Task Group 101 of the AAPM has prepared this report for medical physicists, clinicians, and therapists in order to outline the best practice guidelines for the external-beam radiation therapy technique referred to as stereotactic body radiation therapy (SBRT). The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality. Information is provided for establishing a SBRT program, including protocols, equipment, resources, and QA procedures. Additionally, suggestions for developing consistent documentation for prescribing, reporting, and recording SBRT treatment delivery is provided.

https://aapm.onlinelibrary.wiley.com/doi/pdf/10.1118/1.3438081

Stereotactic body radiation therapy: The report of AAPM Task Group 101

Purpose The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan. Patients and Methods This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient’s anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m 2 , and patients not taking EIAEDs received 125 mg/m 2 . After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging. Results The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli). Conclusion Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity. J Clin Oncol 25:4722-4729. © 2007 by American Society of Clinical Oncology

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.2007.12.2440

Bevacizumab Plus Irinotecan in Recurrent Glioblastoma Multiforme

Ovarian cancer is responsible for 4% of deaths from cancer in women. Treatment comprises a combination of surgery and chemotherapy, but patients typically experience disease relapse within 2 years of the initial treatment. Further treatment can extend survival, although relapse eventually occurs again. A better understanding of the mechanisms that underlie this drug resistance should allow treatment to be optimized, so that substantial improvements in the outlook for women with this disease can be achieved.

Ovarian cancer: strategies for overcoming resistance to chemotherapy

This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.

https://journals.sagepub.com/doi/pdf/10.1016/j.icrp.2012.02.001

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is activated in the majority of human cancers. This pathway is known to play a key role in numerous cellular functions including proliferation, adhesion, migration, invasion, metabolism, and survival, but in the current review we focus on its role in angiogenesis. PI3K activation may occur via RAS mutation, loss of phosphatase and tensin homolog (PTEN), or by increased expression of growth factor receptors such as epidermal growth factor receptor. There is a connection between the PI3K pathway and angiogenesis. Hypoxia leads to HIF-1α stabilization and is a major stimulus for increased vascular endothelial growth factor (VEGF) production by tumor cells. However, activation of the PI3K/AKT pathway in tumor cells can also increase VEGF secretion, both by hypoxia-inducible factor 1 (HIF-1) dependent and independent mechanisms. The PI3K/AKT pathway also modulates the expression of other angiogenic factors such as nitric oxide and angiopoietins. Numerous inhibitors targeting the PI3K/AKT/mTOR pathway have been developed, and these agents have been shown to decrease VEGF secretion and angiogenesis. The effect of these inhibitors on tumor vasculature can be difficult to predict. The vasculature of tumors is aberrant, leading to sluggish bloodflow and elevated interstitial blood pressure, which can be perpetuated by the high levels of VEGF. Hence, decreasing VEGF expression can paradoxically lead to vascular normalization and improved bloodflow in some tumors. In addition to its importance in cancer, the PI3K pathway also plays an essential role in the formation of normal blood vessels during development. Embryos with kinase-dead p110α catalytic subunit of PI3K develop vascular defects. Stimulation of endothelial cells by VEGF leads to activation of the PI3K pathway within these cells, which is important for cell migration. Sustained endothelial activation of AKT1 has been shown to induce the formation of structurally abnormal blood vessels that recapitulate the aberrations of tumor vessels. Hence, the PI3K pathway plays an important role in regulating angiogenesis both in normal tissues and in cancers.

PI3K/AKT/mTOR Pathway in Angiogenesis

Tirapazamine (TPZ) reportedly enhances the tumor cell killing effect of cisplatin up to fivefold and it is an attractive drug for combination with radiotherapy. We evaluated the toxicity of a fractionated combined treatment. Murine RIF-1 fibrosarcomas growing on the right hind foot of C3-H mice were used. Within 2 weeks, animals were treated with six i.p. injections of TPZ (43.2–172.8 mg/kg total), and/or cisplatin (24 mg/kg total) and ten fractions of 2 Gy to the tumor. All treatments were carried out under anesthesia. Maximum follow-up was 35 days. The local tumor control was determined by calculating the tumor doubling time t
 2vo. In addition to standard toxicity assessment, the major inner organs were examined histologically. The administration of low TPZ doses to the cisplatin/radiotherapy treatment caused only little changes in tumor doubling time (t
 2vo) and led to a lethality rate of 15–30%. Higher TPZ doses caused an increase in t
 2vo, but also a further increase in lethality and toxicity in particular to the heart, liver, kidney and stomach. Cisplatin/radiotherapy treatment without TPZ produced no severe toxicity. This is a detailed study of both the acute and delayed toxicities of combined TPZ treatment in a mouse model. In our study the addition of TPZ to the cisplatin/radiotherapy treatment caused a significant increase in toxicity with only moderate effect on the tumor.

Tirapazamine plus cisplatin and irradiation in a mouse model: improved tumor control at the cost of increased toxicity.

Treatment of Newly Diagnosed Glioblastoma Multiforme

Aim: To test whether insulin-like growth factor-1 (IGF-1) ameliorates radiation-induced spinal cord myelopathy and to establish the dose-effect relationship for this growth factor which has not been administered in conjunction with spinal cord irradiation to date.Methods: Animal experiments were conducted to test the feasibility of IGF-1 injection in a model of cervical spinal cord irradiation in adult Fisher F-344 rats and to determine the most effective dose level of IGF-1. Irradiation was given in two fractions (16 Gy followed by 18 Gy) and animals were examined for the development of paresis (follow-up 12 months).Results: The dose-finding experiment revealed significant differences in the incidence of radiation myelopathy (RM). The most effective dose of IGF-1 was 50 μg per day.Conclusions: IGF-1 showed promising activity as a radioprotective agent in a model of high-dose spinal cord irradiation. Further studies are needed to examine the results with multiple small doses of radiation as widely applied...

Evaluation of insulin-like growth factor-1 for prevention of radiation-induced spinal cord damage.

Ziel der Studie war es, die klinischen Ergebnisse nach stereotaktischer Strahlentherapie (Radiochirurgie und stereotaktischer fraktionierter Strahlentherapie) am adaptierten Linearbeschleuniger bei Patienten mit Hirnmetastasen zu evaluieren. Dabei wurden folgende Parameter untersucht: Tumorkontrolle, Uberlebenszeit und Nebenwirkungen. Die Vor- und Nachteile dieser Behandlungstechnik im Vergleich zu traditionellen Behandlungsmethoden (Operation und Ganzschadelbestrahlung) wurden auf der Basis der Literaturdaten und der eigenen Erfahrung analysiert. Nach Behandlung von 80 Lasionen, mit einer medianen Nachbeobachtungszeit von 13 Monaten, kommt die Studie zu folgendem Ergebnis: Die stereotaktische Strahlentherapie am Linearbeschleuniger stellt eine wichtige Therapieoption in der Behandlung der Hirnmetastasen dar. Gegenuber alleiniger Ganzschadelbestrahlung erreicht die stereotaktische Strahlentherapie eine deutlich hohere Tumorkontrolle bei einem niedrigen Nebenwirkungsrisiko. Die stereotaktische Strahlentherapie hat gegenuber der Operation den Vorteil einer kurzeren Behandlungszeit und einer niedrigeren Morbiditat und Mortalitat.

Stereotactic radiation therapy with a modified linear accelerator in patients with brain metastases

Summary Current prognostic models are not accurate enough to identify brain metastases patients with non-small cell lung cancer who have very short survival, i.e. 2 months, but remained unsatisfactory (low positive predictive value) with regard to prediction of survival <2 months even after various optimisation attempts. In conclusion, the prognostic factors for overall survival that form the basis for the recursive partitioning analysis (RPA) classes (age, extracranial metastases, primary tumor control, performance status) do not predict for very short survival. However, we were not able to develop another model that performed accurate enough for clinical decision making.

Carsten Nieder

Papers

Tirapazamine plus cisplatin and irradiation in a mouse model: improved tumor control at the cost of increased toxicity.

Treatment of Newly Diagnosed Glioblastoma Multiforme

Evaluation of insulin-like growth factor-1 for prevention of radiation-induced spinal cord damage.

Stereotactic radiation therapy with a modified linear accelerator in patients with brain metastases

Prediction of very short survival in patients with brain metastases from non-small cell lung cancer