ESTRO clinical practice guideline: Stereotactic body radiotherapy for spine metastases.

BACKGROUND AND PURPOSE: Recent progress in diagnostics and treatment of metastatic cancer patients have improved survival substantially. These developments also affect local therapies, with treatment aims shifting from short-term palliation to long-term symptom or disease control. There is consequently a need to better define the value of stereotactic body radiotherapy (SBRT) for the treatment of spinal metastases. METHODS: This ESTRO clinical practice guideline is based on a systematic literature review conducted according to PRISMA standards, which formed the basis for answering four key questions about the indication and practice of SBRT for spine metastases. RESULTS: The analysis of the key questions based on current evidence yielded 22 recommendations and 5 statements with varying levels of endorsement, all achieving a consensus among experts of at least 75%. In the majority, the level of evidence supporting the recommendations and statements was moderate or expert opinion, only, indicating that spine SBRT is still an evolving field of clinical research. Recommendations were established concerning the selection of appropriate patients with painful spine metastases and oligometastatic disease. Recommendations about the practice of spinal SBRT covered technical planning aspects including dose and fractionation, patient positioning, immobilization and image-guided SBRT delivery. Finally, recommendations were developed regarding quality assurance protocols, including description of potential SBRT-related toxicity and risk mitigation strategies. CONCLUSIONS: This ESTRO clinical practice guideline provides evidence-based recommendations and statements regarding the selection of patients with spinal metastases for SBRT and its safe implementation and practice. Enrollment of patients into well-designed prospective clinical trials addressing clinically relevant questions is considered important.

Efficacy and safety of SBRT for spine metastases: A systematic review and meta-analysis for preparation of an ESTRO practice guideline.

BACKGROUND AND PURPOSE: Advances in characterizing cancer biology and the growing availability of novel targeted agents and immune therapeutics have significantly changed the prognosis of many patients with metastatic disease. Palliative radiotherapy needs to adapt to these developments. In this study, we summarize the available evidence for stereotactic body radiotherapy (SBRT) in the treatment of spinal metastases. MATERIALS AND METHODS: A systematic review and meta-analysis was performed using PRISMA methodology, including publications from January 2005 to September 2021, with the exception of the randomized phase III trial RTOG-0631 which was added in April 2023. Re-irradiation was excluded. For meta-analysis, a random-effects model was used to pool the data. Heterogeneity was assessed with the I2-test, assuming substantial and considerable as I2 > 50 % and I2 > 75 %, respectively. A p-value < 0.05 was considered statistically significant. RESULTS: A total of 69 studies assessing the outcomes of 7236 metastases in 5736 patients were analyzed. SBRT for spine metastases showed high efficacy, with a pooled overall pain response rate of 83 % (95 % confidence interval [CI] 68 %-94 %), pooled complete pain response of 36 % (95 % CI: 20 %-53 %), and 1-year local control rate of 94 % (95 % CI: 86 %-99 %), although with high levels of heterogeneity among studies (I2 = 93 %, I2 = 86 %, and 86 %, respectively). Furthermore, SBRT was safe, with a pooled vertebral fracture rate of 9 % (95 % CI: 4 %-16 %), pooled radiation induced myelopathy rate of 0 % (95 % CI 0-2 %), and pooled pain flare rate of 6 % (95 % CI: 3 %-17 %), although with mixed levels of heterogeneity among the studies (I2 = 92 %, I2 = 0 %, and 95 %, respectively). Only 1.7 % of vertebral fractures required surgical stabilization. CONCLUSION: Spine SBRT is characterized by a favorable efficacy and safety profile, providing durable results for pain control and disease control, which is particularly relevant for oligometastatic patients.

Apparent diffusion coefficient obtained by magnetic resonance imaging as a prognostic marker in glioblastomas: correlation with MGMT promoter methylation status.

OBJECTIVE: To evaluate whether apparent diffusion coefficient (ADC) values can predict the status of MGMT of glioblastoma multiforme (GBM) and correlate with overall survival (OS) and progression-free survival (PFS). METHODS: This retrospective study included 47 patients with pathologically proven glioblastoma. All of them underwent MR DWI study before surgery (mean time 1 week) and the status of methylguanine-DNA-methyltransferase (MGMT) promoter methylation was searched for. Minimum apparent diffusion coefficient (ADC) values were evaluated. OS and PSF parameters were calculated, and Student's t-test, Kaplan-Meier curves, linear and Cox regression were performed. RESULTS: Twenty-five patients showed positive methylation of the MGMT promoter. Patients showing MGMT promoter methylation had higher minimum ADC values, and they survived longer than those without MGMT promoter methylation. The median ADCmin value of 0.80 represents the cutoff value able to distinguish between methylated and un-methylated patients. Patients showing minimum ADC values higher than 0.80 survived longer than patients with minimum ADC values lower than 0.80. A linear correlation between minimum ADC values vs. the OS and PFS was observed. CONCLUSIONS: Minimum ADC values in glioblastoma multiforme could be used as a preoperative parameter to estimate the status of MGMT promoter methylation and the survival of patients.

[Curative radiotherapy in patients with anal cancer: clinical outcomes and prognostic factors in a single-institution experience]. / Risultati clinici e fattori prognostici dopo radioterapia curativa nei pazienti con cancro anale: l'esperienza di una singola istituzione.

PURPOSE: Our aim was to retrospectively analyse a series of patients with anal cancer treated with curative intent at a single institute in terms of survival and local disease control. MATERIALS AND METHODS: Forty-two patients with anal cancer were treated with primary radiotherapy with or without concurrent chemotherapy. The influence of the prognostic factors on overall (OS), disease-free (DFS), disease-specific (DSS), colostomy-free (CFS) and metastasis-free (MFS) survival was evaluated. RESULTS: Nine patients had stage I, 15 stage II, four stage IIIA and 14 stage IIIB disease. Tumour progression/ persistence occurred in five patients (12%). The 5-year OS, DSS, DFS, CFS and MFS were 72.7%, 84.2%, 85.7%, 81.1% and 87.1%, respectively. On univariate analysis, T stage emerged as highly significant for OS, DSS, CFS and DFS, whereas N status was a significant prognostic factor for DSS. On multivariate analysis, T stage was a significant prognostic factor for OS and CFS. CONCLUSIONS: Our data support the view that combined chemoradiation treatment of anal cancer is feasible and may provide survival benefits with an acceptable rate of adverse effects. We should consider T and N stages as important prognostic factors for survival.

Acute toxicity in 14 patients with locally advanced head and neck squamous cell carcinoma treated with concurrent cetuximab and radiotherapy.

PURPOSE: The authors report acute toxicity in 14 patients with locally advanced head and neck squamous cell carcinoma treated with radiotherapy and cetuximab. MATERIALS AND METHODS: Data collection was performed prospectively on patients treated from September 2007 to March 2009. Treatment consisted of 64.8-70 Gy radiotherapy in conventional fractions and cetuximab. RESULTS: Two out of 14 patients did not complete the planned combined treatment; radiotherapy was temporarily suspended in six other patients. Seven of 12 patients received cetuximab until the end of radiotherapy. Treatment breaks were principally due to severe acute cutaneous or mucous toxicity. Any grade acneiform rash occurred in all patients. In-field G3-4 cutaneous toxicity occurred in five (36%) patients and G3-4 mucous toxicity in seven (50%). One patient died of sepsis. CONCLUSIONS: In our experience, severe acute toxic reactions are common in patients treated with radiotherapy and concurrent cetuximab, resulting in frequent breaks or incomplete treatment with potential reduction in disease control.

Clinical applications of dynamic susceptibility contrast perfusion-weighted MR imaging in brain tumours.

Magnetic resonance imaging (MRI) with a dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) sequence to study brain tumours provides information on the haemodynamic characteristics of the neoplastic tissue. Brain perfusion maps and calculation of perfusion parameters, such as relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV) and mean transit time (MTT) allow assessment of vascularity and angiogenesis within tumours of the central nervous system (CNS), thus providing additional information to conventional MRI sequences. Although DSC-PWI has long been used, its clinical use in the study of brain tumours in daily clinical practice is still to be defined. The aim of this review was to analyse the application of perfusion MRI in the study of brain tumours by summarising our personal experience and the main results reported in the literature.

Fractionated stereotactic reirradiation and concurrent temozolomide in patients with recurrent glioblastoma.

The aim of this paper is to evaluate the efficacy of fractionated stereotactic radiotherapy (FSRT) and concomitant temozolomide (TMZ) as a salvage treatment option in patients with recurrent glioblastoma (GBM). Between May 2006 and December 2009, 36 patients with recurrent GBM received FSRT plus concomitant TMZ at University of Rome La Sapienza, Sant' Andrea Hospital. All patients had Karnofsky performance score ≥60 and were previously treated with standard conformal radiotherapy (RT) (60 Gy) with concomitant and adjuvant TMZ for 6-12 cycles. The median time interval between primary RT and reirradiation was 14 months. At the time of recurrence, all patients received FSRT plus concomitant daily TMZ at the dose of 75 mg/m(2), given 7 days per week from the first day of RT. Radiation dose was 37.5 Gy delivered in 15 fractions over 3 weeks. Median overall survival after FSRT was 9.7 months, and the 6- and 12-month survival rates were 84 and 33%, respectively. The median progression-free survival (PFS) was 5 months, and 6- and 12-month PFS rates were 42 and 8%, respectively. In univariate analysis, KPS (P = 0.04), the interval between primary RT and reirradiation (P = 0.02), and O6-methylguanine-DNA-methyltransferase (MGMT) methylation status at the time of diagnosis (P = 0.009) had an effect on survival; however, in multivariate analysis, only MGMT methylation was statistically significant (P = 0.03). In general, FSRT was well tolerated and the treatment was completed in all patients. Neurological deterioration due to radiation-induced necrosis occurred in three patients (8%). FSRT plus concomitant TMZ is a feasible treatment option associated with survival benefits and low risk of complications in selected patients with recurrent GBM. The potential advantages of combined chemoradiation schedules in patients with recurrent GBM need to be explored in future studies.

Folic acid, vitamin B12, and homocysteine levels during fasting and after methionine load in patients with Type 1 diabetes mellitus.

AIMS: To assess plasma concentrations of folic acid, vitamin B12, and total plasma homocysteine (tHCY) during fasting and after methionine load in young patients with Type 1 diabetes mellitus (T1DM). METHODS: We enrolled 41 young patients with T1DM without any sign of microvascular complications and 123 healthy controls in a 1:3 case-control study. Fasting and post-methionine load (PML) tHCY, folic acid, and vitamin B12 levels were measured in both groups. Data regarding chronological age, metabolic control (assessed by mean values of glycated hemoglobin in the last 12 months) and disease duration were also recorded. RESULTS: Fasting and PML tHCY levels were significantly lower in patients than in controls: 7.3+/-2.7 micromol/l vs 8.3+/-2.5 micromol/l (p=0.01), and 16.7+/-5.8 micromol/l vs 17.3+/-4.3 micromol/l (p=0.01), respectively. No correlation was found between fasting and PML tHCY levels and chronological age, disease duration, metabolic control, and insulin requirement. Patients had significantly higher vitamin B12 levels compared to controls: 767+/-318 pg/ml vs 628+/-236 pg/ml (p=0.003), while folic acid turned out to be lower in patients than in controls: 5.3+/-1.9 nmol/l vs 7.5+/-2.6 nmol/l (p<0.0001). CONCLUSIONS: Adolescents and young adults with T1DM without microvascular complications showed lower tHCY both during fasting and after methionine load. Lower folate concentrations in these patients might benefit from food fortification.

Modern techniques for pituitary radiotherapy.

Radiotherapy (RT) remains an effective treatment for residual or recurrent pituitary adenomas with excellent rates of tumour control and normalisation of excess hormone secretion. The main late toxicity is hypopituitarism: other side effects are rare. We discuss technical developments in the delivery of radiotherapy (stereotactic conformal radiotherapy (SCRT) and stereotactic radiosurgery (SRS)), all aiming to reduce the amount of normal brain receiving significant doses of radiation. We provide a comprehensive review of published data on outcome of conventional fractionated radiotherapy and modern RT techniques. SCRT is a suitable treatment technique for all sizes of pituitary adenoma and efficacy is comparable to conventional RT; the lack of long term follow up means that currently there is no information on potential reduction in the incidence of late radiation induced toxicity. Single fraction SRS can only be safely delivered to small tumours away from critical structures. There is no evidence that it produces faster decline of elevated hormone levels than fractionated treatment and is not associated with lesser morbidity.

Pre-surgical planning and MR-tractography utility in brain tumour resection.

The purposes of this study were (1) to evaluate the possible identification of trajectories of fibre tracts, (2) to examine the useful of a neuronavigation system for presurgical planning, (3) to assess pre- and post-surgery patients' clinical condition and (4) to evaluate the impact of this information on surgical planning and procedure. Twenty-eight right-handed patients were prospectively and consecutively studied. All the patients were clinically assessed by a neurologist in both pre- and postsurgical phases. Separately the pyramidal tract, optic radiation and arcuate fasciculus were reconstructed. The trajectories were considered suitable for surgical planning if there were no interruptions of any of the layers at the level of the lesion. Dedicated software 'merged' the acquired images with the tractographic processing, and the whole dataset was sent to the neuronavigation system. The assessment of the 37 visualised trajectories close to the tumour resulted in a modification of the surgical approach to corticotomy in six patients (21%); the impact on the definition of the resection margins during surgery was 64%(18 cases). The overall impact percentage on the surgical procedure was 82%. In 27 cases, the symptoms had not changed. MR-tractography provides the neurosurgeon with a new anatomical view that has an impact on the surgical resection planning for brain neoplasms.

The role of fractionated radiotherapy and radiosurgery in the management of patients with craniopharyngioma.

The optimal management of craniopharyngiomas remains controversial. The first-line treatment usually consists of surgical resection. Complete tumor removal provides a high rate of long-term control; however, aggressive surgery is associated with significant incidence of complications. Radiotherapy (RT) is currently used in patients after limited surgery and achieves excellent long-term tumor control. Stereotactic radiotherapy, both in the form of radiosurgery (RS) or fractionated stereotactic radiotherapy (FSRT), has been developed as a more accurate technique of irradiation with more precise tumor localization and consequently a reduction in the volume of normal brain irradiated to high radiation doses. We provide a review of published data on outcome of conventional fractionated RT and modern radiation techniques. FSRT is a suitable treatment technique for all sizes of craniopharyngiomas, and efficacy is comparable to conventional RT. Single-fraction stereotactic radiosurgery is usually delivered to small tumors away from critical structures. Longer follow-up is necessary to confirm the excellent tumor control and the potential reduction of long-term radiation toxicity.

Salvage radiotherapy with simultaneous integrated boost in non small-cell lung cancer patients with mediastinal relapse after surgery: a pilot study.

BACKGROUND: The aim of our study was to evaluate feasibility, toxicity profile and local control of salvage intensity modulated radiotherapy (IMRT) delivered with simultaneous integrated boost (SIB) associated or not to concomitant weekly cisplatin in patients affected by NSCLC with mediastinal nodal recurrence after surgery. Patterns of recurrence, outcomes and prognostic factors were assessed. METHODS: Fourteen consecutive patients received 25 fractions of 50Gy/2Gy to the elective nodal stations and boost up to 62.5Gy/2.5Gy to the macroscopic lymph node metastases. Concomitant weekly cisplatin (40 mg/m2) was administered to 8 (57.1%) patients. RESULTS: Five (35.7%) patients experienced grade 2 pneumonitis and 5 (35.7%) patients had grade 2 esophagitis. One case of grade 3 pneumonitis occurred and was successfully treated with antibiotics and steroids with no sequelae. No patient recurred locally in the boost volume (local control 100%). Loco-regional control was 79% with 3 patients that developed nodal recurrence principally marginal to the elective volume. Seven patients developed distant metastases. Median PFS was 7 months. The nodal involvement of station 7 was associated to a significantly lower median metastasis-free survival (4 months vs. not reached, p = 0.036). CONCLUSIONS: Salvage radiotherapy with IMRT-SIB is a feasible and a well-tolerated treatment option for mediastinal recurrent NSCLC after surgery. The role of more intensified radiation regimens and association to systemic therapy remain to be evaluated in larger cohorts.

30 Gy single dose stereotactic body radiation therapy (SBRT): Report on outcome in a large series of patients with lung oligometastatic disease.

OBJECTIVES: To evaluate the local control (LC) and long term adverse effects in a series of patients with lung metastases who received 30 Gy in single dose with stereotactic technique. MATERIALS AND METHODS: Between December 2008 and April 2016, a total of 166 lung metastases in 129 patients affected by oligometastatic disease were treated at our Institution with stereotactic body radiotherapy (SBRT). Mainly, the primary tumors were non small-cell lung cancer and colorectal cancer (45.2% and 28.8%, respectively). Prognostic factors were also assessed. RESULTS: The median follow-up was 38 months. Local progression occurred in 24 (14.4%) lesions in 21 patients. Intra-thoracic progression (new lung lesions or thoracic lymph node metastases) occurred in 59 (45.7%) patients. Forty-five (34.8%) patients had distant progression after a median time of 14 months. The 3- and 5-years local relapse-free survival (LPFS) were 80.1% and 79.2% (median not reached), respectively. One-hundred forty-eight patients were evaluated for late toxicity (follow-up >6 months): 51 (34.4%) patients had grade ≤2 fibrosis, 11 (7.4%) patients experienced grade 3 fibrosis. Two (1.3%) cases of rib fracture occurred. One case of toxic death (grade 5) has been reported. Median OS was 39 months. At the univariate analysis, lesion diameter ≤18 mm correlated significantly with a longer LPFS (p = 0.001). At the multivariate analysis, lesion diameter <18 mm was predictive for longer LPFS (p = 0.006). Also, oligometastases from primary colorectal cancer was a significant predictive factor for worse LPFS (p = 0.041) and progression-free survival (p = 0.04). CONCLUSIONS: To our knowledge, the current study represents the largest series on the use of SBRT 30 Gy single dose for lung metastases. Our results confirm the effectiveness and safety of this schedule administered in selected oligometastatic patients. Further prospective series could better validate these results.

Homocysteine, reactive oxygen species and nitric oxide in type 2 diabetes mellitus.

INTRODUCTION: Type 2 diabetes mellitus shows a characteristic altered platelet function that can be due to several mechanisms such as oxidative stress. Hyperhomocysteinemia, considered as a risk factor for various arterial thrombosis, may have a role in generating oxidative damage, even if the pathogenic mechanisms are still not clear. In this report we aimed to determine the role of plasma homocysteine in inducing oxidative stress in type 2 diabetes mellitus. MATERIALS AND METHODS: The study was performed on a group of 34 males with type 2 diabetes and 36 healthy subjects matched for sex and age. Patients and healthy subjects were undergone to laboratory evaluation for plasma homocysteine levels and other metabolic parameters. In both groups of subjects platelet reactive oxygen species, nitric oxide and guanosine 3',5' cyclic monophosphate levels were measured. Moreover the reduced glutathione content in platelets of patients and of healthy subjects was assayed. RESULTS: Plasma homocysteine levels were significantly increased in patients compared with healthy subjects. The basal level of reactive oxygen species was significantly higher in patients than in controls. In addition platelets of patients stimulated with thrombin produced more reactive oxygen species than healthy subjects ones. The nitric oxide, guanosine 3',5' cyclic monophosphate and reduced glutathione content were decreased in platelets of patients. CONCLUSIONS: As homocysteine stimulates oxidative stress and inhibits nitric oxide formation, hyperhomocysteinemia measured in type 2 diabetic patients, promoting platelet hyperactivity, could have a role in the atherogenic effects described in type 2 diabetes.

Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years.

We assessed the risk of second brain tumors in a cohort of patients with pituitary adenoma treated with conservative surgery and external beam radiotherapy. Four hundred and twenty-six patients (United Kingdom residents) with pituitary adenomas received radiotherapy at the Royal Marsden Hospital (RMH) between 1962 and 1994. They were followed up for 5749 person-years. The cumulative incidence of second intracranial tumors and systemic malignancy was compared with population incidence rates through the Thames Cancer Registry and the National Health Service Central Register (previously OPCS) to record death and the potential causes. Eleven patients developed a second brain tumor, including five meningiomas, four high grade astrocytomas, one meningeal sarcoma, and one primitive neuroectodermal tumor. The cumulative risk of second brain tumors was 2.0% [95% confidence interval (CI), 0.9-4.4%] at 10 yr and 2.4% (95% CI, 1.2-5.0%) at 20 yr, measured from the date of radiotherapy. The relative risk of second brain tumor compared with the incidence in the normal population was 10.5 (95% CI, 4.3-16.7). The relative risk was 7.0 for neuroepithelial and 24.3 for meningeal tumors. The relative risks were 24.2 (95% CI, 4.8-43.5), 2.9 (95% CI, 0-8.5), and 28.6 (95% CI, 0.6-56.6) during the intervals 5-9, 10-19, and more than 20 yr after radiotherapy (four cases occurred >20 yr after treatment). There was no evidence of excess risk of second systemic malignancy. An additional 10-yr update confirmed our previous report of an increased risk of second brain tumors in patients with pituitary adenoma treated with surgery and radiotherapy. The 2.4% risk at 20 yr remains low and should not preclude the use of radiotherapy as an effective treatment option. However, an increased risk of second brain tumors continues beyond 20 and 30 yr after treatment.

Evolving criteria for post-operative biochemical remission of acromegaly: can we achieve a definitive cure? An audit of surgical results on a large series and a review of the literature.

Criteria to define the biochemical remission of acromegaly following surgery have changed over the years, and the current use of stringent criteria needs a critical re-evaluation of the surgical results. On the other hand, few data are currently available concerning the possible impact of pituitary surgery on the quality of life of operated acromegalic patients. In this prospective study, we wished to evaluate the initial outcome and long-term recurrence rate in a large series of acromegalic patients operated on by transsphenoidal surgery (TSS), to carefully analyse predictive factors for surgical outcome and to point out possible additional effects of surgery in these patients. Ninety-two out of 98 operated patients could be considered for follow-up. Biochemical remission was strictly defined as plasma GH levels <1 ng/ml during an oral glucose tolerance test (OGTT) and normalisation of age-related IGF-I levels. Hormonal assessment, including an OGTT, was performed 6 months following surgery and then annually to evaluate pituitary function. Fifty-five per cent of patients achieved a biochemical remission of acromegaly. The remission rate at 6 months was 80% for patients with microadenoma and 50% for macroadenoma. Univariate analysis showed that a large extrasellar extension, preoperative high GH levels and dural invasion were correlated with a poor outcome of surgery while, according to multivariate analysis, only invasion of cavernous sinus and preoperative GH levels > 10 ng/ml were independent negative predictors. Mortality was 0% and the overall complication rate was about 10%. Pituitary function worsened in five patients but improved in 16 out of 30 patients with preoperative pituitary defects. No recurrence was observed during a median follow-up of about 8 years. We conclude that TSS is able to achieve a biochemical remission in more than half of acromegalic patients, and that the current criteria for remission seem to indicate a cure in most cases.