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Although conventional fractionated (CF) radiotherapy (RT) became the most common non-surgical approach delivering 66-70 Gy in 33-35 daily fractions (fx) in 6.5-7 weeks several decades ago due to a good local control (LC) with low normal tissue complication rates, recent decades also brought altered fractionated RT regimens based on better understanding of radiobiology. Of these, split course RT is largely abandoned due to inferior results caused by the treatment gap, which led to inferior local control rates and consequently survival. Hyperfractionated (Hfx) RT and various forms of accelerated (Acc) RT had consistently shown improvement in the treatment outcome, given either alone or with concurrent chemotherapy (CHT). Hfx RT was most consistently superior to CF and frequently to Acc RT, while moderate Acc RT also holds promise to be used more often in daily clinical practice. The use of Hfx RT may face the challenge of applicability in busy radiotherapy departments around the world despite unequivocally having been proven as superior regarding both local/regional tumor control and overall survival. With concurrent CHT, although results favor it, risks of accompanying toxicity rise and should be considered when planning such intensified treatment approach. [ABSTRACT FROM AUTHOR]

Meta-analyses of chemotherapy in Head and Neck Cancer (MAC-HNC) showed that adding chemotherapy (CHT) to locoregional treatment improves the treatment outcome. However, it was observed only with concurrent administration of radiotherapy (RT) and CHT. Among many drugs used in this setting, cisplatin (CDDP) has most consistently been used as a single-agent with radical RT. The two most common administrations of CDDP included 100 mg/sqm every three weeks and 40 mg/sqm weekly, both during the course of RT. While a direct comparison of the two modes of CDDP administration in the definitive treatment of locally advanced squamous cell (SQC) HNC is basically lacking, recent summary brought somewhat conflicting results. Questions largely unexplored is the total CDDP dose deemed necessary when administered concurrently with radical RT. Subset analyses from various prospective randomized trials and meta-analyses seem to indicate that one may not need a total CDDP dose of significantly higher than 200 mg/sqm if at all higher than that, irrespective of the type of RT administered and seemingly unnecessary in HPV+ oropharyngeal cancer patients. Due to presumably lower but still effective threshold level of total CDDP given with RT may depend on other factors, such as frequency of CDDP administration or RT fractionation pattern and be closely interrelated with anticipated toxicity, researchers continue with their quest to find optimal approach in this setting. Large clinical trials should detect small differences between treatment options in an era when "old" but effective drugs still dominate the research arena of SQC HNC. [ABSTRACT FROM AUTHOR]

Abstract Extensive stage small cell lung cancer (ES-SCLC) carries a poor prognosis, and the thoracic progression is common. Consolidation radiation to thoracic disease (cRT) could improve progression-free survival (PFS) and overall survival (OS). We conducted an electronic search of PubMed and Embase with no language, year or publication status restrictions and evaluated randomised controlled trials (RCTs) addressing the role of cRT in ES-SCLC. Preferred Reporting of Systematic Reviews and Meta-Analyses guidelines for systematic review and Cochrane methodology for meta-analysis were followed. Effect estimates (hazard ratios [HRs] and confidence intervals [CIs]) and risk ratios were extracted, with a fixed/random-effects model created to estimate treatment effects. I2 statistics and heterogeneity statistics were performed. Comprehensive and systematic search identified 1107 records, after removal of duplicate records screened 922 records, assessed 31 full-text articles for eligibility and 3 RCTs with a total of 690 patients were included. Pooled analysis showed cRT significant improved PFS (p < 0.0001) with HR 0.72 (95% CI: 0.61–0.83, I2-0%). In addition, cRT significantly (p < 0.001) reduced the risk of thoracic progression as the first site of progression with a relative risk of 0.52 (95% CI: 0.44–0.61, I2-0%). OS analysis showed no significant (p = 0.36) benefit with HR of 0.88 (95% CI 0.66–1.18, I2-52%) with cRT. Pooled meta-analysis of 3 randomised controlled studies shows consolidation thoracic radiotherapy (RT) offers significant improvement in PFS and reduction in thoracic failures. Further research on subclassification of ES-SCLC (limited vs extensive metastasis), optimise strategy for RT integration (sequential vs concurrent) and optimal RT dose is needed to identify the subset of ES-SCLC likely to have significant OS benefit. Highlights • Systematic review and meta-analysis of RCT evaluating consolidation radiation to thoracic disease (cRT) in extensive stage small cell lung cancer (ES-SCLC). • cRT significantly improves progression-free survival in ES-SCLC. • cRT significantly improves reduces thoracic failures in ES-SCLC. [ABSTRACT FROM AUTHOR]

Background To optimize palliation in incurable locally advanced non-small cell lung cancer (NSCLC), the International Atomic Energy Agency conducted a prospective randomized study (NCT00864331) comparing protracted palliative radiotherapy (RT) course with chemotherapy (CHT) followed by short-course palliative RT. Methods and materials Treatment-naive patients with histologically confirmed NSCLC, stage IIIA/IIIB, received either 39 Gy in 13 fractions as RT alone (arm A, n = 31) or 2–3 platinum-based CHT cycles followed by 10 Gy in a single fraction or 16 Gy in 2 fractions separated by one week (arm B, n = 34). Primary outcome was overall survival. Results Treatment groups were balanced with respect to various variables. Median survival for all 65 patients was 8 months, while median survival was 7.1 and 8.1 months for the two arms, respectively (log-rank p = 0.4 by study arm, and p = 0.6 by Cox regression and stratified by country and sub-stage). One and three year survival rates for the two arms were 29%, and 9% and 41%, and 6%, respectively. There were no differences in any of the following endpoints: any failure, local failure, regional failure, contralateral thoracic failure, and distant failure between the two arms. High-grade (⩾3) toxicity was similar between the two arms. Symptoms, adverse events of any kind, KPS and body-mass index, were not different during treatment and during follow-up. There was no grade 5 toxicity. Conclusions This incomplete and underpowered trial only hinted similar outcome between the treatment arms. Therefore, combined CHT-RT can perhaps be considered, in limited resource setting, where access to RT remains inadequate. [ABSTRACT FROM AUTHOR]

Purpose: To provide updated outcome data (10 years) of a Phase II study of combined surgery, postoperative radiotherapy, and adjuvant chemotherapy in patients with anaplastic oligodendroglioma and oligoastrocytoma.Methods and materials: In 23 adult patients, surgery, postoperative radiotherapy (60 Gy in 30 daily fractions within 6 weeks), and adjuvant modified chemotherapy (procarbazine 60 mg/m2 on Days 1–14, lomustine 100 mg/m2 on Day 1, and vincristine 1.4 mg/m2 [maximum 2 mg] on Days 1 and 8) were administered every 6 weeks for up to six cycles or until progression occurred.Results: The median follow-up was 116 months for all patients. The median survival time was 118 months, and the 5-year and 10-year survival rate was 57% and 47%, respectively. The median time to tumor progression was 78 months, with a 5-year and 10-year progression-free survival rate of 52% and 39%, respectively. Gender, age, Karnofsky performance status, location, and histologic type did not influence survival. Patients with tumors ≤4 cm did better than those with tumors >4 cm (p = 0.0470), as did those with total tumor resection compared with those with subtotal tumor resection or biopsy only (p = 0.0024). Gender, Karnofsky performance status, location, and histologic type did not influence progression-free survival, but younger age (p = 0.0389), smaller tumor size (p = 0.0357), and more radical surgery (p = 0.0033) correlated positively with it. Acute high-grade (Grade 3 or worse) chemotherapy-related toxicity was mainly hematologic, with 3 patients (13%) experiencing acute Grade 4 toxicity.Conclusion: The results of this 10-year update confirmed that the trimodality approach is effective in patients with anaplastic oligodendroglioma and oligoastrocytoma. [Copyright &y& Elsevier]

: PurposeTo provide a 10-year update of hyperfractionated radiation therapy (Hfx RT) in adults with incompletely resected supratentorial low-grade glioma.: Methods and materialsA total of 37 patients were treated with 55 Gy in 50 fractions in 25 treatment days in 5 weeks to tumor plus 2 cm, and additional 17.6 Gy given in 16 fractions in 8 treatment days in 1.5 weeks to tumor plus 1 cm, (1.1 Gy twice daily). Total dose was 72.6 Gy in 66 fractions in 33 treatment days in 6.5 weeks.: ResultsAfter a median follow-up time of 121 months for all patients, the median survival time (MST) for all 37 patients was 145 months, whereas 10-year survival rate was 67%. Median time to tumor progression (MTP) has not yet been attained, but 10-year progression-free survival (PFS) rate was 62%. There was no difference in survival or PFS regarding gender, age, location, site, size, CT enhancement, and histology; whereas lower KPS, higher neurologic status, and lesser extent of surgery had an adverse influence. Infield progression occurred in 15 (88%), whereas in only 2 (12%) patients, tumor progression was described as marginal. Brain necrosis has not been observed so far. Autopsy findings confirmed recurrent glioma and excluded post-RT necrosis in 14 (38%) patients. Of those, 7 (50%) patients had either Grade 3 (n = 4) or Grade 4 (n = 3) glioma.: ConclusionHigh-dose HFX RT is effective with mild to moderate toxicity. Further studies are warranted with more patients before testing it against standard fractionation RT in this patient population. [Copyright &y& Elsevier]

We investigated the influence of various clinical prognostic factors in patients with glioblastoma multiforme (GBM) treated with a combined modality approach. A total of 175 patients with GBM was treated in four consecutive prospective phase II studies using surgery, hyperfractionted or accelerated hyperfractionated radiotherapy (RT) and either adjuvant or concurrent or pre-irradiation chemotherapy (CHT) between Janaury 1988 and December 1993. The median survival time for all 175 patients was 14 months and 1–3-year survival (OS) rates were 57%, 34% and 24%, respectively. The median time to tumour progression was 12 months, and 1–3-year progression-free survival (PFS) rates were 43%, 11% and 7%, respectively. Survival analysis showed that of all investigated prognostic factors, only gender did not influence survival. Patients ≤55 years did better than those >55 years; patients with KPS 80–100 did better than those with KPS 50–70; patients with frontal tumours did better than those with tumours in other locations; patients with tumours up to 4 cm did better than those with larger tumours, as did patients with either subtotal or gross total tumour resection when compared to those undergoing biopsy only. Multivariate analysis showed that gender and tumour location did not independently influence survival. When PFS was used as the endpoint, only gender did not influence PFS, as confirmed by multivariate analysis. [ABSTRACT FROM AUTHOR]

We investigated the effect of treatment interruptions due to high-grade (&ges;3) toxicity on outcome of patients with early stage (I/II) non-small-cell lung cancer treated with hyperfractionated radiation therapy (Hfx RT). Of 116 patients treated with total tumour doses of 69.6 Gy, 1.2 Gy b.i.d. fractionation, 44 patients refused surgery while 72 patients were medically inoperable due to existing co-morbid states. Patients who were medically inoperable had worse KPS (P=0.0059) and more pronounced weight loss (P=0.0005). Among them, 12 patients experienced high-grade toxicity and 11 of them with either acute (n=6) or ‘consequential’ late (n=5) high-grade toxicity requested interruption in the Hfx RT course (range, 12–25 days; median, 17 days). Superior survival (OS) was observed in patients who refused surgery when compared to those who were medically inoperable (P=0.0041), as well as superior local recurrence-free survival (LRFS) (P=0.011), but not different distant metastasis-free survival (P=0.14). Cause-specific survival (CSS) also favoured patients who refused surgery (P=0.004). Multivariate analysis showed independent influence of the reason for not undergoing surgery on OS (P=0.035), but not on LRFS (P=0.084) or CSS (P=0.068). Patients who refused surgery did not experience high-grade toxicity (0/44), whereas 11 of 72 patients with medical inoperability and co-morbid states experienced high-grade toxicity and had treatment interruptions to manage toxicity (P=0.0064). Patients without treatment interruptions had significantly better OS (P=0.00000), LRFS (P=0.00000) and CSS (P=0.00000) than those with treatment interruptions. When corrected for treatment interruptions, the reason for not undergoing surgery independently influenced OS (P=0.040), but not LRFS (P=0.092) or CSS (P=0.068). In contrast to this, treatment interruption was independent prognosticator of all three endpoints used (P=0.00031, P=0.0075 and P=0.00033, respectively). When 11 patients with treatment interruptions were excluded, the reason for not undergoing surgery still affected OS (P=0.037) and CSS (P=0.039) but not LRFS (P=0.11). Multivariate analyses using OS, CSS and LRFS showed that the reason for not undergoing surgery affected OS (P=0.0436), but neither CSS (P=0.083) nor LRFS (P=0.080). [Copyright &y& Elsevier]

There is a general trend worldwide of an increasing incidence of elderly population. Age is the greatest risk factor for cancer; therefore, this demographic shift is a main reason for an increase of cancer incidence. Lung cancer is a typical disease of the elderly patients. Small cell lung cancer (SCLC) accounts for approximately 20% of all lung cancer cases. This review summarises the issues of treatment of SCLC in elderly. The number of randomised phase III trials concerning treatment of SCLC in elderly patients are very limited. Although currently most treatment decisions are based on lower grades of evidence, some conclusions can be drawn from the current studies. Age alone is a very uncertain prognostic criteria for outcome or tolerability of treatment. Much more important is the geriatric assessment of each individual patient. Current treatment standards for limited disease (LD)-SCLC (polychemotherapy plus local thoracic irradiation and additional prophylactic cranial irradiation in case of complete remission) seems to be also feasible for ‘fit’ elderly (>70 years) LD-SCLC patients with a good performance and full functional capacities. There are preliminary data indicating that a similar outcome in elderly patients can probably be achieved a with reduced number of treatment schedules (e.g. 2 instead of 4 cycles in combination with radiotherapy. Surgical resection is also feasible in selected elderly patients with very early stage SCLC, where this maybe an appropriate approach, although no phase III data are available, which demonstrated the benefit of additional surgery compared to chemotherapy alone in early stage SCLC. In patients with extensive disease-SCLC age alone does not necessarily restrict the use of multiagent regimen, although the risk of haematological toxicity seems to be higher than in the younger patients. When standard treatment is not feasible due to co-morbidity or loss of functional capacity, several alternative combination regimens are available, which appear to be slightly superior to single agent treatment, although randomised data for elderly on that issue are sparse. Carboplatin and etoposide seems currently the most appropriate two-drug combination in elderly patients, but there are a variety of active and low toxic third generation agents like taxanes, gemcitabine and vinorelbine which are active in both, non-small cell lung cancer and SCLC. For the comparison of trials in elderly patients it will be of key importance to include a comprehensive and standardised geriatric assessment in such studies. [Copyright &y& Elsevier]

There is a general trend worldwide of an increasing incidence of elderly population. Age is the greatest risk factor for cancer; therefore, this demographic shift is the main reason for an increase of cancer incidence. Lung cancer is a typical disease of the elderly patients. This review summarizes the issues of treatment of non-small cell lung cancer (NSCLC) in the elderly. Early stage NSCLC is usually treated with radical surgery, locally advanced NSCLC with radiotherapy (RT) and/or chemotherapy (CHT) and metastatic disease with CHT, but the evidence for these approaches is based on studies which are usually performed with highly selected patients while elderly patients are under-represented. We used the data from studies addressing particularly elderly or providing subgroup information on age to analyse the feasibility of current standard approaches for elderly and discuss alternative approaches. Surgery is an effective method in elderly patients with early stage NSCLC although some approaches bear a somewhat higher risk of operative morbidity and mortality. RT for early stage may be an alternative with curative potential. For locally advanced stage RT alone, or combined radiochemotherapy in selected cases, is feasible for elderly patients with locally advanced NSCLC when a careful assessment of pre-therapeutic status is made and appropriate drugs are selected. Advanced age alone also should not preclude CHT, although the risk of adverse effect may be higher in certain cases. New generation drugs seem to be particularly feasible and efficient in elderly patients. In general, age itself does not seem to preclude patients from standard treatments although in some cases co-morbidity forces to alternative approaches. Currently, single-agent CHT should be considered as the standard treatment of advanced NSCLC elderly patients. [Copyright &y& Elsevier]

Purpose: To evaluate the effectiveness of stereotactic fractionated radiotherapy (SFRT) in the treatment of optic nerve sheath meningioma (ONSM).Methods and Materials: Between 1994 and 2000, a total of 39 patients with either primary (n = 15) or secondary (n = 24) ONSM were treated with SFRT and received a median total tumor dose of 54 Gy using 1.8 Gy/fraction.Results: The radiographic response to SFRT was documented in all patients as stable disease (no change) except for 1 patient with a partial response. After a median follow-up of 35.5 months, all patients with ONSM were alive without recurrence. The visual fields and visual acuity were improved in 6 of 15 and 1 of 16 examined eyes in patients with primary ONSM, respectively, and in 6 of 24 and 7 of 26 examined eyes in patients with secondary ONSM, respectively. Stable visual fields and visual acuity was observed in 8 of 14 and 15 of 16 patients with primary ONSM, respectively, and in 17 of 24 and 19 of 26 patients with secondary ONSM, respectively. Except for reversible alopecia and erythema, no other SFRT-related toxicity was observed.Conclusion: SFRT represents a very effective and low-toxic treatment modality for ONSM. Despite a median follow-up of 3 years, this series of primary ONSM holds promise for future studies. It adds substantial evidence that SFRT may definitely become a standard treatment approach in selected cases of ONSM. [Copyright &y& Elsevier]

Purpose: To investigate the effectiveness of high-dose, curative radiotherapy (RT) given alone in technically operable, but medically inoperable, patients with early-stage (I–II) non-small-cell lung cancer (NSCLC).Methods and Materials: Computerized and manual searches were done to identify published reports dealing with curative RT for NSCLC. Relevant studies were identified and the information provided therein was extracted regarding patient and treatment characteristics, treatment outcome, and various pretreatment and treatment-related factors influencing outcome, as well as toxicity and quality-of-life issues.Results: Although a large variation of pretreatment and treatment characteristics was noted in the available studies, a median survival time of >30 months and a 5-year survival rate of up to 30% had been achieved. Accumulated experience seems to suggest that doses of at least 65 Gy with standard fractionation, or its equivalent when altered fractionation is used, are necessary for control of NSCLC. Smaller tumors seem to have a favorable prognosis, and the issue of elective nodal RT continues to be controversial. Analyses of patterns of failure have clearly identified local failure as the predominant pattern. Although a number of potential pretreatment patient- and tumor-related prognostic factors have been examined, none has been shown to clearly influence survival. Toxicity was usually low, but very high doses (e.g., 80 Gy) given with a conventional approach may carry a risk of an excessive rate of side effects.Conclusion: High-dose, curative RT is an effective treatment modality in technically operable, but medically inoperable, patients with early-stage NSCLC. [Copyright &y& Elsevier]

Background and purpose: External beam radiation therapy (EBRT) is occasionally used in the treatment of bronchial stump recurrences after complete surgical resection in patients with non-small-cell lung cancer (NSCLC), but no prospective study exists, so far. The objective of this review is to determine effectiveness of high-dose EBRT in this disease.Methods: A systematic review was undertaken using electronic databases, reference lists and hand searching of journals to identify potentially eligible studies. Selection criteria included studies that provided outcome after high-dose EBRT in this disease. Six retrospective studies were reviewed, including a total of 54 patients.Results and conclusion: High-dose EBRT appears to be an effective treatment modality for recurrent NSCLC confined to the bronchial stump after curative resection with a median survival time of approximately 30 months and 5-year survival of approximately 30%. Although small patient numbers and unclear indications for radical versus palliative EBRT may obscure the overall conclusions, among patients with intrathoracic recurrence those with bronchial stump recurrence only do better than those with non-stump recurrence. It seems there is a dose–response effect in this patient population and a predominantly local pattern of failure, both observations having an implication for future studies. The optimal dose/fractionation pattern or treatment fields must be further investigated in the future. Identification of an unfavourable subset of patients may help optimize treatment in the future by omitting high-dose, curative RT in those patients who may be best treated with palliative RT. Prospective studies on EBRT in both bronchial stump and other post-surgical recurrences are urgently needed. [Copyright &y& Elsevier]

We investigated a risk of developing radiation myelitis during four prospective studies using hyperfractionated radiation therapy (HFX RT) with and without concurrent chemotherapy (CHT) during which a portion of thoracic spinal cord received a dose ≥50.4 Gy given via 1.2 Gy b.i.d. fractionation. Of 536 patients with Stage III non-small cell lung cancer (NSCLC) which were treated on three prospective randomised Phase III studies and one Phase II study, 336 patients received irradiation dose ≥50.4 Gy to a portion of their spinal cord and survived >1 year after the beginning of therapy. None of these 336 patients developed thoracic radiation myelitis. Therefore, the influence of potentially contributing factors on the occurrence of radiation myelitis, such as cord length, interfraction interval, or administration of concurrent CHT was not possible to investigate. These results give new insight about the influence of total dose/dose per fraction/interfraction interval with or without concurrent CHT on the thoracic spinal cord toxicity. [Copyright &y& Elsevier]

Purpose: To retrospectively investigate the effectiveness of linear accelerator based radiosurgery (RS) in the treatment of brain metastases (BM).Material and methods: Of 55 patients with a total of 72 BM, 41 patients had a single brain metastasis and 14 patients had two or three metastases. Median tumour dose of 15 Gy (range 8–20 Gy) was prescribed to a median isodose surface of 90% (range 70–100%) encompassing the target volume.Results: The median survival time (MST) for all 55 patients was 7 months [95% confidence interval (CI), 5–10 months] and 2-year survival is 18%. There was no significant difference between patients who had one brain metastasis and those with either two or three metastases (log rank P=0.7565). Multivariate analysis in patients with a single BM showed that interval between primary diagnosis (PD) to BM, maximum size of metastasis, and histology (renal cell carcinoma and melanoma versus others) were independent prognostic factors influencing survival. Local control was obtained in 66/72 (92%) metastases. Actuarial local control at 24 months was 52%. Only age (≤50 years vs >50 years) and histology (renal cell versus others) influenced local control in the univariate analysis in patients with a single BM. In multivariate analysis, size, histology (renal cell and melanoma versus others), activity of extracranial metastatic disease, age, interval from PD to BM and location (midline versus other) independently influenced local control, while the dose was not significant for our patient group. Only one patient developed radiographically suspected RS-induced necrosis after previous whole brain RT.Conclusion: RS was effective and little toxic in BM. Identification of prognostic factors must be performed to gain knowledge on patients most likely to benefit from this procedure. [Copyright &y& Elsevier]

To investigate the efficacy of the second 4 Gy given as a single fraction radiotherapy (RT) for patients with painful bone metastasis who had already twice received single fraction RT (4, 6, or 8 Gy plus 4 Gy), a total of 25 patients were assessed before and after re-irradiation. The patients included 19 responders and 6 nonresponders to two prior single fraction RT, the latter one being 4 Gy. The overall response rate was 80%, with both complete response (CR) and partial response (PR) being 40%. No difference was found between the previous responders and previous nonresponders regarding both CR (P = 0.70) and overall response rate (P = 0.35). Response duration was longer in the previous responders (P = 0.0041), but the time to pain relief was similar between the two treatment groups. No acute or late high-grade toxicity was observed during this study and no pathological fractures or spinal cord compressions were seen. In this small and highly selected series of patients, the third single fraction RT of 4 Gy was effective and not toxic in the treatment of painful bone metastasis. [Copyright &y& Elsevier]

Simple Summary: Current options for the curative treatment of the non-metastatic oropharyngeal carcinoma associated with human papillomavirus include minimally-invasive surgery or radiotherapy, which is combined with chemotherapy in many clinical situations. The aim of this review is to summarize the current treatment recommendations in the local therapy of human papillomavirus-associated oropharyngeal cancer, with respect to the latest published evidence in the field. Future perspectives and next-generation research pathways, including treatment deintensification methods, are thoroughly discussed. Over the last two decades, human papillomavirus (HPV) has caused a new pandemic of cancer in many urban areas across the world. The new entity, HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), has been at the center of scientific attention ever since, not only due to its distinct biological behavior, but also because of its significantly better prognosis than observed in its HPV-negative counterpart. The very good treatment outcomes of the disease after primary therapy (minimally-invasive surgery, radiation therapy with or without chemotherapy) resulted in the creation of a separate staging system, reflecting this excellent prognosis. A substantial proportion of newly diagnosed HPV-driven OPSCC is diagnosed in stage I or II, where long-term survival is observed worldwide. Deintensification of the primary therapeutic methods, aiming at a reduction of long-term toxicity in survivors, has emerged, and the quality of life of the patient after treatment has become a key-point in many clinical trials. Current treatment recommendations for the treatment of HPV-driven OPSCC do not differ significantly from HPV-negative OPSCC; however, the results of randomized trials are eagerly awaited and deemed necessary, in order to include deintensification into standard clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: The effects of heat treatment, involving solutionizing at temperature of 370°C for a relatively short period of time (3 or 5h), followed by quenching in water, on tribological behavior of ZA-27 alloys were examined. Dry sliding wear tests were conducted on as-cast and heat-treated ZA-27 samples using block-on-disk machine over a wide range of applied loads. To determine the wear mechanisms, the worn surfaces of the samples were examined by scanning electron microscopy (SEM). The tribological results were related to the microstructure and mechanical properties. The heat treatment resulted in reduction in the hardness and tensile strength but increase in elongation. The heat-treated alloy samples attained improved tribological behavior over the as-cast ones, both from the aspects of friction and wear. The improved tribological behavior of the heat-treated alloys, in spite of reduced hardness, could be the result of breaking the dendrite structure, when the fraction of interdendrite regions was considerably decreased and a very fine α and η mixture was formed at the same time. The wear response of the samples has been corroborated through characteristics of worn surfaces and dominant wear mechanisms. [Copyright &y& Elsevier]

The prescribed total radiation dose should be administered within a specific time. In daily clinical practice, however, unplanned treatment interruptions resulting in prolongation of the overall treatment time are predictable. The present review evaluated the existing published data regarding the affect of the prolongation of the overall treatment time on the tumor control rate and outcome of patients with head-and-neck, lung, and uterine cervical cancer and other treatment sites. In most studies, including the planned interruption (split-course) schedules, as well as the retrospective studies analyzing the role of overall treatment time, a detrimental effect from the treatment break on the outcome was evident. This is suggestive of the deleterious effect of accelerated repopulation of tumor clonogens. In particular for the cancers of the head and neck for which the evidence is the strongest for such a consequence, even a 1-day interruption resulted in a decrease in the local control rate by 1.4%. Although the increased number of gaps was associated with a negative outcome, the data are contradictory concerning the effect of the number of gaps. The main recommendation is to exert all efforts to retain the planned irradiation schedule; however, existing data have shown that interruptions that effect the programmed time-course for irradiation need to be compensated for. This is to ensure biologic equivalence in treatment efficacy compared with uninterrupted regimens with respect to cancer site and stage. Practical methods for compensation using radiobiologic modeling and their limitations are also discussed. [Copyright &y& Elsevier]

Background: A novel unconventional SBRT-based PArtial Tumor irradiation targeting HYpoxic clonogenic cells (SBRT-PATHY) for induction of the tumoricidal bystander (BE) and abscopal effects (AE) was developed by translating our preclinical findings to a clinic in 2016. In order to further improve BE/AE response rate, SBRT-PATHY was upgraded in 2018 by the sparing of peritumoral immune microenvironment as a new OAR, defined by its own dose-constraints. Considering the anti-tumor immune response homeostatic fluctuation, which is cyclically suppressed and incited ("switched off and on"), we synchronized SBRT-PATHY with its most excitable phase, in order to overcome tumor tolerance locally and systemically. The aim of this study, therefore, was to report on the initial results of our latest innovation aimed to further improve BE/AE response rate by testing the effectiveness of the time-synchronized immune-guided SBRT-PATHY.Materials and Methods: In order to serially map the homeostatic anti-tumor immune response-fluctuations, High Sensitive C-Reactive Protein (HS-CRP), Lactate Dehydrogenase (LDH) and Lymphocyte/Monocyte Ratio (LMR) were analyzed using high-order polynomial trend analysis as surrogate of immune system response. After the biomarker data analysis detected the immune fluctuations and related idiosyncratic immune cycle periodicity, we determined the "most favourable" and "least favourable" treatment time-positions in the immune cycle. In order to evaluate the impact of an idiosyncratic immune cycle on treatment outcomes, our first consecutive four patients were treated on the "most favourable" while the remaining four on the "least favourable" day.Results: The median follow-up was 11.8 months. The biomarker data analysis showed periodic immune response fluctuations of regular frequency. The "right" synchronization of SBRT-PATHY with the "most favorable day" of anti-tumor immune response was accompanied with improved clinical outcomes in terms of BE/AE-response rate.Conclusion: We believe the right synchronization of radiotherapy with the homeostatically oscillating immune response may improve the probability of inducing BE/AE. Present study has been retrospectively registered on 18th of October 2019 by the ethic committee for Austrian region "Kärnten "in Klagenfurt (AUT), under study number A 37/19. [ABSTRACT FROM AUTHOR]

The records of 208.777 (100%) clinical trials registered at ClinicalTrials.gov were downloaded on the 19th of February 2016. Phase II and III trials including patients with glioblastoma were selected for further classification and analysis. Based on the disease settings, trials were classified into three groups: newly diagnosed glioblastoma, recurrent disease and trials with no differentiation according to disease setting. Furthermore, we categorized trials according to the experimental interventions, the primary sponsor, the source of financial support and trial design elements. Trends were evaluated using the autoregressive integrated moving average model. Two hundred sixteen (0.1%) trials were selected for further analysis. Academic centers (investigator initiated trials) were recorded as primary sponsors in 56.9% of trials, followed by industry 25.9%. Industry was the leading source of monetary support for the selected trials in 44.4%, followed by 25% of trials with primarily academic financial support. The number of newly initiated trials between 2005 and 2015 shows a positive trend, mainly through an increase in phase II trials, whereas phase III trials show a negative trend. The vast majority of trials evaluate forms of different systemic treatments (91.2%). In total, one hundred different molecular entities or biologicals were identified. Of those, 60% were involving drugs specifically designed for central nervous system malignancies. Trials that specifically address radiotherapy, surgery, imaging and other therapeutic or diagnostic methods appear to be rare. Current research in glioblastoma is mainly driven or sponsored by industry, academic medical oncologists and neuro-oncologists, with the majority of trials evaluating forms of systemic therapies. Few trials reach phase III. Imaging, radiation therapy and surgical procedures are underrepresented in current trials portfolios. Optimization in research portfolio for glioblastoma is needed. [ABSTRACT FROM AUTHOR]

Background: To evaluate the current status of prospective interventional clinical trials that includes brachytherapy (BT) procedures.Methods: The records of 175,538 (100 %) clinical trials registered at ClinicalTrials.gov were downloaded on September 2014 and a database was established. Trials using BT as an intervention were identified for further analyses. The selected trials were manually categorized according to indication(s), BT source, applied dose rate, primary sponsor type, location, protocol initiator and funding source. We analyzed trials across 8 available trial protocol elements registered within the database.Results: In total 245 clinical trials were identified, 147 with BT as primary investigated treatment modality and 98 that included BT as an optional treatment component or as part of the standard treatment. Academic centers were the most frequent protocol initiators in trials where BT was the primary investigational treatment modality (p < 0.01). High dose rate (HDR) BT was the most frequently investigated type of BT dose rate (46.3 %) followed by low dose rate (LDR) (42.0 %). Prostate was the most frequently investigated tumor entity in trials with BT as the primary treatment modality (40.1 %) followed by breast cancer (17.0 %). BT was rarely the primary investigated treatment modality for cervical cancer (6.8 %).Conclusion: Most clinical trials using BT are predominantly in early phases, investigator-initiated and with low accrual numbers. Current investigational activities that include BT mainly focus on prostate and breast cancers. Important questions concerning the optimal usage of BT will not be answered in the near future. [ABSTRACT FROM AUTHOR]

Background: Hydraulic dilatation is a novel method of cervical dilatation that is based on continuous controllable dilatation (CCBD) by the pumping of fluid into the balloon extension of the system. The main advantage of this procedure is that it allows control of and insight into the process of cervical dilatation. Methods: For the purposes of our research, we created a new and upgraded system for CCBD which consists of a programmed hydrostatic pump connected to a balloon extension. With regard to our aim to precisely measure and determine the location of the cervical resistance, we placed two pressure-measuring films, one on the top and one on the bottom of the balloon extension. This study included 42 patients in whom cervical resistance was measured before suction curettage. Results: Cervical dilatation and measurement of cervical resistance were successful in all patients. The analysis of the pressure-measuring films showed that the points of highest resistance were located in the zone of the internal cervical os and that these values were much higher than those in the zone of the external cervical os (0.402 versus 0.264 MPa at the upper pressure-sensitive film; 0.387 versus 0.243 MPa at the lower pressure-sensitive film). This study also showed that an increase in cervical resistance in the zone of the internal cervical os was followed by an increase in cervical resistance in the zone of the external cervical os. Conclusions: During CCBD, the internal cervical os is the centre of cervical resistance, and the values do not decline with the number of miscarriages or the number of previous births. Trial registration number: ISRCTN Registry identifier: ISRCTN30949871. Date of registration: 13 May 2015 [ABSTRACT FROM AUTHOR]

Background To determine the optimal single-dose radiotherapy schedule for pain from bone metastases in a multi-centre, international, randomised trial. Patients and methods 651 patients were randomised to either 8 Gy ( n = 325) or 4 Gy ( n = 326) radiotherapy. Pain at 4, 8, 12, 24 and 52 weeks was assessed using a Categorical Scale (CS) and a Visual Analogue Scale (VAS). The primary endpoint was response at 4 weeks. Results There was no significant difference in patient demographics and other co-variates. The complete response (CR) rate and ORR (complete or partial response) for all follow-up times were higher after 8 Gy ( p = 0.02). The Kaplan–Meier actuarial rate (categorical scale) at 4 weeks for ORR was 80% after 8 Gy compared to 68% after 4 Gy ( p = 0.0015). 117 re-treatments were given of which 72 were in the 4 Gy group and 45 in 8 Gy arm ( p = 0.01). Conclusions There was a marked consistent difference in pain relief at all time points in favour of 8 Gy. These data reinforce the case for single dose 8 Gy radiotherapy to be recommended for metastatic bone pain in all healthcare settings. [ABSTRACT FROM AUTHOR]

Background There is a strong interest in the investigation of extremely low frequency Electromagnetic Fields (EMF) in the clinic. While evidence about anticancer effects exists, the mechanism explaining this effect is still unknown. Methods We investigated in vitro, and with computer simulation, the influence of a 50 Hz EMF on three cancer cell lines: breast cancer MDA-MB-231, and colon cancer SW-480 and HCT- 116. After 24 h preincubation, cells were exposed to 50 Hz extremely low frequency (ELF) radiofrequency EMF using in vitro exposure systems for 24 and 72 h. A computer reactiondiffusion model with the net rate of cell proliferation and effect of EMF in time was developed. The fitting procedure for estimation of the computer model parameters was implemented. Results Experimental results clearly showed disintegration of cells treated with a 50 Hz EMF, compared to untreated control cells. A large percentage of treated cells resulted in increased early apoptosis after 24 h and 72 h, compared to the controls. Computer model have shown good comparison with experimental data. Conclusion Using EMF at specific frequencies may represent a new approach in controlling the growth of cancer cells, while computer modelling could be used to predict such effects and make optimisation for complex experimental design. Further studies are required before testing this approach in humans. [ABSTRACT FROM AUTHOR]

This paper is focused on the process of ball burnishing. The influence of tool stiffness on surface roughness parameters was considered theoretically, while experimental investigation was conducted to establish the influence of initial surface roughness (previous machining) on the effects of ball burnishing as the finishing process. Experimental investigations were conducted over a wide interval of most influential process parameters (burnishing forces, burnishing feed, and number of burnishing passes). The material used in the experiments was aluminum alloy EN AW-6082 (AlMgSi1) T651. Burnishing was performed using a specially designed tool of high stiffness. Statistical analysis of experimental data revealed strong correlation between roughness, R, and burnishing force, burnishing feed, and number of passes for the three surfaces, each with different roughness parameters. Particular combinations of process parameters yielded very low surface roughness, R, equivalent to polishing. It is worth noting that high surface quality can be achieved with relatively small burnishing forces, which differs from the investigations published so far. Contrary to conventional approaches, which are based on elastic tool systems, the authors propose the burnishing process to be conducted with high-stiffness tools. Further investigation shall be focused on optimization of burnishing process parameters in order to achieve surface finish equivalent to high polish. [ABSTRACT FROM AUTHOR]

We report a case of successful sternum and ribs/cartilage resection and chest wall reconstruction with a methacrylate implant produced using a three-dimensional model in a patient with a tuberculotic mass in this region. Clinical and radiologic follow-up 2 years after surgery showed excellent cosmetic and functional outcome. [ABSTRACT FROM AUTHOR]

Background: Cervical dilation using mechanical dilators is associated with various complications, such as uterine perforation, cervical laceration, infections and intraperitoneal hemorrhage. To achieve safe and painless cervical dilation, we constructed a new medical device to achieve confident mechanical cervical dilation: a continuous controllable balloon dilator (CCBD). Methods: Controlled pumping of incompressible fluid into the CCBD increases the pressure and outer diameter of the CCBD, continuously dilating the cervical canal. The reliability of the CCBD was confirmed in vitro (testing for consistency and endurance, with no detected risk for breakage) and in vivo. A multi-center clinical study was conducted,with 120 pregnant women randomly assigned to one of three groups: Group I,control group, no dilation;Group II,mechanical dilation, Hegar dilator (HeD); and Group III,CCBD. The tissue material for histological evaluation was obtained from the endocervical mucosa before and after dilation using the HeD or CCBD. Results: The CCBD dilations were successful and had no complications in all 40 patients of Group III. The cervical tissue was markedly less damaged after CCBD dilation compared with HeD dilation (epithelium damage: 95% (HeD) vs. 45% (CCBD), P <0.001; basal membrane damage: 82.5% (HeD) vs. 27.5% (CCBD), P <0.001; stromal damage: 62.5% (HeD) vs. 37.5% (CCBD), P <0.01). Cervical hemorrhagia was observed in 90% of the patients after HeD dilation versus in 32.5% of the patients after CCBD dilation. Conclusions: The CCBD should be used as a replacement for mechanical dilators to prevent uterine and cervical injury during cervical dilation. Trial registration: ISRCTN54007498 [ABSTRACT FROM AUTHOR]

To evaluate the current status of stereotactic body radiotherapy (SBRT) and identify both advantages and disadvantages of its use in developing countries, a meeting composed of consultants of the International Atomic Energy Agency was held in Vienna in November 2006. Owing to continuous developments in the field, the meeting was extended by subsequent discussions and correspondence (2007–2010), which led to the summary presented here. The advantages and disadvantages of SBRT expected to be encountered in developing countries were identified. The definitions, typical treatment courses, and clinical results were presented. Thereafter, minimal methodology/technology requirements for SBRT were evaluated. Finally, characteristics of SBRT for developing countries were recommended. Patients for SBRT should be carefully selected, because single high-dose radiotherapy may cause serious complications in some serial organs at risk. Clinical experiences have been reported in some populations of lung cancer, lung oligometastases, liver cancer, pancreas cancer, and kidney cancer. Despite the disadvantages expected to be experienced in developing countries, SBRT using fewer fractions may be useful in selected patients with various extracranial cancers with favorable outcome and low toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Help identify and define potential normal tissue dose constraints to minimize the mortality and morbidity of hypofractionated lung radiotherapy. Materials and methods: A method to generate isodose-based constraints and visually evaluate treatment plans, based on the published peer reviewed literature and the linear quadratic model, is presented. The radiobiological analysis assumes that the linear quadratic model isvalid up to 28Gy per fraction, the α/β ratio is 2 for the spinal cord and brachial plexus, 4 for pneumonitis, 4 or 10 for acute skin reactions depending on treatment length, and 3 for late complications in other normal tissues. A review of the literature was necessary to identify possible endpoints and normal tissue constraints for thoracic hypofractionated lung radiotherapy. Results: Preliminary normal tissue constraints to reduce mortality and morbidity were defined for organs at risk based upon hypofractionated lung radiotherapy publications. A modified dose nomenclature was introduced to facilitate the comparison of hypofractionated doses. Potential side effects from hypofractionated lung radiotherapy such as aortic dissection, neuropathy, and fatal organ perforation rarely seen in conventional treatments were identified. The isodose-based method for treatment plan analysis and normal tissue dose constraint simplification was illustrated. Conclusions: The radiobiological analysis based on the LQ method, biologically equivalent dose nomenclature, and isodose-based method proposed in this study simplifies normal tissue dose constraints and treatment plan evaluation. This may also be applied to extrathoracic hypofractionated radiotherapy. Prospective validation of these preliminary thoracic normal tissue dose constraints for hypofractionated lung radiotherapy is necessary. [Copyright &y& Elsevier]

Abstract: Positron Emission Tomography (PET) is a significant advance in cancer imaging with great potential for optimizing radiation therapy (RT) treatment planning and thereby improving outcomes for patients. The use of PET and PET/CT in RT planning was reviewed by an international panel. The International Atomic Energy Agency (IAEA) organized two synchronized and overlapping consultants’ meetings with experts from different regions of the world in Vienna in July 2006. Nine experts and three IAEA staff evaluated the available data on the use of PET in RT planning, and considered practical methods for integrating it into routine practice. For RT planning, 18F fluorodeoxyglucose (FDG) was the most valuable pharmaceutical. Numerous studies supported the routine use of FDG-PET for RT target volume determination in non-small cell lung cancer (NSCLC). There was also evidence for utility of PET in head and neck cancers, lymphoma and in esophageal cancers, with promising preliminary data in many other cancers. The best available approach employs integrated PET/CT images, acquired on a dual scanner in the radiotherapy treatment position after administration of tracer according to a standardized protocol, with careful optimization of images within the RT planning system and carefully considered rules for contouring tumor volumes. PET scans that are not recent or were acquired without proper patient positioning should be repeated for RT planning. PET will play an increasing valuable role in RT planning for a wide range of cancers. When requesting PET scans, physicians should be aware of their potential role in RT planning. [Copyright &y& Elsevier]

Lymphatic spread is an important pathway of progression in non–small-cell lung cancer (NSCLC), along with local spread and distant metastasis. The probability of lymph node (LN) involvement is dependent on the site of the primary tumor, stage, and histology. Elective nodal irradiation (ENI) is the irradiation of clinical and radiological uninvolved LN to account for microscopic tumor invasion in these LNs because we have not been able to determine the extent of LN spread accurately. The clinical value of ENI is uncertain. The impact of ENI is dependent on many (staging-, treatment-, and patient-related) factors. The purpose of this report is to analyze the current status of ENI and to provide comprehensive in-depth analysis and guidance on how to generally approach this issue in NSCLC. [Copyright &y& Elsevier]

Thoracic radiotherapy (RT) is an integral part of the management of small-cell lung cancer (SCLC) because its administration provides a survival benefit in patients with limited-stage disease. However, there are many areas of controversy with respect to the delivery of curative RT, and these include definition of the target to be irradiated. A current area of concern is defining what the RT portal must encompass with respect to the mediastinal lymph nodes; that is, whether one should electively treat all mediastinal nodes, or selectively include those with some clinical risk for harboring disease, or perhaps omit elective nodal irradiation altogether. The purpose of the present report is therefore to address the concepts underlying elective or selective nodal irradiation as it applies to SCLC, looking at clinical, imaging, and RT reports to help define the parameters appropriate to treating individual patients. [Copyright &y& Elsevier]