Abstract Aims To update previous meta-analyses of randomised palliative radiotherapy trials comparing single fractions versus multiple fractions. Materials and methods All published randomised controlled trials comparing single fraction versus multiple fraction schedules for the palliation of uncomplicated bone metastases were included in this analysis. Odds ratios and 95% confidence intervals were calculated for each trial. Forest plots were created using a random effects model and the Mantel–Haenszel statistic. Results In total, 25 randomised controlled trials were identified. For intention-to-treat patients, the overall response rate was similar in patients receiving single fractions (1696 of 2818; 60%) and multiple fractions (1711 of 2799; 61%). Complete response rates were 620 of 2641 (23%) in the single fraction arm and 634 of 2622 (24%) in the multiple fraction arm. No significant difference was seen in overall or complete response rates. Pathological fracture did not favour either arm, but spinal cord compression trended towards favouring multiple fractions; however, neither was statistically significant ( P = 0.72 and P = 0.13, respectively). Retreatment rates favoured patients in the multiple fraction arm, where the likelihood of requiring re-irradiation was 2.6-fold greater in the single fraction arm (95% confidence interval: 1.92–3.47; P < 0.00001). Repeated analyses excluding drop-out patients did not alter these findings. In general, no significant differences in acute toxicities were seen. Conclusion Overall and complete response rates were similar in both intention-to-treat and assessable patients. Single and multiple fraction regimens provided equal pain relief; however, significantly higher retreatment rates occurred in those receiving single fractions.
Abstract DNA damage of exposed tumour tissue leading to cell death is one of the detrimental effects of ionising radiation that is exploited, with beneficial consequences, for radiotherapy. The pattern of the discrete energy depositions during passage of the ionising track of radiation defines the spatial distribution of lesions induced in DNA with a fraction of the DNA damage sites containing clusters of lesions, formed over a few nanometres, against a background of endogenously induced individual lesions. These clustered DNA damage sites, which may be considered as a signature of ionising radiation, underlie the deleterious biological consequences of ionising radiation. The concepts developed rely in part on the fact that ionising radiation creates significant levels of clustered DNA damage, including complex double-strand breaks (DSB), to kill tumour cells as clustered damage sites are difficult to repair. This reduced repairability of clustered DNA damage using specific repair pathways is exploitable in radiotherapy for the treatment of cancer. We discuss some potential strategies to enhance radiosensitivity by targeting the repair pathways of radiation-induced clustered damage and complex DNA DSB, through inhibition of specific proteins that are not required in the repair pathways for endogenous damage. The variety and severity of DNA damage from ionising radiation is also influenced by the tumour microenvironment, being especially sensitive to the oxygen status of the cells. For instance, nitric oxide is known to influence the types of damage induced by radiation under hypoxic conditions. A potential strategy based on bioreductive activation of pro-drugs to release nitric oxide is discussed as an approach to deliver nitric oxide to hypoxic tumours during radiotherapy. The ultimate aim of this review is to stimulate thinking on how knowledge of the complexity of radiation-induced DNA damage may contribute to the development of adjuncts to radiotherapy.
Abstract Thyroid cancer comprises a broad spectrum of diseases with variable prognoses. Although most patients with this disease have excellent overall survival, there are some who do not fare so well. With the worldwide increase in incidence, the need to identify which tumours pose the greatest risk to patients is more acute than ever. This paper will discuss this rising trend in incidence with an analysis of the possible reasons for the increase. In addition, the paper will explore the factors that portend a worse prognosis for the individual patient. Finally, the limitations of the current staging systems will be discussed, with particular emphasis on why they are not as informative in the management of patients with thyroid cancer.
Abstract About 57% of the total number of cancer cases occur in low and middle income countries. Radiotherapy is one of the main components of cancer treatment and requires substantial initial investment in infrastructure and training. Many departments continue to have basic facilities and to use simple techniques, while modern technologies have only been installed in big cities in upper-middle income countries. More than 50% of cancer patients requiring radiotherapy in low and middle income countries lack access to treatment. The situation is dramatic in low income countries, where the proportion is higher than 90%. The overall number of additional teletherapy units needed corresponds to about twice the installed capacity in Europe. The figures for different income level groups clearly show the correlation between gross national income per capita and the availability of services. The range of radiotherapy needs currently covered varies from 0% and 3–4% in low income countries in Latin America and Africa up to 59–79% in upper-middle income countries in Europe and Central Asia. The number of additional radiation oncologists, medical physicist, dosimetrists and radiation therapists (RTTs) required to operate additional radiotherapy departments needed is 43 200 professionals. Training and education programmes are not available in every developing country and in many cases the only option is sending trainees abroad, which is not a cost-effective solution. The implementation of adequate local training should be the following step after establishing the first radiotherapy facility in any country. Joint efforts should be made to establish at least one radiotherapy facility in countries where they do not exist, in order to create radiotherapy communities that could be the base for future expansion.
Abstract Anaplastic thyroid carcinoma ranges from 1.3 to 9.8% of all thyroid cancers globally. Mutations, amplifications, activation of oncogenes and silencing of tumour suppressor genes contribute to its aggressive behaviour, and recent studies (e.g. microarrays, microRNAs) have provided further insights into its complex molecular dysregulation. Preclinical studies have identified numerous proteins over- or underexpressed that affect critical cellular processes, including transcription, signalling, mitosis, proliferation, cell cycle, apoptosis and adhesion, and a variety of agents that effectively inhibit these processes and tumour growth. In clinical studies of 1771 patients, 64% were women, the median survival was 5 months, and 1-year survival was 20%. The variables associated with survival in some series included age, tumour size, extent of surgery, higher dose radiotherapy, absence of distant metastases at presentation, co-existence of differentiated thyroid cancer and multimodality therapy. However, considerable bias exists in these non-randomised studies. Although more aggressive radiotherapy has reduced locoregional recurrences, the median overall survival has not improved in over 50 years. Newer systemic therapies are being tried, and more effective combinations are needed to improve patient outcomes.
Abstract Aims The Canadian Association of Radiation Oncology-Stereotactic Body Radiotherapy (CARO-SBRT) Task Force was established in 2010. The aim was to define the scope of practice guidelines for the profession to ensure safe practice specific for the most common sites of lung, liver and spine SBRT. Materials and methods A group of Canadian SBRT experts were charged by our national radiation oncology organisation (CARO) to define the basic principles and technologies for SBRT practice, to propose the minimum technological requirements for safe practice with a focus on simulation and image guidance and to outline procedural considerations for radiation oncology departments to consider when establishing an SBRT programme. Results We recognised that SBRT should be considered as a specific programme within a radiation department, and we provide a definition of SBRT according to a Canadian consensus. We outlined the basic requirements for safe simulation as they pertain to spine, lung and liver tumours, and the fundamentals of image guidance. The roles of the radiation oncologist, medical physicist and dosimetrist have been detailed such that we strongly recommend the development of SBRT-specific teams. Quality assurance is a key programmatic aspect for safe SBRT practice, and we outline the basic principles of appropriate quality assurance specific to SBRT. Conclusion This CARO scope of practice guideline for SBRT is specific to liver, lung and spine tumours. The task force recommendations are designed to assist departments in establishing safe and robust SBRT programmes.
Abstract Hypoxia was identified as a microenvironmental component of solid tumours over 60 years ago and was immediately recognised as a potential barrier to therapy through the reliance of radiotherapy on oxygen to elicit maximal cytotoxicity. Over the last two decades both clinical and experimental studies have markedly enhanced our understanding of how hypoxia influences cellular behaviour and therapy response. Furthermore, they have confirmed early assumptions that low oxygenation status in tumours is an exploitable target in cancer therapy. Generally such approaches will be more beneficial to patients with hypoxic tumours, necessitating the use of biomarkers that reflect oxygenation status. Tissue biomarkers have shown utility in many studies. Further significant advances have been made in the non-invasive measurement of tumour hypoxia with positron emission tomography, magnetic resonance imaging and other imaging modalities. Here, we describe the complexities of defining and measuring tumour hypoxia and highlight the therapeutic approaches to combat it.
Abstract The Chernobyl Forum Report from the 20th anniversary of the Chernobyl nuclear power plant disaster concluded that mental health effects were the most significant public health consequence of the accident. This paper provides an updated review of research on the psychological impact of the accident during the 25 year period since the catastrophe began. First responders and clean-up workers had the greatest exposure to radiation. Recent studies show that their rates of depression and post-traumatic stress disorder remain elevated two decades later. Very young children and those in utero who lived near the plant when it exploded or in severely contaminated areas have been the subject of considerable research, but the findings are inconsistent. Recent studies of prenatally exposed children conducted in Kiev, Norway and Finland point to specific neuropsychological and psychological impairments associated with radiation exposure, whereas other studies found no significant cognitive or mental health effects in exposed children grown up. General population studies report increased rates of poor self-rated health as well as clinical and subclinical depression, anxiety, and post-traumatic stress disorder. Mothers of young children exposed to the disaster remain a high-risk group for these conditions, primarily due to lingering worries about the adverse health effects on their families. Thus, long-term mental health consequences continue to be a concern. The unmet need for mental health care in affected regions remains an important public health challenge 25 years later. Future research is needed that combines physical and mental health outcome measures to complete the clinical picture.
Abstract Aims Intensity-modulated radiotherapy (IMRT) is a development of three-dimensional conformal radiotherapy that offers improvements in dosimetry in many clinical scenarios. Here we review the clinical evidence for IMRT and present ongoing or unpublished randomised controlled trials (RCTs). Methods We identified randomised and non-randomised comparative studies of IMRT and conventional radiotherapy using MEDLINE, hand-searching Radiotherapy and Oncology and the International Journal of Radiation Oncology, Biology and Physics and the proceedings of the American Society for Therapeutic Radiology and Oncology and the European Society for Therapeutic Radiology and Oncology annual meetings. The meta Register of Controlled Trials was searched to identify completed-unpublished, ongoing and planned RCTs. Results Sixty-one studies comparing IMRT and conventional radiotherapy were identified. These included three RCTs in head and neck cancer (205 patients) and three in breast cancer (664 patients) that had reported clinical outcomes; these were all powered for toxicity-related end points, which were significantly better with IMRT in each trial. There were 27 additional non-randomised studies in head and neck (1119 patients), 26 in prostate cancer (>5000 patients), four in breast cancer (875 patients) and nine in other tumour sites. The results of these studies supported those of the RCTs with benefits reported in acute and late toxicity, health-related quality of life and tumour control end points. Twenty-eight completed-unpublished, ongoing or planned RCTs incorporating IMRT were identified, including at least 12,310 patients, of which 15 compared conventional radiotherapy within IMRT as a randomisation or pre-planned stratification. Discussion Inverse-planned IMRT maintains parotid saliva production and reduces acute and late xerostomia during radiotherapy for locally advanced head and neck cancer, reduces late rectal toxicity in prostate cancer patients allowing safe dose escalation and seems to reduce toxicity in several other tumour sites. Forward-planned IMRT reduces acute toxicity and improves late clinician-assessed cosmesis compared with conventional tangential breast radiotherapy.
Abstract Advanced radiotherapy techniques, such as intensity-modulated radiotherapy (IMRT), may significantly benefit cervical cancer patients, in terms of reducing late toxicity and potentiating dose escalation. Given the steep dose gradients around the planning target volume (PTV) with IMRT planning, internal movement of organs during treatment may cause geographical miss of the target and unnecessary organs at risk (OAR) inclusion into high dose regions. It is therefore important to consider the extent and patterns of organ motion and to investigate potential image-guided radiotherapy (IGRT) solutions before implementing IMRT for cervical cancer. A systematic literature search was carried out using Medline, Embase, Cochrane Library, Web of Science, Cinahl and Pubmed. Database-appropriate search strategies were developed based upon terms for uterine neoplasms, IGRT, organ motion and target volume. In total, 448 studies were identified and screened to find 39 relevant studies, 12 of which were abstracts. These studies show that within the target volume for cervical cancer radiotherapy, uterine motion is greater than cervical. Uterine motion is predominantly influenced by bladder filling, cervical motion by rectal filling. Organ motion patterns are patient specific, with some having very little (5 mm) and others having much larger shifts (40 mm) of the target volume. Population-based clinical target volume (CTV)–PTV margins would be large (up to 4 cm around the uterus), resulting in unnecessary OAR inclusion within the PTV, reducing the benefits of IMRT. Potential solutions include anisotropic margins with increased margins in the anteroposterior and superoinferior directions, or greater PTV margins around the uterine fundus than the cervix. As pelvic organ motion seems to be patient specific, individualised PTV margins and adaptive IGRT strategies have also been recommended to ensure target volume coverage while increasing OAR sparing. Although these strategies are promising, they need significant validation before they can be adopted into clinical practice.
Abstract Substantial insight into the mechanisms responding to DNA double-strand breaks has been gained from molecular, biochemical and structural approaches. Attention is now focusing on understanding the interplay between the pathways, how they interface through the cell cycle and the communication with other DNA transactions, such as replication and transcription. Understanding these aspects will facilitate an assessment of how cancer cells have modified these processes to achieve unlimited proliferative capacity and adaptability, and pave the way to identify targets suitable for therapy. Here, we briefly overview the processes responding to double-strand breaks and discuss our current understanding of their interplay in a cellular context.
Abstract Twenty-five years have passed since radioactive releases from the Chernobyl nuclear accident led to the exposure of millions of people in Europe. Studies of affected populations have provided important new data on the links between radiation and cancer—particularly the risk of thyroid tumours from exposure to iodine isotopes—that are important not only for a fuller scientific understanding of radiation effects, but also for radiation protection. It is now well documented that children and adolescents exposed to radioiodines from Chernobyl fallout have a sizeable dose-related increase in thyroid cancer, with the risk greatest in those youngest at exposure and with a suggestion that deficiency in stable iodine may increase the risk. Data on thyroid cancer risks to other age groups are somewhat less definitive. In addition, there have been reported increases in incidence and mortality from non-thyroid cancers and non-cancer end points. Although some studies are difficult to interpret because of methodological limitations, recent investigations of Chernobyl clean-up workers (‘liquidators’) have provided evidence of increased risks of leukaemia and other haematological malignancies and of cataracts, and suggestions of an increase in the risk of cardiovascular diseases, following low doses and low dose rates of radiation. Further careful follow-up of these populations, including the establishment and long-term support of life-span study cohorts, could provide additional important information for the quantification of radiation risks and the protection of persons exposed to low doses of radiation.
Abstract The aim of this meta-analysis was to evaluate the effects of different exercise prescription parameters during cancer treatment on cancer-related fatigue (CRF). We also aimed to gain insight into the safety and feasibility of exercise during adjuvant cancer treatment. A systematic search of CINAHL, Cochrane Library, Embase, Medline, Scopus and PEDro was carried out. Randomised controlled trials studying the effects of exercise during cancer treatment on CRF were included. In total, 18 studies (12 in breast, four in prostate and two in other cancer patients) met all the inclusion criteria. During breast cancer treatment, home-based exercise lead to a small, non-significant reduction (standardised mean difference 0.10, 95% confidence interval −0.25 to 0.45), whereas supervised aerobic exercise showed a medium, significant reduction in CRF (standardised mean difference 0.30, 95% confidence interval 0.09 to 0.51) compared with no exercise. A subgroup analysis of home-based ( n = 65) and supervised aerobic ( n = 98) and resistance exercise programmes ( n = 208) in prostate cancer patients showed no significant reduction in CRF in favour of the exercise group. Adherence ranged from 39% of the patients who visited at least 70% of the supervised exercise sessions to 100% completion of a home-based walking programme. In more than half the studies (12 of 18; 67%) adverse events were reported. Eight events in total (0.72%) occurred in these studies.
Abstract Aims Over 30% of patients with non-small cell lung cancer (NSCLC) develop brain metastases. If inoperable, optimal supportive care (OSC), including steroids, and whole brain radiotherapy (WBRT) are generally considered to be standard care, although there is no randomised evidence demonstrating that the addition of WBRT to OSC improves survival or quality of life. Materials and methods QUARTZ is a randomised, non-inferiority, phase III trial comparing OSC + WBRT versus OSC in patients with inoperable brain metastases from NSCLC. The primary outcome measure is quality-adjusted life years (QALYs). QUARTZ was threatened with both loss of funding and early closure due to poor accrual. A lack of preliminary randomised data supporting the trial's hypotheses was thought to underlie the poor accrual, so, with no knowledge of the data, the independent trial steering committee agreed to the unusual step of releasing interim data. Results Between March 2007 and April 2010, 151 (of the planned 534) patients were randomised (75 OSC + WBRT, 76 OSC). Participants' baseline demographics included median age 67 years (interquartile range 62–73), 60% male, 50% with a Karnofsky performance status <70; steroid usage was similar in the two groups; 64/75 (85%) received WBRT (20 Gy in five fractions). Median survival was: OSC + WBRT 49 days (95% confidence interval 39–61), OSC 51 days (95% confidence interval 27–57) – hazard ratio 1.11 (95% confidence interval 0.80–1.53) in favour of WBRT. Quality of life assessed using EQ-5D showed no evidence of a difference. The estimated mean QALYs was: OSC + WBRT 31 days and OSC 30 days, difference −1 day (95% confidence interval −12.0 to +13.2 days). Conclusion These interim data indicate no early evidence of detriment to quality of life, overall survival or QALYs for patients allocated to OSC alone. They provide key information for discussing the trial with patients and strengthen the argument for continuing QUARTZ to definitively answer this important clinical question.
Abstract Radiosensitizers are intended to enhance tumour cell killing while having much less effect on normal tissues. Some drugs target different physiological characteristics of the tumour, particularly hypoxia associated with radioresistance. Oxygen is the definitive hypoxic cell radiosensitizer, the large differential radiosensitivity of oxic vs hypoxic cells being an attractive factor. The combination of nicotinamide to reduce acute hypoxia with normobaric carbogen breathing is showing clinical promise. ‘Electron-affinic’ chemicals that react with DNA free radicals have the potential for universal activity to combat hypoxia-associated radioresistance; a nitroimidazole, nimorazole, is clinically effective at tolerable doses. Hypoxia-specific cytotoxins, such as tirapazamine, are valuable adjuncts to radiotherapy. Nitric oxide is a potent hypoxic cell radiosensitizer; variations in endogenous levels might have prognostic significance, and routes to deliver nitric oxide specifically to tumours are being developed. In principle, many drugs can be delivered selectively to hypoxic tumours using either reductase enzymes or radiation-produced free radicals to activate drug release from electron-affinic prodrugs. A redox-active agent based on a gadolinium chelate is being evaluated clinically. Pyrimidines substituted with bromine or iodine are incorporated into DNA and enhance free radical damage; fluoropyrimidines act by different mechanisms. A wide variety of drugs that influence the nature or repair of DNA damage are being evaluated in conjunction with radiation; it is often difficult to define the mechanisms underlying chemoradiation regimens. Drugs being evaluated include topoisomerase inhibitors (e.g. camptothecin, topotecan), and the hypoxia-activated anthraquinone AQ4N; alkylating agents include temozolomide. Drugs involved in DNA repair pathways being investigated include the potent poly(ADP ribose)polymerase inhibitor, AG14361. Proteins involved in cell signalling, such as the Ras family, are attractive targets linked to radioresistance, as are epidermal growth factor receptors and linked kinases (drugs including vandetanib [ZD6474], cetuximab and gefitinib), and cyclooxygenase-2 (celecoxib). The suppression of radioprotective thiols seems to offer more potential with alkylating agents than with radiotherapy, although it remains a strategy worthy of exploration.
Abstract Hyperthermia is generally regarded as an experimental treatment with no realistic future in clinical cancer therapy. This is totally wrong. Although the role of hyperthermia alone as a cancer treatment may be limited, there is extensive pre-clinical data showing that in combination with radiation it is one of the most effective radiation sensitisers known. Moreover, there are a number of large randomised clinical trials in a variety of tumour types that clearly show the potential of hyperthermia to significantly improve both local tumour control and survival after radiation therapy, without a significant increase in side-effects. Here we review the pre-clinical rationale for combining hyperthermia with radiation, and summarise the clinical data showing its efficacy.
Abstract Medullary thyroid carcinoma (MTC) accounts for 5–8% of all thyroid cancers. MTC is mainly sporadic in nature, but an hereditary pattern [multiple endocrine neoplasia type 2 (MEN 2)] is present in 20–30% of cases, transmitted as an autosomal-dominant trait due to germline mutations of the RET proto-oncogene. About 98% of patients with MEN 2 have germline mutations in exons 5, 8, 10, 11, 13, 14, 15 or 16 of the RET gene. The primary treatment of both hereditary and sporadic forms of MTC is total thyroidectomy and removal of all neoplastic tissue present in the neck. The therapeutic option for lymph node surgery should be dictated by the results of presurgical evaluation. After total thyroidectomy, measurements of serum calcitonin (CT) and carcinoembryonic antigen are of paramount importance in the postsurgical follow-up of patients with MTC as they reflect the presence of persistent or recurrent disease. Complete remission is demonstrated by undetectable and stimulated serum CT measurement. On the contrary, if serum CT is detectable under basal conditions or becomes detectable after stimulation, the patient is probably not cured, but imaging techniques will not demonstrate any disease until serum CT approaches levels >150 pg/ml. The tumour metastasises early to both paratracheal and lateral cervical lymph nodes. Metastases outside the neck may occur in the liver, lungs, bones and, less frequently, brain and skin. Surgery is the main treatment for local and distant metastases whenever feasible. Systemic chemotherapy with dacarbazine, 5-fluorouracil and doxorubicin (alone or in combination) has shown very limited efficacy, achieving only partial responses in the range of 10–20% and of short duration. Several kinase inhibitors are currently under evaluation and preliminary results are promising. Familial cases must be identified by searching for RET proto-oncogene mutations in the proband and in family members. Carriers of the RET gene are candidates for prophylactic thyroidectomy at different ages depending on the risk associated with the specific RET mutations.
Abstract Thyroid cancer typically has a good outcome following standard treatments, which include surgery, radioactive iodine ablation for differentiated tumours and treatment with thyrotropine hormone-suppressive levothyroxine. Thyroid cancers that persist or recur following these therapies have a poorer prognosis. Cytotoxic chemotherapy or external beam radiotherapy has a low efficacy in these patients. ‘Target therapy’ with tyrosine kinase inhibitors (TKIs) represent an important therapeutic option for the treatment of advanced cases of radioiodine refractory (RAI-R) differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC) and possibly for cases of poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC). In the last few years, several TKIs have been tested for the treatment of advanced, progressive and RAI-R thyroid cancers and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC; vandetanib and cabozantinib for MTC. The objective of this overview is to present the current status of the treatment of advanced DTC, MTC, PDTC and ATC with the use of TKIs by describing the benefits and the limits of their use. A comprehensive analysis and description of the molecular basis of these drugs and the new therapeutic perspectives are also reported. Some practical suggestions are also given for the management to the potential side-effects of these drugs.