Seminars in Radiation Oncology最新文献

Radiotherapy elicits dose- and lineage-dependent effects on immune cell survival, migration, activation, and proliferation in targeted tumor microenvironments. Radiation also stimulates phenotypic changes that modulate the immune susceptibility of tumor cells. This has raised interest in using radiotherapy to promote greater response to immunotherapies. To clarify the potential of such combinations, it is critical to understand how best to administer radiation therapy to achieve activation of desired immunologic mechanisms. In considering the multifaceted process of priming and propagating anti-tumor immune response, radiation dose heterogeneity emerges as a potential means for simultaneously engaging diverse dose-dependent effects in a single tumor environment. Recent work in spatially fractionated external beam radiation therapy demonstrates the expansive immune responses achievable when a range of high to low dose radiation is delivered in a tumor. Brachytherapy and radiopharmaceutical therapies deliver inherently heterogeneous distributions of radiation that may contribute to immunogenicity. This review evaluates the interplay of radiation dose and anti-tumor immune response and explores emerging methodological approaches for investigating the effects of heterogeneous dose distribution on immune responses.

FLASH radiotherapy (RT) is emerging as a potentially revolutionary advancement in cancer treatment, offering the potential to deliver RT at ultra-high dose rates (>40 Gy/s) while significantly reducing damage to healthy tissues. Democratizing FLASH RT by making this cutting-edge approach more accessible and affordable for healthcare systems worldwide would have a substantial impact in global health. Here, we review recent developments in FLASH RT and present perspective on further developments that could facilitate the democratizing of FLASH RT. These include upgrading and validating current technologies that can deliver and measure the FLASH radiation dose with high accuracy and precision, establishing a deeper mechanistic understanding of the FLASH effect, and optimizing dose delivery conditions and parameters for different types of tumors and normal tissues, such as the dose rate, dose fractionation, and beam quality for high efficacy. Furthermore, we examine the potential for democratizing FLASH radioimmunotherapy leveraging evidence that FLASH RT can make the tumor microenvironment more immunogenic, and parallel developments in nanomedicine or use of smart radiotherapy biomaterials for combining RT and immunotherapy. We conclude that the democratization of FLASH radiotherapy represents a major opportunity for concerted cross-disciplinary research collaborations with potential for tremendous impact in reducing radiotherapy disparities and extending the cancer moonshot globally.

Treating radioresistant and bulky tumors is challenging due to their inherent resistance to standard therapies and their large size. GRID and lattice spatially fractionated radiation therapy (simply referred to GRID RT and LRT) offer promising techniques to tackle these issues. Both approaches deliver radiation in a grid-like or lattice pattern, creating high-dose peaks surrounded by low-dose valleys. This pattern enables the destruction of significant portions of the tumor while sparing healthy tissue. GRID RT uses a 2-dimensional pattern of high-dose peaks (15-20 Gy), while LRT delivers a three-dimensional array of high-dose vertices (10-20 Gy) spaced 2-5 cm apart. These techniques are beneficial for treating a variety of cancers, including soft tissue sarcomas, osteosarcomas, renal cell carcinoma, melanoma, gastrointestinal stromal tumors (GISTs), pancreatic cancer, glioblastoma, and hepatocellular carcinoma. The specific grid and lattice patterns must be carefully tailored for each cancer type to maximize the peak-to-valley dose ratio while protecting critical organs and minimizing collateral damage. For gynecologic cancers, the treatment plan should align with the international consensus guidelines, incorporating concurrent chemotherapy for optimal outcomes. Despite the challenges of precise dosimetry and patient selection, GRID RT and LRT can be cost-effective using existing radiation equipment, including particle therapy systems, to deliver targeted high-dose radiation peaks. This phased approach of partial high-dose induction radiation therapy with standard fractionated radiation therapy maximizes immune modulation and tumor control while reducing toxicity. Comprehensive treatment plans using these advanced techniques offer a valuable framework for radiation oncologists, ensuring safe and effective delivery of therapy for radioresistant and bulky tumors. Further clinical trials data and standardized guidelines will refine these strategies, helping expand access to innovative cancer treatments.

Despite the promise of combining immunotherapy and radiotherapy (RT) for metastatic cancers, existing randomized data have not been consistent on whether RT to a single irradiated site improves clinical outcomes. Mechanistically, this could result from a low quantity/diversity of tumor antigens released for immune detection, immunosuppressive molecules released by tumor masses, and the lack of immune infiltration into tumor bulk. Herein, multi-site RT is discussed as a potential solution, given that it can directly improve upon each of the mechanistic issues. Just as it is illogical to use systemic therapy alone in place of a dedicated local therapeutic option (e.g., RT) for most stage II-III malignancies, so too is illogical to irradiate one site only in case of metastatic neoplasms instead of implementing systemic therapy and/or multi-site RT. Although it may theoretically be possible to address all systemic disease with systemic therapy, that notion assumes that all areas of systemic disease will be responsive to systemic therapy in the first place. However, in reality, certain sites may develop innate or acquired resistance to systemic therapy, hence opening the door to multi-site localized treatment strategies. Further investigation is required to address whether multi-site RT would be effective in the setting of suboptimal immune function and/or resistance/refractoriness to multiple prior systemic therapies. Methods to improve the effectiveness of multi-site RT are also discussed, such as ablatively-/definitively-dosed RT, along with staggered timing of RT administration (pulsed RT).

Spatially fractionated radiotherapy (SFRT) includes historical grid therapy approaches but more recently encompasses the controlled introduction of one or more cold dose regions using intensity modulation delivery techniques. The driving hypothesis behind SFRT is that it may allow for an increased immune response that is otherwise suppressed by radiation effects. With both two- and three-dimensional SFRT approaches, SFRT dose distributions typically include multiple dose cold spots or valleys. Despite its unconventional methods, reported clinical experience shows that SFRT can sometimes induce marked tumor regressions, even in patients with large hypoxic tumors. Preclinical models using extreme dose distributions (i.e., half-sparing) have been shown to nevertheless result in full tumor eradications, a more robust immune response, and systemic anti-tumor immunity. SFRT takes advantage of the complementary immunomodulatory features of low- and high-dose radiotherapy to integrate the delivery of both into a single target. Clinical trials using three-dimensional SFRT (i.e., lattice-like dose distributions) have reported both promising tumor and toxicity results, and ongoing clinical trials are investigating synergy between SFRT and immunotherapies.

Spatially fractionated radiation therapy (SFRT), also known as the GRID and LATTICE radiotherapy (GRT, LRT), the concept of treating tumors by delivering a spatially modulated dose with highly non-uniform dose distributions, is a treatment modality of growing interest in radiation oncology, physics, and radiation biology. Clinical experience in SFRT has suggested that GRID and LATTICE therapy can achieve a high response and low toxicity in the treatment of refractory and bulky tumors. Limited initially to GRID therapy using block collimators, advanced, and versatile multi-leaf collimators, volumetric modulated arc technologies and particle therapy have since increased the capabilities and individualization of SFRT and expanded the clinical investigation of SFRT to various dosing regimens, multiple malignancies, tumor types and sites. As a 3D modulation approach outgrown from traditional 2D GRID, LATTICE therapy aims to reconfigure the traditional SFRT as spatial modulation of the radiation is confined solely to the tumor volume. The distinctively different beam geometries used in LATTICE therapy have led to appreciable variations in dose-volume distributions, compared to GRID therapy. The clinical relevance of the variations in dose-volume distribution between LATTICE and traditional GRID therapies is a crucial factor in determining their adoption in clinical practice. In this Point-Counterpoint contribution, the authors debate the pros and cons of GRID and LATTICE therapy. Both modalities have been used in clinics and their applicability and optimal use have been discussed in this article.

A large proportion of cancer patients present with unresectable bulky disease at baseline or following treatment failure. The data available in the literature suggest that the vast majority of these patients do not benefit from available standard therapies. Therefore the clinical outcomes are poor; patients are desperate and usually relegated to palliative or best supportive care as the only options. Large tumor masses are usually hypoxic, resistant to radiation and systemic therapy, with extensive regional infiltration of the surrounding critical organs, the presence of which makes it impossible to deliver a radical dose of radiation. Promising data in terms of improved therapeutic ratio where such complex tumors are concerned can be seen with the use of new emerging unconventional radiotherapy techniques known as spatially fractionated radiotherapies (SFRT). One of them is PATHY, or PArtial Tumor irradiation targeting HYpoxic segment, which is characterized by a very short treatment course offering a large spectrum of therapeutic benefits in terms of the symptom relief, quality of life, local tumor control, neoadjuvant and immunomodulatory effects.

Extremity and truncal soft tissue sarcomas are a heterogeneous group of rare cancers that arise from mesenchymal tissues. Hence, the adoption of tailored risk assessment and prognostication tools plays a crucial role in optimizing the decision-making for which of the many possible treatment strategies to select. Management of these tumors requires a multidisciplinary strategy, which has seen significant development in recent decades. Surgery has emerged as the primary treatment approach, with the main goal of achieving microscopic negative tumor margins. To reduce the likelihood of local recurrence, loco-regional treatments such as radiation therapy and isolated limb perfusion are often added to the treatment regimen in combination with surgery. This approach also enables surgeons to perform limb-sparing surgery, particularly in cases where a positive tumor margin is expected. Chemotherapy may also provide a further benefit in decreasing the probability of local recurrence or reducing distant metastasis in selected patients. Selecting the optimal treatment strategy for these rare tumors is best accomplished by an experienced multi-disciplinary team.

Immunotherapy has shifted the treatment paradigm for many types of cancer. Unfortunately, the most commonly used immunotherapies, such as immune checkpoint inhibitors (ICI), have yielded limited benefit for most types of soft tissue sarcoma (STS). Radiotherapy (RT) is a mainstay of sarcoma therapy and can induce immune modulatory effects. Combining immunotherapy and RT in STS may be a promising strategy to improve sarcoma response to RT and increase the efficacy of immunotherapy. Most combination strategies have employed immunotherapies, such as ICI, that derepress immune suppressive networks. These have yielded only modest results, possibly due to the limited immune stimulatory effects of RT. Combining RT with immune stimulatory agents has yielded promising preclinical and clinical results but can be limited by the toxic nature of systemic administration of immune stimulants. Using intralesional immune stimulants may generate stronger RT immune modulation and less systemic toxicity, which may be a feasible strategy in accessible tumors such as STS. In this review, we summarize the immune modulatory effects of RT, the mechanism of action of various immune stimulants, including toll-like receptor agonists, and data for combinatorial strategies utilizing these agents.

This critical review aims to summarize the relevant published data regarding hypofractionation regimens for preoperative radiation therapy (RT) prior to surgery for soft tissue sarcoma (STS) of the extremity or superficial trunk. We identified peer-reviewed publications using a PubMed search on the MeSH headings of “soft tissue sarcoma” AND “hypofractionated radiation therapy.” To obtain complication data on similar anatomical radiotherapeutic scenarios we also searched “hypofractionated radiation therapy” AND “melanoma” as well as “hypofractionated radiation therapy” AND “breast cancer.” We then used reference lists from relevant articles to obtain additional pertinent publications. We also incorporated relevant abstracts presented at international sarcoma meetings and relevant clinical trials as listed on the ClinicalTrials.gov website. Detailed data are presented and contextualized for ultra-hypofractionated and moderately hypofractionated regimens with respect to local control, wound complications, and amputation rates. Comparative data are also presented for late toxicities including: fibrosis, joint limitation, edema, skin integrity, and bone fracture or necrosis. These data are compared to a standard regimen of 50 Gy in 25 daily fractions delivered over 5 weeks. This analysis supports the continued use of a standard regimen for preoperative RT for STS of 25 × 2 Gy over 5 weeks without concurrent chemotherapy. Use of concurrent chemotherapy with preoperative RT for STS should be reserved for well-designed clinical trials. A randomized trial of ultra-hypofractionated and moderately hypofractionated pre op RT for STS is warranted, but it is critical for the primary endpoint (or co-primary endpoint) to be late toxicity to: bone, soft tissue, joint, and skin.