Surveying the Challenges to Improve Linear Accelerator-based Radiation Therapy in Africa: a Unique Collaborative Platform of All 28 African Countries Offering Such Treatment.

Radiation therapy is a critical component for curative and palliative treatment of cancer and is used in more than half of all patients with cancer. Yet there is a global shortage of access to this treatment, especially in Sub-Saharan Africa, where there is a shortage of technical staff as well as equipment. Linear accelerators (LINACs) offer state-of-the-art treatment, but this technology is expensive to acquire, operate and service, especially for low- and middle-income countries (LMICs), and often their harsh environment negatively affects the performance of LINACs, causing downtime. A global initiative was launched in 2016 to address the technology and system barriers to providing radiation therapy in LMICs through the development of a novel LINAC-based radiation therapy system designed for their challenging environments. As the LINAC prototype design phase progressed, it was recognised that additional information was needed from LMICs on the performance of LINAC components, on variables that may influence machine performance and their association, if any, with equipment downtime. Thus, a survey was developed to collect these data from all countries in Africa that have LINAC-based radiation therapy facilities. In order to understand the extent to which these performance factors are the same or different in high-income countries, facilities in Canada, Switzerland, the UK and the USA were invited to participate in the survey, as was Jordan, a middle-income country. Throughout this process, LMIC representatives have provided input on technology challenges in their respective countries. This report presents the method used to conduct this multilevel study of the macro- and microenvironments, the organisation of departments, the technology, the training and the service models that will provide input into the design of a LINAC prototype for a LINAC-based radiation therapy system that will improve access to radiation therapy and thus improve cancer treatment outcomes. It is important to note that new technology should be introduced in a contextual manner so as not to disrupt existing health systems inadvertently, especially with regards to existing staffing, infrastructure and socioeconomic issues. A detailed analysis of data is underway and will be presented in a follow-up report. Selected preliminary results of the study are the observation that LINAC-based facilities in LMICs experience downtime associated with failures in multileaf collimators and vacuum pumps, as well as power instability. Also, that there is a strong association of gross national product per capita with the number of LINACs per population.

Mobilising Expertise and Resources to Close the Radiotherapy Gap in Cancer Care.

Closing the gap in cancer care within low- and middle-income countries and in indigenous and geographically isolated populations in high-income countries requires investment and innovation. This is particularly true for radiotherapy, for which the global disparity is one of the largest in healthcare today. New models and paradigms and non-traditional collaborations have been proposed to improve global equity in cancer control. We describe recent initiatives from within the radiation oncology community to increase access to treatment, build the low- and middle-income countries' radiation oncology workforce, mobilise more professionals from within high-income countries and raise awareness of the global need for equitable cancer care.

Public health oncology: a framework for progress in low- and middle-income countries.

BACKGROUND: The problems of cancer are increasing in low- and middle-income countries (LMCs), which now have significant majorities of the global case and mortality burdens. The professional oncology community is being increasingly called upon to define pragmatic and realistic approaches to these problems. PATIENTS AND METHODS: Focusing on mortality and case burden outcomes defines public health oncology or population-affecting cancer medicine. We use this focus to consider practical approaches. RESULTS: The greatest cancer burdens are in Asia. A public health oncology perspective mandates: first, addressing the major and social challenges of cancer medicine for populations: human rights, health systems, corruption, and our limited knowledge base for value-conscious interventions. Second, adoption of evolving concepts and models for sustainable development in LMCs. Third, clear and realistic statements of action and inaction affecting populations, grounded in our best cancer science, and attention to these. Finally, framing the goals and challenges for population-affecting cancer medicine requires a change in paradigm from historical top-down models of technology transfer, to one which is community-grounded and local-evidence based. CONCLUSION: Public health oncology perspectives define clear focus for much needed research on country-specific practical approaches to cancer control.

Normal tissue protection for improving radiotherapy: Where are the Gaps?

Any tumor could be controlled by radiation therapy if sufficient dose were delivered to all tumor cells. Although technological advances in physical treatment delivery have been developed to allow more radiation dose conformity, normal tissues are invariably included in any radiation field within the tumor volume and also as part of the exit and entrance doses relevant for particle therapy. Mechanisms of normal tissue injury and related biomarkers are now being investigated, facilitating the discovery and development of a next generation of radiation protectors and mitigators. Bringing recent research advances stimulated by development of radiation countermeasures for mass casualties, to clinical cancer care requires understanding the impact of protectors and mitigators on tumor response. These may include treatments that modify cellular damage and death processes, inflammation, alteration of normal flora, wound healing, tissue regeneration and others, specifically to counter cancer site-specific adverse effects to improve outcome of radiation therapy. Such advances in knowledge of tissue and organ biology, mechanisms of injury, development of predictive biomarkers and mechanisms of radioprotection have re-energized the field of normal tissue protection and mitigation. Since various factors, including organ sensitivity to radiation, cellular turnover rate, and differences in mechanisms of injury manifestation and damage response vary among tissues, successful development of radioprotectors/mitigators/treatments may require multiple approaches to address cancer site specific needs. In this review, we discuss examples of important adverse effects of radiotherapy (acute and intermediate to late occurring, when it is delivered either alone or in conjunction with chemotherapy, and important limitations in the current approaches of using radioprotectors and/or mitigators for improving radiation therapy. Also, we are providing general concepts for drug development for improving radiation therapy.

Long-term survival and PSA control with radiation and immunotherapy for node positive prostate cancer.

We describe a patient with node positive prostate cancer treated with radiation, androgen deprivation, and immunotherapy with long-term overall survival and PSA control. ELISPOT immunoassay studies demonstrated PSA specific T-cells prior to starting vaccine therapy suggesting that this positive response may be related to an improved antitumor immune response of the patient, increased immunogenicity of the tumor, or decreased activation of immune escape pathways. Further evaluation of therapeutic cancer vaccines in combination with radiation and hormonal therapy in the definitive management of prostate cancer is warranted.

Transcriptional responses to ionizing radiation reveal that p53R2 protects against radiation-induced mutagenesis in human lymphoblastoid cells.

The p53 protein has been implicated in multiple cellular responses related to DNA damage. Alterations in any of these cellular responses could be related to increased genomic instability. Our previous study has shown that mutations in p53 lead to hypermutability to ionizing radiation. To investigate further how p53 is involved in regulating mutational processes, we used 8K cDNA microarrays to compare the patterns of gene expression among three closely related human cell lines with different p53 status including TK6 (wild-type p53), NH32 (p53-null), and WTK1 (mutant p53). Total RNA samples were collected at 1, 3, 6, 9, and 24 h after 10 Gy gamma-irradiation. Template-based clustering analysis of the gene expression over the time course showed that 464 genes are either up or downregulated by at least twofold following radiation treatment. In addition, cluster analyses of gene expression profiles among these three cell lines revealed distinct patterns. In TK6, 165 genes were upregulated, while 36 genes were downregulated. In contrast, in WTK1 75 genes were upregulated and 12 genes were downregulated. In NH32, only 54 genes were upregulated. Furthermore, we found several genes associated with DNA repair namely p53R2, DDB2, XPC, PCNA, BTG2, and MSH2 that were highly induced in TK6 compared to WTK1 and NH32. p53R2, which is regulated by the tumor suppressor p53, is a small subunit of ribonucleotide reductase. To determine whether it is involved in radiation-induced mutagenesis, p53R2 protein was inhibited by siRNA in TK6 cells and followed by 2 Gy radiation. The background mutation frequencies at the TK locus of siRNA-transfected TK6 cells were about three times higher than those seen in TK6 cells. The mutation frequencies of siRNA-transfected TK6 cells after 2 Gy radiation were significantly higher than the irradiated TK6 cells without p53R2 knock down. These results indicate that p53R2 was induced by p53 protein and is involved in protecting against radiation-induced mutagenesis.

Workshop on partial breast irradiation: state of the art and the science, Bethesda, MD, December 8-10, 2002.

Breast conserving surgery followed by radiation therapy has been accepted as an alternative to mastectomy in the management of patients with early-stage breast cancer. Over the past decade there has been increasing interest in a variety of radiation techniques designed to treat only the portion of the breast deemed to be at high risk for local recurrence (partial-breast irradiation [PBI]) and to shorten the duration of treatment (accelerated partial-breast irradiation [APBI]). To consider issues regarding the equivalency of the various radiation therapy approaches and to address future needs for research, quality assurance, and training, the National Cancer Institute, Division of Cancer Treatment and Diagnosis, Radiation Research Program, hosted a Workshop on PBI in December 2002. Although 5- to 7-year outcome data on patients treated with PBI and APBI are now becoming available, many issues remain unresolved, including clinical and pathologic selection criteria, radiation dose and fractionation and how they relate to the standard fractionation for whole breast irradiation, appropriate target volume, local control within the untreated ipsilateral breast tissue, and overall survival. This Workshop report defines the issues in relation to PBI and APBI, recommends parameters for consideration in clinical trials and for reporting of results, serves to enhance dialogue among the advocates of the various radiation techniques, and emphasizes the importance of education and training in regard to results of PBI and APBI as they become emerging clinical treatments.

The Harvard Joint Center for Radiation Therapy, 1968-1999: a unique concept and its relationship to the prevailing times in academic medicine.

PURPOSE: Institutional structure, function, and philosophy reflect the organizational needs, and tend to mirror societal values of the times. For many years, the field of radiation oncology had among its major academic centers, an organization that served as a model for collaboration among health care institutions in an effort to serve the common good of its patients, hospitals, professional colleagues, and community. For over three decades, the Joint Center for Radiation Therapy (JCRT) was a leader in developing new organizational approaches for academic and clinical radiation oncology through the philosophy of collaboration in patient care, education, and research. METHODS AND RESULTS: In tracing the development and changes in organizational philosophy and structure of the JCRT, one can see the impact on academic oncology and cancer care through the emergence of both radiation and medical oncology as independent subspecialties, the importance of the National Cancer Act of 1971 accompanied by the growth of the NIH research and training programs and, more recently, the effect of the changing attitudes and approaches of hospitals, academicians, practitioners, and policy makers to health care delivery, structures, and cooperation. CONCLUSION: Lessons learned from the 31-year history of the JCRT may help provide organizational insight useful in guiding academic oncology and academic medical centers through periods of change.

Report of the 1997 SCAROP survey on resident training. Society of Chairmen of Academic Radiation Oncology Programs.

RATIONALE AND OBJECTIVES: Members of the Society of Chairmen of Academic Radiation Oncology Programs (SCAROP) were surveyed in November 1997 to evaluate the current status of radiation oncology training in the United States and to help determine how it should be carried out in the coming decade. MATERIALS AND METHODS: A detailed questionnaire was sent to all members of SCAROP; 68 of 82 questionnaires were returned, for a response rate of 83%. RESULTS: The responses to the survey show a serious shortage of radiation oncologists in university settings, despite an apparent surplus in private practice. Although recent changes in health care have added additional clinical responsibilities for radiation oncologists in university practices, approximately 75% of the chairpersons answering the survey continue to give their faculty protected time for research. Even with additional research and teaching responsibilities, the average radiation oncologist in university practice saw 206 patients per year in 1997, a number similar to that reported by the Patterns of Care Study for radiation oncologists overall. Approximately two-thirds of respondents believe that academic chairs should strive to have all clinical faculty members participating in research. Nevertheless, most think that basic research is better performed by dedicated researchers with PhD degrees rather than radiologists with MD degrees. Most respondents believe that the training programs adequately prepare radiation oncologists for a career in academic medicine but do not provide good training in research. Eighty-four percent agreed that resident performance on the American Board of Radiology examination should be considered in the accreditation of residency programs in radiation oncology but should not be the major criterion. CONCLUSION: There is a shortage of academic radiation oncologists in the United States despite the large number of radiation oncologists completing training. This probably is due to a variety of factors, including a relatively small pool of candidates for academic positions, increasing demands for performance from academic physicians (to see more patients, perform research, publish, write grants, and teach), and competition from the private sector for recruitment of these individuals.

Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen.

Apoptotic pathways controlled by the Rel/NF-kappaB family of transcription factors may regulate the response of cells to DNA damage. Here, we have examined the NF-kappaB status of several prostate tumor cell lines. In the androgen-independent prostate tumor cells PC-3 and DU-145, the DNA-binding activity of NF-kappaB was constitutively activated and IkappaB-alpha levels were decreased. In contrast, the androgen-sensitive prostate tumor cell line LNCaP had low levels of NF-kappaB which were upregulated following exposure to cytokines or DNA damage. The activity of the IkappaB-alpha kinase, IKKalpha, which mediates NF-kappaB activation, was also measured. In PC-3 cells, IKKalpha activity was constitutively active, whereas LNCaP cells had minimal IKKalpha activity that was activated by cytokines. The anti-inflammatory agent ibuprofen inhibited the constitutive activation of NF-kappaB and IKKalpha in PC-3 and DU-145 cells, and blocked stimulated activation of NF-kappaB in LNCaP cells. However, ibuprofen did not directly inhibit IkappaB-alpha kinase. The results demonstrate that NF-kappaB is constitutively activated in the hormone-insensitive prostate tumor cell lines PC-3 and DU-145, but not in the hormone responsive LNCaP cell line. The constitutive activation of NF-kappaB in prostate tumor cells may increase expression of anti-apoptotic proteins, thereby decreasing the effectiveness of anti-tumor therapy and contributing to the development of the malignant phenotype.

Molecular biology in radiation oncology. Radiation oncology perspective of BRCA1 and BRCA2.

The breast cancer susceptibility genes, BRCA1 and BRCA2, are used to illustrate the application of molecular biology to clinical radiation oncology. Identified by linkage analysis and cloned, the structure of the genes and the numerous mutations are determined by molecular biology techniques that examine the structure of the DNA and the proteins made by the normal and mutant alleles. Mutations in the non-transcribed portion of the gene will not be found in protein structure assays and may be important in gene function. In addition to potential deleterious mutations, normal polymorphisms of the gene will also be detected, therefore not all differences in gene sequence may represent important mutations, a finding that complicates genetic screening and counseling. The localization of the protein in the nucleus, the expression in relation to cell cycle and the association with RAD51 led to the discovery that the two BRCA genes may be involved in transcriptional regulation and DNA repair. The defect in DNA repair can increase radiosensitivity which might improve local control using breast-conserving treatment in a tumor which is homozygous for the loss of the gene (i.e., BRCA1 and BRCA2 are tumor suppressor genes). This is supported by the early reports of a high rate of local control with breast-conserving therapy. Nonetheless, this radiosensitivity theoretically may also lead to increased susceptibility to carcinogenic effects in surviving cells, a finding that might not be observed for decades. The susceptibility to radiation-induced DNA damage appears also to make the cells more sensitive to chemotherapy. Understanding the role of the normal BRCA genes in DNA repair might help define a novel mechanism for radiation sensitization by interfering with the normal gene function using a variety of molecular or biochemical therapies.

Salicylic acid and aspirin inhibit the activity of RSK2 kinase and repress RSK2-dependent transcription of cyclic AMP response element binding protein- and NF-kappa B-responsive genes.

Sodium salicylate (NaSal) and other nonsteroidal anti-inflammatory drugs (NSAIDs) coordinately inhibit the activity of NF-kappa B, activate heat shock transcription factor 1 and suppress cytokine gene expression in activated monocytes and macrophages. Because our preliminary studies indicated that these effects could be mimicked by inhibitors of signal transduction, we have studied the effects of NSAIDs on signaling molecules potentially downstream of LPS receptors in activated macrophages. Our findings indicate that ribosomal S6 kinase 2 (RSK2), a 90-kDa ribosomal S6 kinase with a critical role as an effector of the RAS-mitogen-activated protein kinase pathway and a regulator of immediate early gene transcription is a target for inhibition by the NSAIDs. NSAIDs inhibited the activity of purified RSK2 kinase in vitro and of RSK2 in mammalian cells and suppressed the phosphorylation of RSK2 substrates cAMP response element binding protein (CREB) and I-kappa B alpha in vivo. Additionally, NaSal inhibited the phosphorylation by RSK2 of CREB and I-kappa B alpha on residues crucial for their transcriptional activity in vivo and thus repressed CREB and NF-kappa B-dependent transcription. These experiments suggest that RSK2 is a target for NSAIDs in the inhibition of monocyte-specific gene expression and indicate the importance of RSK2 and related kinases in cell regulation, indicating a new area for anti-inflammatory drug discovery.