide a basic overview of SBRT indications, radiation doses used, and potential side effects. It is not intended to be a detailed description of treatment itself (such as discussion of patient fixation systems, management of respiratory movements, or image guided strategies of treatment). This review also discusses rarer indications for SBRT, such as pancreatic carcinoma or hepatocellular carcinoma. CONCLUSION: Advances in image navigation, radiation planning, and dose application have enabled successful introduction of SBRT as a treatment regimen for many primary tumors and oligometastatic disease. If surgery is not possible or the patient refuses surgery, it is always reasonable to consider SBRT. SBRT has curative potential for the treatment of primary lung or prostate tumors. High-dose irradiation of oligometastases of various primary tumors can lead to long-term survival without disease symptoms, delay administration of toxic systemic therapies, and improve the quality of life of oncological patients. Key words radiotherapy - stereotactic body radiotherapy - review - ablative radiotherapy - lung cancer - prostate cancer - oligometastatic disease This work was supported in part by the Ministry of Health, Czech Republic - Conceptual Development of Research Organization (MMCI 00209805). The results of this research have been acquired within CEITEC 2020 (LQ1601) project with the financial contribution made by the Minis-try of Education, Youths and Sports of the Czech Republic within special support paid from the National Programme for Sustainability II funds. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 30. 10. 2018 Accepted: 4. 11. 2018.

The technique of craniospinal irradiation in the management of intracranial ependymomas.

PURPOSE: To present a new technique of craniospinal irradiation as a postoperative prophylactic treatment in patients with intracranial ependymomas being at risk for relapse. PATIENTS AND METHODS: In the last 3 years, 9 pediatric patients under 15 years of age with grade 2-4 ependymomas located infratentorially received postoperative craniospinal axis radiotherapy by a new technique developed in our department. This technique was based on a proper usage of the asymmetric jaws of the linear accelerator. In whole brain and cervical spine irradiation (with the caudal border at C3-C4 level), two opposite lateral fields were chosen with shielding blocks of the eye bulbs and the face part of the scull. The spinal cord was irradiated from C3 to S2-4 with two direct radiation fields using asymmetric jaws as well. Doses of 35 Gy to the whole craniospinal axis and 54 Gy to the tumor bed were delivered. In cases of residual tumor doses were increased up to 58-60 Gy. RESULTS: Radiotherapy was well tolerated and dose reduction was not needed in any case. Skin reactions were mild in all patients. The gastrointestinal and hematological toxicity were also mild to moderate (World Health Organization - WHO grade 1-2). Four patients also received postirradiation chemotherapy because of large tumor size and unfavorable histology. Six patients entered clinical and imaging complete remission (CR) for a median of 22 months (range 14-30 months). The evaluation of the effectiveness of the method was limited by the short follow-up interval. CONCLUSION: The proposed new technique of craniospinal irradiation in the postoperative management of highrisk ependymomas is advantageous in terms of side effects and could be recommended for wide usage.

[Cytoprotective effects of amifostine in the treatment of tumors]. / Cytoprotektivní úcinek amifostinu v lécbe nádorových onemocnení.

An efficient therapy of patients with tumorous diseases should include maximum killing of malignant cells with minimal damage to cells in healthy tissues. Radiotherapy and chemotherapy are frequently associated with a series of undesirable effects. Side effects related to the therapy may unfavorably influence quality of life for a short or long period of time, may cause the need to decrease the dosage or shorten the overall period of treatment or survival of the patient. Therefore, particular attention has recently been paid to compounds, which mitigate or eliminate the undesirable effects of the therapy. A way to decrease toxicity is the administration of radioprotective or chemoprotective compounds. The cytoprotection of healthy tissues by compounds from the aminothiol group is one of the most promising directions of research and clinical practice. Amifostin protects healthy tissue from damage induced by radio- or chemotherapy. In comparison with patients treated by radiotherapy only, radiotherapy supplemented with amifostin proved to cause significantly less acute and late untoward effects of therapy. The paper describes the possibilities of using radioprotective drugs, especially amifostin, in the therapy of tumors with particular emphasis to the needs of physicians dealing with the problems of internal medicine.