Radium-223 in the treatment of osteoblastic metastases: a critical clinical review.

The element radium (Ra) was discovered by the Curies in 1898 and within a decade was in broad scientific testing for the management of several forms of cancer. The compound was known to give rise to a series of both high-energy particulate and penetrating γ-emissions. The latter found an important role in early 20th century brachytherapy applications, but the short-range α-particles seemed much less useful. Although highly cytotoxic when released within a few cell diameters of critical cell nuclei, the dense double-strand break damage was poorly repaired, and concerns regarding treatment-related toxicities and secondary malignancies halted clinical development. Moreover, the most common isotope of Ra has an exceptionally long half-life (>1600 years for (226)Ra) that proved daunting when aiming for a systemic cancer therapy. Fortunately, other radium isotopes have more convenient half-lives while still producing cytotoxic α particles. Radium-223 dichloride has a half-life of 11.4 days, and this isotope was identified as an excellent candidate for radionuclide therapy of cancers metastatic to bone. The calcium-mimetic chemical properties of the radium allowed intravenous infusion with rapid uptake to sites of new bone formation. The highly efficient bone localization suggested a potential therapeutic role for osteoblastic bone metastases, and a series of phase 1, 2, and 3 clinical trials was undertaken to explore this possibility. This series of clinical explorations culminated in the ALSYMPCA trial, an international, placebo-controlled, phase 3 study that accrued 921 symptomatic men with bone-metastatic, castrate-resistant prostate cancer. Results of this trial demonstrated a prolongation of overall survival, and regulatory agencies around the world have now approved this product as a treatment for advanced prostate cancer.

Surface levels of CD20 determine anti-CD20 antibodies mediated cell death in vitro.

BACKGROUND: The sensitivity of human Burkitt's lymphoma cells to rituximab (Rtx) and tositumomab (Tst) was assessed on cells expressing different levels of CD20 on surface. Cells that harbor low CD20 levels may resists against therapeutics response to CD20-specific antibodies. We postulated that, radiation-induced modulation of CD20 surface levels may play a crucial and central role in determining the relative efficacy of rituximab and tositumomab in treating Burkitt's lymphoma disease. Here, we examined the γ-radiation-induced CD20 expression in the Burkitt lymphoma cell line 'Daudi' and the relation of differential levels of CD20 with anti-CD20 mAbs mediated cell death. METHODOLOGY: In this study we examined kinetics of CD20 expression following sub lethal doses ofγ-radiation to Daudi cells and thereafter anti-CD20 mAbs (rituximab and tositumomab) were added in cell suspensions. The correlation of kinetics of CD20 expression and cells treated with anti-CD20 mAbs/or corresponding isotype Abs with special reference to changes in mitochondrial membrane potential and reactive oxygen species generation was also examined. Further, we also investigated the efficacy of anti-CD20 mAbs and possible induction of cell death in relation to levels of CD20 cell surface expression. CONCLUSION: This report provides evidence that CD20 expression can be induced by exposure of cells to γ-radiation. In addition, these findings demonstrated that the efficacy of anti-CD20 mAbs is dependent on the surface levels of CD20. Based on these findings, we hypothesized (i) irradiation just prior to immunotherapy may provide new treatment options even in aggressive B cell tumors, which are resistant to current therapies in vivo (ii) The efficacy of induction of apoptosis varies with type of monoclonal antibodies in vitro.

Clinical characteristics of 95 patients with ocular adnexal and uveal lymphoma: treatment outcomes in extranodal marginal zone subtype.

BACKGROUND: Lymphoma rarely presents in the ocular adnexa but is usually extranodal marginal zone (ENMZ) lymphoma when it does. Involved-field radiotherapy (IFRT) is the standard of care for unilateral disease, but the optimal management of more extensive disease is unclear. PATIENTS AND METHODS: We retrospectively evaluated the clinical characteristics and outcomes of 95 patients with ocular adnexal lymphoma (OAL) or uveal lymphoma treated or diagnosed at our institution. All patients identified were included in the risk factor analysis for progression-free survival (PFS). The initial treatment-related outcomes were assessed for ENMZ OAL only (n = 62). RESULTS: With a median follow-up of 32 months, significant risk factors for PFS after initial treatment were age (hazard ratio, 1.33; 95% confidence interval, 1.02-1.74), female gender (hazard ratio, 2.04; 95% confidence interval, 1.04-4.00), and a history of lymphoma (hazard ratio, 2.31; 95% confidence interval, 1.12-4.78). In ENMZ, IFRT was associated with improved PFS (median, 5.4 years; P < .001). Progression occurred in 7 of 39 (23%), with 6 of the 7 (86%) at systemic sites. Single-agent rituximab was typically used for bilateral ocular or systemic presentations of ENMZ OAL. Progression occurred in 7 of 11 (64%), with no progression at systemic sites. All progression events in those initially treated with rituximab occurred in the ocular adnexa. CONCLUSION: The results of the present study have confirmed IFRT as the standard for unilateral ENMZ OAL. Single-agent rituximab was an effective agent for bilateral ocular or systemic ENMZ OAL, particularly for systemic control, but ocular progression should be closely monitored. Combined modality therapy should be studied further in bilateral and systemic ENMZ OAL.

Overview of accountable care organizations for oncology specialists.

Accountable care organizations (ACOs) are poised to become major components of health care delivery in the United States. The practice of oncology, often laden with high charges, is likely to undergo major shifts as ACOs become widespread. In this article, we review the economic factors leading to the growth of ACOs and discuss some elements of the current ACO model proposed in the Affordable Care Act. Oncology specialists-in medicine, surgery, and radiation oncology-will have important roles in determining the place of specialty care in an ACO framework and will have to take the lead in educating patients, primary care physicians, and administrators on the value propositions related to their activities. We also describe how oncology specialists may participate in the model to ensure success for physicians and patients.

Introduction to radiotherapy and standard teletherapy techniques.

Radiation was first discovered in the late 19th century by Wilhelm Roentgen and has since been used extensively to treat a variety of cancers. Over the last century, we have developed an extensive understanding of the physical properties of radiation as well as radiation biology. Technological advances in the last few decades in medical imaging and radiotherapy delivery have led to the development of highly complex radiation delivery systems such as intensity modulated radiotherapy, which can be utilized to conformally treat complex tumor shapes while minimizing radiation dose to the surrounding normal tissue. To completely appreciate the application of radiotherapy for ophthalmic cancers, it is important to have a basic understanding of radiation therapy. In this chapter, we will discuss the fundamentals of radiation and radioactive decay, the mechanism of tumor cell damage leading to tumor cell apoptosis, as well as radiation and treatment parameters that are relevant for an ophthalmic oncologist. We will also discuss the concept of tissue tolerance which is of critical importance when prescribing radiation treatment as well as introduce the principles of three-dimensional conformal radiotherapy and intensity modulated radiotherapy.

Brachytherapy.

Brachytherapy is the preferred radiation treatment modality for various intraocular tumors, most commonly, uveal melanoma. Radioactive sources are placed directly onto or around the tumor with the aid of episcleral plaques, whereby the employed sources exhibit an extremely sharp fall-off of dosage outside the few millimeters around the tumor. With such high focality, radiation dose to vision critical structures is minimized. Various sources have been used over the years, with iodine-125 being the most common. This chapter will highlight the history of brachytherapy for the treatment of intraocular tumors, current practice including isotopes and plaques utilized, as well as a comprehensive treatment planning and physics review.

Teletherapy: advanced techniques.

Radiotherapy has been utilized as a treatment for ophthalmologic processes for more than one hundred years. Over this century, the field of ophthalmologic oncology has been revolutionized through medical discoveries, development of novel surgical interventions, and innovation of advanced radiotherapy techniques. In this chapter, novel radiotherapy techniques are considered. Material presented will build on basic radiation therapy principles, techniques, and treatment parameters established in the previous chapter through consideration of intensity modulated radiotherapy, stereotactic radiotherapy, and heavy ion therapy. Deliberation of matters common across advanced radiotherapy techniques including target delineation, treatment planning, and requisites for ensuring accurate, precise treatment delivery will precede discussion of advanced radiotherapy techniques as applied to the management ophthalmologic malignancies.

Radiation therapy: orbital tumors.

Orbital tumors are rare overall, comprising 0.1% of all tumors and less than 20% of all orbital diseases. Tumors may be benign, locally aggressive, or malignant. Of the malignant tumors, lymphomas and metastases are the most common and are primarily seen in the elderly population. While surgery and chemotherapeutic agents are often employed in the management of these lesions, not all patients are candidates for these therapies. Radiation therapy offers a noninvasive, well-tolerated primary treatment modality, whereby vision-sparing is feasible in many cases. In this chapter, we review an array of non-neoplastic entities and orbital tumors, for which there exists a role for radiation, and the radiotherapeutic techniques and applications in their management.

Dosimetric benefit of a new ophthalmic radiation plaque.

PURPOSE: To determine whether the computed dosimetry of a new ophthalmic plaque, EP917, when compared with the standard Collaborative Ocular Melanoma Study (COMS) plaques, could reduce radiation exposure to vision critical structures of the eye. METHODS AND MATERIALS: One hundred consecutive patients with uveal melanoma treated with COMS radiation plaques between 2007 and 2010 were included in this study. These treatment plans were generated with the use of Bebig Plaque Simulator treatment-planning software, both for COMS plaques and for EP917 plaques using I-125. Dose distributions were calculated for a prescription of 85 Gy to the tumor apex. Doses to the optic disc, opposite retina, lens, and macula were obtained, and differences between the 2 groups were analyzed by standard parametric methods. RESULTS: When compared with the COMS plaques, the EP917 plaques used fewer radiation seeds by an average difference of 1.94 (P<.001; 95% confidence interval [CI], -2.8 to -1.06) and required less total strength of radiation sources by an average of 17.74 U (air kerma units) (P<.001; 95% CI, -20.16 to -15.32). The total radiation doses delivered to the optic disc, opposite retina, and macula were significantly less by 4.57 Gy, 0.50 Gy, and 11.18 Gy, respectively, with the EP917 plaques vs the COMS plaques. CONCLUSION: EP917 plaques deliver less overall radiation exposure to critical vision structures than COMS treatment plaques while still delivering the same total therapeutic dose to the tumor.

Plaque brachytherapy for uveal melanoma: a vision prognostication model.

PURPOSE: To generate a vision prognostication model after plaque brachytherapy for uveal melanoma. METHODS AND MATERIALS: All patients with primary single ciliary body or choroidal melanoma treated with iodine-125 or ruthenium-106 plaque brachytherapy between January 1, 2005, and June 30, 2010, were included. The primary endpoint was loss of visual acuity. Only patients with initial visual acuity better than or equal to 20/50 were used to evaluate visual acuity worse than 20/50 at the end of the study, and only patients with initial visual acuity better than or equal to 20/200 were used to evaluate visual acuity worse than 20/200 at the end of the study. Factors analyzed were sex, age, cataracts, diabetes, tumor size (basal dimension and apical height), tumor location, and radiation dose to the tumor apex, fovea, and optic disc. Univariate and multivariable Cox proportional hazards were used to determine the influence of baseline patient factors on vision loss. Kaplan-Meier curves (log rank analysis) were used to estimate freedom from vision loss. RESULTS: Of 189 patients, 92% (174) were alive as of February 1, 2011. At presentation, visual acuity was better than or equal to 20/50 and better than or equal to 20/200 in 108 and 173 patients, respectively. Of these patients, 44.4% (48) had post-treatment visual acuity of worse than 20/50 and 25.4% (44) had post-treatment visual acuity worse than 20/200. By multivariable analysis, increased age (hazard ratio [HR] of 1.01 [1.00-1.03], P=.05), increase in tumor height (HR of 1.35 [1.22-1.48], P<.001), and a greater total dose to the fovea (HR of 1.01 [1.00-1.01], P<.001) were predictive of vision loss. This information was used to develop a nomogram predictive of vision loss. CONCLUSIONS: By providing a means to predict vision loss at 3 years after treatment, our vision prognostication model can be an important tool for patient selection and treatment counseling.

Impact of postmastectomy radiation on locoregional recurrence in breast cancer patients with 1-3 positive lymph nodes treated with modern systemic therapy.

PURPOSE: Postmastectomy radiation therapy (PMRT) remains controversial for patients with 1-3 positive lymph nodes (LN+). METHODS AND MATERIALS: We conducted a retrospective review of all 369 breast cancer patients with 1-3 LN+ who underwent mastectomy without neoadjuvant systemic therapy between 2000 and 2007 at Cleveland Clinic. RESULTS: We identified 271 patients with 1-3 LN+ who did not receive PMRT and 98 who did receive PMRT. The median follow-up time was 5.2 years, and the median number of LN dissected was 11. Of those not treated with PMRT, 79% received adjuvant chemotherapy (of whom 70% received a taxane), 79% received hormonal therapy, and 5% had no systemic therapy. Of the Her2/neu amplified tumors, 42% received trastuzumab. The 5-year rate of locoregional recurrence (LRR) was 8.9% without PMRT vs 0% with PMRT (P=.004). For patients who did not receive PMRT, univariate analysis showed 6 risk factors significantly (P<.05) correlated with LRR: estrogen receptor/progesterone receptor negative (hazard ratio [HR] 2.6), lymphovascular invasion (HR 2.4), 2-3 LN+ (HR 2.6), nodal ratio >25% (HR 2.7), extracapsular extension (ECE) (HR 3.7), and Bloom-Richardson grade III (HR 3.1). The 5-year LRR rate was 3.4% (95% confidence interval [CI], 0.1%-6.8%] for patients with 0-1 risk factor vs 14.6% [95% CI, 8.4%-20.9%] for patients with ≥2 risk factors (P=.0006), respectively. On multivariate analysis, ECE (HR 4.3, P=.0006) and grade III (HR 3.6, P=.004) remained significant risk factors for LRR. The 5-year LRR was 4.1% in patients with neither grade III nor ECE, 8.1% with either grade III or ECE, and 50.4% in patients with both grade III and ECE (P<.0001); the corresponding 5-year distant metastasis-free survival rates were 91.8%, 85.4%, and 59.1% (P=.0004), respectively. CONCLUSIONS: PMRT offers excellent control for patients with 1-3 LN+, with no locoregional failures to date. Patients with 1-3 LN+ who have grade III disease and/or ECE should be strongly considered for PMRT.

Future of radiation therapy for malignant melanoma in an era of newer, more effective biological agents.

The incidence of melanoma is rising. The primary initial treatment for melanoma continues to be wide local excision of the primary tumor and affected lymph nodes. Exceptions to wide local excision include cases where surgical excision may be cosmetically disfiguring or associated with increased morbidity and mortality. The role of definitive or adjuvant radiotherapy has largely been relegated to palliative measures because melanoma has been viewed as a prototypical radiotherapy-resistant cancer. However, the emerging clinical and radiobiological data summarized here suggests that many types of effective radiation therapy, such as radiosurgery for melanoma brain metastases, plaque brachytherapy for uveal melanoma, intensity modulated radiotherapy for melanoma of the head and neck, and adjuvant radiotherapy for selected high-risk, node-positive patients can improve outcomes. Similarly, although certain chemotherapeutic agents and biologics have shown limited responses, long-term control for unresectable tumors or disseminated metastatic disease has been rather disappointing. Recently, several powerful new biologics and treatment combinations have yielded new hope for this patient group. The recent identification of several clinically linked melanoma gene mutations involved in mitogen-activated protein kinase (MAPK) pathway such as BRAF, NRAS, and cKIT has breathed new life into the drive to develop more effective therapies. Some of these new therapeutic approaches relate to DNA damage repair inhibitors, cellular immune system activation, and pharmacological cell cycle checkpoint manipulation. Others relate to the investigation of more effective targeting and dosing schedules for underutilized therapeutics, such as radiotherapy. This paper summarizes some of these new findings and attempts to give some context to the renaissance in melanoma therapeutics and the potential role for multimodality regimens, which include certain types of radiotherapy as aids to locoregional control in sensitive tissues.

ACR-ASTRO practice guideline for the performance of therapy with unsealed radiopharmaceutical sources.

This guideline is intended to guide appropriately trained and licensed physicians performing therapy with unsealed radiopharmaceutical sources. Adherence to this guideline should help to maximize the efficacious use of these procedures, maintain safe conditions, and ensure compliance with applicable regulations. The topics dealt with in this guideline include indications for the use of iodine-131, both for the treatment of hyperthyroidism and thyroid carcinoma. In addition, indications for other less common procedures include those for the use of phosphorous-32 in its liquid and colloidal forms, strontium-89, samarium-153, and the use of Y-90 antibodies.

Treatment recommendations for radioimmunotherapy in follicular lymphoma: a consensus conference report.

Radioimmunotherapy (RIT) with (90)Y-ibritumomab tiuxetan or (131)I-tositumomab combines a radiation-emitting radionuclide with an antibody targeting CD20 to treat B-cell non-Hodgkin lymphoma. Multiple studies demonstrate favorable RIT efficacy and safety profiles in follicular lymphoma (FL). The primary toxicity is reversible myelosuppression. Various FL treatment options include single-agent immunotherapy, radiation, chemoimmunotherapy, and RIT. Examining RIT clinical effects and position within treatment algorithms is important to optimal patient benefit. Clinical studies support using single-agent RIT in relapsed/refractory FL, in selected patients with new, untreated FL, and as consolidation after induction chemotherapy or chemoimmunotherapy. RIT as consolidation enhances response rates (with conversion of partial to complete responses following induction therapy) and prolongs disease control versus observation. The overall response rate is 60-80% in the relapsed setting. Time to progression is longer with low-bulk disease, fewer prior therapies, and retained rituximab sensitivity. RIT apparently does not preclude subsequent therapies or increase risk of secondary malignancies compared with chemotherapy's known risk. This article summarizes consensus recommendations for RIT and presents RIT treatment algorithms developed by hematologists/oncologists who regularly treat patients with FL. Maximizing RIT benefit requires healthcare providers to utilize algorithms assisting with treatment decisions.

The evolving role of radiation therapy in the management of malignant melanoma.

The incidence of melanoma is rising in the United States, leading to an estimated 68,720 new diagnoses and 8,650 deaths annually. The natural history involves metastases to lymph nodes, lung, liver, brain, and often to other sites. Primary treatment for melanoma is surgical excision of the primary tumor and affected lymph nodes. The role of adjuvant or definitive radiation therapy in the treatment of melanoma remains controversial, because melanoma has traditionally been viewed as a prototypical radioresistant cancer. However, recent studies suggest that under certain clinical circumstances, there may be a significant role for radiation therapy in melanoma treatment. Stereotactic radiosurgery for brain metastases has shown effective local control. High dose per fraction radiation therapy has been associated with a lower rate of locoregional recurrence of sinonasal melanoma. Plaque brachytherapy has evolved into a promising alternative to enucleation at the expense of moderate reduction in visual acuity. Adjuvant radiation therapy following lymphadenectomy in node-positive melanoma prevents local and regional recurrence. The newer clinical data along with emerging radiobiological data indicate that radiotherapy is likely to play a greater role in melanoma management and should be considered as a treatment option.

Convergence technology in cancer medicine.

The field of convergence technology may be defined as an area of technologic innovation in which multiple devices or functionalities are combined within a single platform in a way that adds functional, operational or economic synergies. Within the field of medical devices, this concept embodies many different types of novel combinations representing syntheses of therapeutic, diagnostic and digital information technologies. In the current era of healthcare reform, such combinatorial technologies will be pressed to demonstrate improvements in comparative effectiveness compared with the use of separate independent components. Moreover, the new more stringent regulatory environment will require much greater levels of pre- and post-market safety reviews conducted under the auspices and authority of the US FDA Office of Combination Products. This branch of the FDA scrutinizes submissions and divides them into drugs, devices and biological products and includes many submissions previously regulated by disparate centers, such as the Center for Devices and Radiologic Health and the Center for Drug Evaluation and Research. The field of convergence technologies already amounts to a worldwide market extending to tens of billions of dollars and this article will attempt to summarize some of the key elements of this continued push for added value and more personalized medicine.

The Role of Functional Imaging in Radiotherapy Planning and Management for Gynecologic Malignancies.

In addition to allowing much greater technical precision, the modern era allows investigation of target physiology and it is the potential incorporation of physiologic information into the treatment-planning rubric that gives modern PET-CT its allure and promise. Although oncologic PET scanning has been clinically available for more than 10 years, it is only recently that sufficient investigative and retrospective data have become available to confidently assert that future radiotherapy treatment planning will include functional imaging as an obligatory dimension of clinical characterization for most gynecologic tumors. This article explores the role of functional imaging in radiotherapy planning and management of gynecologic malignancies.