ORTHOVOLTAGE THERAPY—Is There Still a Need for It?

Since there has been no significant increase in cancer cure rates in recent years that can be attributed to the treatment method alone, new and more radical procedures have been introduced in an effort to improve the results. In radiation therapy this has taken the form of supervoltage generators and in the use of high energy sources of radiation such as Cobalt 60 and Cesium 137. As this trend gains momentum, the place and future of orthovoltage therapeutic radiation (250 to 400 kilovolts) must be considered. General agreement is that supervoltage radiation offers an increase in depth dose and fewer local and systemic reactions, but it is too early to assess any change in cure rate. Measured against this is the danger of deep tissue damage, less relative biological efficiency and increased costs.In view of our ignorance regarding cancer, abandoning proved procedures prematurely is unjustified. The most promising trend lies in improved training and in the skillful use of what we have. While it may be that radiation of higher voltages will improve the morbidity and mortality rates, it would be better to concentrate these new modalities in centers where large numbers of cases are available.     

THE EFFECT OF A SERVICE TYPE MEDICAL CARE PROGRAM ON THE PRACTICE OF MEDICINE

Statistical evidence is presented to suggest that cure rates achieved by supervoltage are not significantly different from those achieved by orthovoltage in carcinoma of the tonsil and of the ovary.     

Chemoradiation for carcinoma of the cervix: advances and opportunities

Although it is possible to cure many patients with locally advanced cervical cancer using radiation therapy alone, loco-regional relapse continues to be a component of most recurrences. To improve control rates, clinicians have investigated ways of combining chemotherapy and radiation for more than 30 years. Despite encouraging results from phase II trials of neoadjuvant chemotherapy, randomized trials failed to improve on the results with radiation therapy alone. For a number of reasons, early trials of concurrent chemoradiation were inconclusive. However, recent reports of five large prospective randomized trials demonstrated dramatic improvements in survival and local control rates when cisplatin-containing chemotherapy was given during radiation therapy. These results also suggest a number of avenues for future research.     

Computed tomographies and cancer risk in children: a literature overview of CT practices,risk estimations and an epidemiologic cohort study proposal

Radiation protection is a topic of great public concern and of many scientific investigations, because ionizing radiation is an established risk factor for leukaemia and many solid tumours. Exposure of the public to ionizing radiation includes exposure to background radiation, as well as medical and occupational exposures. A large fraction of the exposure from diagnostic procedures comes from medical imaging. Computed tomography (CT) is the major single contributor of diagnostic radiation exposure. An increase in the use of CTs has been reported over the last decades in many countries. Children have smaller bodies and lower shielding capacities, factors that affect the individual organ doses due to medical imaging. Several risk models have been applied to estimate the cancer burden caused by ionizing radiation from CT. All models predict higher risks for cancer among children exposed to CT as compared to adults. However, the cancer risk associated with CT has not been assessed directly in epidemiological studies. Here, plans are described to conduct an historical cohort study to investigate the cancer incidence in paediatric patients exposed to CT before the age of 15 in Germany. Patients will be recruited from radiology departments of several hospitals. Their individual exposure will be recorded, and time-dependent cumulative organ doses will be calculated. Follow-up for cancer incidence via the German Childhood Cancer Registry will allow computation of standardized incidence ratios using population-based incidence rates for childhood cancer. Dose–response modelling and analyses for subgroups of children based on the indication for and the result of the CT will be performed.     

Medical diagnostic radiation exposures and risk of gliomas

High-dose ionizing radiation is an established risk factor for glioma, but it remains unknown whether moderate- and low-dose radiation increase glioma risk. In this analysis, we assessed the evidence that self-reported exposures to diagnostic ionizing radiation, including computerized tomography (CT) scans, is associated with increased risk of adult glioma. While no independent association was observed for CT scans alone (3+ scans compared to none P = 0.08 and 1-2 scans compared to none P = 0.68), our findings suggest an increased risk of adult gliomas with cumulative exposure to three or more CT scans to the head and neck region (OR = 1.97, 95% CI: 0.92-4.23) limited to those who reported a family history of cancer: the P value for the interaction between having three or more CT scans and family history of cancer was 0.08. The stratum-specific adjusted OR for those with family history of cancer was more than three times that for the sub-group without family history of cancer. While there is some potential for symptom-related bias, one might expect this to be present for all diagnostic procedures rather than specific to one procedure. The interaction between CT scans and glioma with family history of cancer supports the biological plausibility of our findings, because similar results have been found for breast cancer and radiation. This observational data will increase awareness about potential risks associated with CT scans and the need to minimize the use of unnecessary examinations.     

Supervoltage Radiation Therapy—Use of the Linear Accelerator for Treating Ovarian Adenocarcinoma

In a study of patients treated thus far by supervoltage radiation from the Stanford linear accelerator, the following conclusions were reached:Homogenous radiation in doses of 4,000 rads may be delivered to the upper abdomen and 5,500 rads to the lower abdomen and pelvis for the treatment of ovarian cancer by the proper utilization of modern super-voltage radiation sources.Patients with Stage 2 and Stage 3 lesions are best treated by total hysterectomy and bilateral salpingo-oophorectomy followed by total pelvic irradiation.Stage 4 disease was seldom controlled by high dose radiation therapy to the entire peritoneal cavity.An unusual histologic pattern has been found in the liver of three patients who died three to nine months after 4,000 to 5,000 rads had been given in a period of five or six weeks.     

Treatment of Advanced Tumours of Head and Neck with Fast Neutrons

Fast neutrons interact with matter in a different way from x and gamma rays. They have been used at Hammersmith Hospital for the past four years in the treatment of advanced tumours in several sites of the body, and the results of this treatment in the first 100 cases of tumours of the head and neck are described here. Altogether 62 patients who had been referred for fast neutron therapy because it was thought that no other treatment would be effective experienced complete regression of the tumours, and only two recurred. Tumours of the buccal cavity and salivary glands responded particularly well and the relief of pain and ulceration was striking. Side effects were not serious and did not differ from those seen with supervoltage radiation, apart from the reaction of the skin. Follow-up was short, however, owing to deaths from metastases, and out of 76 patients treated more than one year previously only 30 survived. Cases which have not metastasized must therefore be treated so that the effects on tumours and adjacent normal tissues can be observed for several years after treatment. The results obtained so far indicate that it is now justifiable to use neutrons in such cases.     

Molecular mechanisms of radiation carcinogenesis and the linear, non-threshold dose response model of radiation risk estimation

Recent research in molecular radiation carcinogenesis is reviewed with the specific aim of exploring the implications this research may have on the dose response relationship of radiation-induced cancer at low doses and low dose rates. It is concluded that the linear non-threshold dose response hypothesis may be used in radiation protection planning as a simple, convenient method to optimize procedures and regulations, but should not be mistaken as a stringent scientific conclusion directly derived from the present state of knowledge of the processes involved in radiation carcinogenesis.     

Immunological approach in the diagnosis, therapy and prognosis of the exocrine pancreatic cancer

The aim of the paper is to outline the most important up-to-date methods regarding the immunological approach in the diagnosis, treatment and prognosis of the exocrine pancreatic cancer, keeping in mind that this localisation of neoplastic disease represents the 5th cause of cancer-related death and especially, an important cause of morbidity. This disease, diagnosed in the past in later stages, being therefore associated with poor results, has turned to be characterized by increasing survival rates due to the improvements in diagnostic and therapeutic methods. Regarding the diagnosis strategy, progress was made in imagistic sphera, aiming: 1. an early diagnosis of pancreatic cancer and, implicitly, a high resectability rate of tumor, and 2. an evaluation of the timing for palliative therapeutic methods. So that, if in the past the diagnostic algorithm meant endoscopic retrograde-cholangio-pancreatography, computed tomography and angiography, at present it means nuclear magnetic resonance and helicoidal tomography. Concerning the treatment, it has to be multidisciplinary (surgery, radiotherapy, chemotherapy, immunotherapy), complex, because, after a resection for cure (R0), the main stay of the treatment, the mean survival at 5 years is 3%-28% and the rate of recurrences is 33%-80%. Biological therapy (sometimes called immunotherapy, biotherapy or biological response modifier therapy) is a relatively new addition to the family of cancer treatments that also includes surgery, chemotherapy and radiation therapy. Biological therapies are designed to repair, stimulate or enhance the immune system responses. We shall try to point out how the exocrine pancreatic cancers, the same stages and undergoing the same approaches, have had different responses due to a different biological behavior and how the biological response modifiers (interferons, interleukins, colony-stimulating factors, monoclonal antibodies and vaccines) can improve the results in pancreatic cancer.     

Molecular targeting in radiotherapy: epidermal growth factor receptor

Radiation therapy is utilized as a treatment to cure or manage cancer; however, because of risk to local healthy tissue-and a modest success rate of some radiotherapy-strategies have been sought that would increase the therapeutic index of the treatment while reducing damage to surrounding tissue. Cell and tissue irradiation stimulates a series of biochemical and molecular signals; various components of this ionizing radiation (IR)-inducible signal transduction cascade can promote the survival of tumor cells. Identification of interactions between IR and a signaling pathway creates an opportunity to target those signaling intermediates to improve the outcome of radiotherapy. The epidermal growth factor receptor (EGFR, also termed ErbB1) is involved in normal development and differentiation of epithelial cells as well as in tumorigenesis. The EGFR is activated by IR, thus making this receptor and other members of the ErbB family important targets for radiosensitizing molecular interventions. Recent approaches have utilized monoclonal antibodies, small molecules, and transgenic technologies to undermine the kinase activity of EGFR.     

Breast cancer 2004: Progress and promise on the clinical front

Carcinoma of the breast is the most common cancer in u.s. women (excluding skin cancer), and the second leading cause of cancer-related mortality. In 2004, it is estimated that 215,000 u.s. women will develop invasive breast cancer, and 40,000 women will die of the disease. Advancing age and female sex are the two greatest risk factors for the development of breast cancer, although family history, reproductive and hormonal history, lifestyle and environmental factors all contribute to risk. Models are available to help estimate risk of developing breast cancer in individual patients. Inherited mutations, specifically in the genes BRCA1 and BRCA2, account for approximately 5–10% of all breast cancer cases. Significant advances have recently been made in both the primary prevention of breast cancer (including chemoprevention), and secondary prevention (early detection through breast imaging). Breast mri as a tool for screening high risk women is a particularly exciting new tool.When breast cancer is diagnosed, optimal treatment involves a multidisciplinary approach, including surgery, radiation therapy, and systemic therapies. In the field of breast surgery, breast conservation and sentinel lymph node biopsy techniques have allowed substantially decreased surgery in appropriated selected patients with corresponding decreases in complication rates and long-term sequelae. Radiation oncologists are comparing partial breast irradiation versus conventional whole breast radiation in an attempt to minimize toxicity and treatment time, and maximize efficacy. The field of breast medical oncology has evolved at a rapid pace in the past decade, with numerous new hormonal agents, chemotherapeutic agents, and biologically targeted therapies in clinical use and under investigation. The addition of ‘adjuvant’ systemic therapy to the treatment of early stage breast cancer patients has dramatically reduced relapse and death rates. Unfortunately, metastatic recurrence still occurs. Once the cancer has spread beyond the breast and locoregional nodal areas it is felt to be incurable, although still treatable. A better understanding of breast cancer biology has led to the development of a host of new biologically targeted agents, many of which hold substantial promise for improving quality of life and survival rates in metastatic breast cancer patients.     

Serum markers in small cell lung cancer: Opportunities for improvement

Lung cancer is one of the leading causes of death from malignancy worldwide. In particular small cell lung cancers, which comprise about 15–20% of all lung cancers, are extremely aggressive and cure rates are extremely low. Therefore, new treatment modalities are needed and detection at an early stage of disease, as well as adequate monitoring of treatment response is essential in order to improve outcome. In this respect, the use of non-invasive tools for screening and monitoring has gained increasing interest and the clinical applicability of reliable, tumor-related substances that can be detected as tumor markers in easily accessible body fluids is subject of intense investigation. Some of these indicators, such as high LDH levels in serum as a reflection of the disease, have been in use for a long time as a general tumor marker. To allow for improved monitoring of the efficacy of new therapeutic modalities and for accurate subtyping, there is a strong need for specific and sensitive markers that are more directly related to the biology and behavior of small cell lung cancer. In this review the current status of these potential markers, like CEA, NSE, ProGRP, CK-BB, SCC, CgA, NCAM and several cytokeratins will be critically analyzed with respect to their performance in blood based assays. Based on known cleavage sites for cytoplasmic and extracellular proteases, a prediction of stable fragments can be obtained and used for optimal test design. Furthermore, insight into the synthesis of specific splice variants and neo-epitopes resulting from protein modification and cleavage, offers further opportunities for improvement of tumor assays.     

Management of radiation necrosis and advanced cancer of the chest wall in patients with breast malignancy.

Aggressive resection, with individualized reconstruction by several methods, is of value in many patients with radiation necrosis and/or advanced breast cancer of the chest wall. Although this does not always significantly lengthen survival, it can improve the quality of life markedly in many instances. Remarkably large defects can be reconstructed with single-stage procedures.     

Moving cancer diagnostics from bench to bedside

To improve treatment and reduce the mortality from cancer, a key task is to detect the disease as early as possible. To achieve this, many new technologies have been developed for biomarker discovery and validation. This review provides an overview of omics technologies in biomarker discovery and cancer detection, and highlights recent applications and future trends in cancer diagnostics. Although the present omic methods are not ready for immediate clinical use as diagnostic tools, it can be envisaged that simple, fast, robust, portable and cost-effective clinical diagnosis systems could be available in near future, for home and bedside use.     

Radiations and female fertility

Hundreds of thousands of young women are diagnosed with cancer each year, and due to recent advances in screening programs, diagnostic methods and treatment options, survival rates have significantly improved. Radiation therapy plays an important role in cancer treatment and in some cases it constitutes the first therapy proposed to the patient. However, ionizing radiations have a gonadotoxic action with long-term effects that include ovarian insufficiency, pubertal arrest and subsequent infertility. Cranial irradiation may lead to disruption of the hypothalamic-pituitary-gonadal axis, with consequent dysregulation of the normal hormonal secretion. The uterus might be damaged by radiotherapy, as well. In fact, exposure to radiation during childhood leads to altered uterine vascularization, decreased uterine volume and elasticity, myometrial fibrosis and necrosis, endometrial atrophy and insufficiency. As radiations have a relevant impact on reproductive potential, fertility preservation procedures should be carried out before and/or during anticancer treatments. Fertility preservation strategies have been employed for some years now and have recently been diversified thanks to advances in reproductive biology. Aim of this paper is to give an overview of the various effects of radiotherapy on female reproductive function and to describe the current fertility preservation options.     

Roentgen therapy for infections: an historical review.

Radiation was used extensively for the treatment of all types of infections before the advent of antibiotics. Although this mode of therapy is now in disrepute, radiation therapists of that era were firm believers in the ability of radiation to cure infections. A review of the literature suggests, but certainly does not prove, that low-dose local radiation, in the range of 75 to 300 roentgens, is an effective treatment modality for a wide variety of infections. Two then-prevailing rationales held that the effect was due either to radiation damage to the immune cells, causing stimulation of the immune response, or to the increase in local inflammation with resultant increased blood flow. Modern research has been limited but provides support for both arguments. Although there are no present indications for using radiation as therapy for infectious disease, a reasonable argument can be made from the available data that radiation is effective for the treatment of localized infections. The mechanisms of low-dose radiation as a treatment for infections remain unclear. The known and probable long-term sequelae of low-dose local irradiation preclude its common use for this condition. Nevertheless, it is hoped that this review will stimulate investigations into this relatively unexplored area of radiobiology.     

Oral Contraceptives and Female Mortality Trends

Death rates for Ontario females aged 15 to 44 during the years 1959-61 and 1966-68 have been compared to see if there have been any changes in these rates which might be related to the widespread use of oral contraceptives since 1961. Overall mortality (all causes) has declined significantly during this time, as have the rates for deaths due to child-birth and pregnancy, and from cancer of the uterus. Death rates from ischemic heart disease and cancer of the breast have not shown any significant change, but there has been a substantial increase in the rates ascribed to venous thromboembolism and suicide.It must be stressed that a change in the recorded death rate does not necessarily mean that there has been a corresponding change in the incidence of the disease in question, or that such a change is related to the use of oral contraceptives. However, if oral contraceptives do cause an increase in a fatal disease, the effect should show up, sooner or later, in routine mortality statistics, and periodic examination of death rates may therefore provide a useful starting point for more detailed epidemiological investigation.To assist physicians in counselling patients, a diagram has been prepared showing the relative importance of some selected causes of death in females aged 15 to 44, and the extent to which these death rates have changed since the introduction of oral contraceptives.     

Dual Functional Mesoporous Silicon Nanoparticles Enhance the Radiosensitivity of VPA in Glioblastoma

Radiotherapy is a critical strategy and standard adjuvant approach to glioblastoma treatment. One of the major challenges facing radiotherapy is to minimize radiation damage to normal tissue without compromising therapeutic effects on cancer cells. Various agents and numerous approaches have been developed to improve the therapeutic index of radiotherapy. Among them, radiosensitizers have attracted much attention because they selectively increase susceptibility of cancer cells to radiation and thus enhance biological effectiveness of radiotherapy. However, clinical translation of radiosensitizers has been severely limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this hindrance. In this study, a dual functional mesoporous silica nanoparticle (MSN) formulation of the valproic acid (VPA) radiosensitizer was developed, which specifically recognized folic acid–overexpressing cancer cells and released VPA conditionally in acidic turmeric microenvironment. The efficacy of this targeted and pH-responsive VPA nanocarrier was evaluated as compared to VPA treatment approach in two cell lines: rat glioma cells C6 and human glioma U87. Compared to VPA treatment, targeted VPA-MSNs not only potentiated the toxic effects of radiation and led to a higher rate of cell death but also enhanced inhibition on clonogenic assay. More interestingly, these effects were further accentuated by VPA-MSNs at low pH values. Western blot analysis showed that the effects were mediated via enhanced apoptosis-inducing effects. Our results suggest that the adjunctive use of VPA-MSNs may enhance the effectiveness of radiotherapy in glioma treatment by lowering the radiation doses required to kill cancer cells and thereby minimize collateral damage to healthy adjacent tissue.     

Thematic Review Series: Calorie Restriction and Ketogenic Diets: The ketogenic diet for the treatment of malignant glioma

Advances in our understanding of glioma biology has led to an increase in targeted therapies in preclinical and clinical trials; however, cellular heterogeneity often precludes the targeted molecules from being found on all glioma cells, thus reducing the efficacy of these treatments. In contrast, one trait shared by virtually all tumor cells is altered (dysregulated) metabolism. Tumor cells have an increased reliance on glucose, suggesting that treatments affecting cellular metabolism may be an effective method to improve current therapies. Indeed, metabolism has been a focus of cancer research in the last few years, as many pathways long associated with tumor growth have been found to intersect metabolic pathways in the cell. The ketogenic diet (high fat, low carbohydrate and protein), caloric restriction, and fasting all cause a metabolic change, specifically, a reduction in blood glucose and an increase in blood ketones. We, and others, have demonstrated that these metabolic changes improve survival in animal models of malignant gliomas and can potentiate the anti-tumor effect of chemotherapies and radiation treatment. In this review we discuss the use of metabolic alteration for the treatment of malignant brain tumors.