Aaron Laine

Key role for neutrophils in radiation-induced antitumor immune responses: Potentiation with G-CSF

Significance The role of tumor-associated neutrophils (TANs) in cancer progression versus regression remains controversial. TANs are known to have dichotomous antitumor (N1) and protumor (N2) phenotypes depending on the tumor microenvironment. Past studies have demonstrated that TANs are polarized from an N2 to an N1 phenotype in the absence of TGF-β; N1 TANs are not induced in the absence of IFN-β. Our study demonstrates that radiation therapy (RT) and, especially, the combination of RT and granulocyte colony-stimulating factor (G-CSF) induces the polarization of N1 TANs [RT-recruited TANs (RT-Ns)]. Reactive oxygen species produced by RT-Ns damage tumor tissues in a manner analogous to the manner in which neutrophils affect damaged normal tissues. Our studies suggest that enhancing the activity of TANs during RT improves its antitumor activity. Radiation therapy (RT), a major modality for treating localized tumors, can induce tumor regression outside the radiation field through an abscopal effect that is thought to involve the immune system. Our studies were designed to understand the early immunological effects of RT in the tumor microenvironment using several syngeneic mouse tumor models. We observed that RT induced sterile inflammation with a rapid and transient infiltration of CD11b+Gr-1high+ neutrophils into the tumors. RT-recruited tumor-associated neutrophils (RT-Ns) exhibited an increased production of reactive oxygen species and induced apoptosis of tumor cells. Tumor infiltration of RT-Ns resulted in sterile inflammation and, eventually, the activation of tumor-specific cytotoxic T cells, their recruitment into the tumor site, and tumor regression. Finally, the concurrent administration of granulocyte colony-stimulating factor (G-CSF) enhanced RT-mediated antitumor activity by activating RT-Ns. Our results suggest that the combination of RT and G-CSF should be further evaluated in preclinical and clinical settings.

The Role of Inflammatory Pathways in Cancer-Associated Cachexia and Radiation Resistance

Dysregulated inflammatory responses are key contributors to a multitude of chronic ailments, including cancer. Evidence indicates that disease progression in cancer is dependent on the complex interaction between the tumor and the host microenvironment. Most recently, the inflammatory response has been suggested to be critical, as both the tumor and microenvironment compartments produce cytokines that act on numerous target sites, where they foster a complex cascade of biologic outcomes. Patients with cancer-associated cachexia (CAC) suffer from a dramatic loss of skeletal muscle and adipose tissue, ultimately precluding them from many forms of therapeutic intervention, including radiotherapy. The cytokines that have been linked to the promotion of the cachectic response may also participate in radiation resistance. The major changes at the cytokine level are, in part, due to transcriptional regulatory alterations possibly due to epigenetic modifications. Herein we discuss the role of inflammatory pathways in CAC and examine the potential link between cachexia induction and radiation resistance. Mol Cancer Res; 11(9); 967–72. ©2013 AACR.

Radiation Therapy as a Backbone of Treatment of Locally Advanced Non-Small Cell Lung Cancer

Locally advanced non-small cell lung cancer (LA-NSCLC) is a heterogeneous disease, encompassing stage IIIA, for which surgery in combination with chemotherapy and/or radiation therapy (RT) represents a potential treatment approach for select patients, and stage IIIB, for which chemoradiation represents the standard of care. Recent advances in systemic cytotoxic and molecularly targeted therapies coupled with technologic innovations in radiotherapy have the potential to improve outcomes for this patient population. Many ongoing clinical trials use specific genetic mutations or histologic status to determine the combination of targeted therapies and RT, as well as to determine the optimal chemoradiotherapy platforms. Additionally, use of modern RT techniques has improved outcomes for some patients with limited metastatic disease, thereby prompting further studies on how to best integrate aggressive management of oligometastases using RT with chemotherapeutic regimens.

The Role of Hypofractionated Radiation Therapy with Photons, Protons, and Heavy Ions for Treating Extracranial Lesions.

Traditionally, the ability to deliver large doses of ionizing radiation to a tumor has been limited by radiation-induced toxicity to normal surrounding tissues. This was the initial impetus for the development of conventionally fractionated radiation therapy, where large volumes of healthy tissue received radiation and were allowed the time to repair the radiation damage. However, advances in radiation delivery techniques and image guidance have allowed for more ablative doses of radiation to be delivered in a very accurate, conformal, and safe manner with shortened fractionation schemes. Hypofractionated regimens with photons have already transformed how certain tumor types are treated with radiation therapy. Additionally, hypofractionation is able to deliver a complete course of ablative radiation therapy over a shorter period of time compared to conventional fractionation regimens making treatment more convenient to the patient and potentially more cost-effective. Recently, there has been an increased interest in proton therapy because of the potential further improvement in dose distributions achievable due to their unique physical characteristics. Furthermore, with heavier ions the dose conformality is increased and, in addition, there is potentially a higher biological effectiveness compared to protons and photons. Due to the properties mentioned above, charged particle therapy has already become an attractive modality to further investigate the role of hypofractionation in the treatment of various tumors. This review will discuss the rationale and evolution of hypofractionated radiation therapy, the reported clinical success with initially photon and then charged particle modalities, and further potential implementation into treatment regimens going forward.

Dosimetric comparison of rectal-sparing capabilities of rectal balloon vs injectable spacer gel in stereotactic body radiation therapy for prostate cancer: Lessons learned from prospective trials

This study aimed to compare the rectal-sparing capabilities of rectal balloons vs absorbable injectable spacer gel in stereotactic body radiation therapy (SBRT) for prostate cancer. Patient samples included in this analysis were obtained from 2 multi-institutional prospective trials of SBRT for prostate cancer using a rectal balloon (n = 36 patients) and injectable spacer gel (n = 36). Treatment prescription dose was 45 Gy in 5 fractions in 42 patients; for equal comparison, the remaining 30 patients were rescaled to 45 Gy from 47.5 Gy prescription (n = 6) and 50 Gy prescription (n = 24). The median prostate volumes and body mass index in the 2 patient samples were not statistically significantly different (p= 0.67 and 0.45, respectively), supporting anatomic similarity between cohorts. The injectable spacer gel achieved dosimetric superiority over the rectal balloon with respect to the maximum dose to the rectum (42.3 vs 46.2 Gy, p < 0.001), dose delivered to 33% of the rectal circumference (28 vs 35.1 Gy, p < 0.001), and absolute volume of rectum receiving 45 Gy (V45Gy), V40Gy, and V30Gy (0.3 vs 1.7 cc, 1 vs 5.4 cc, and 4.1 vs 9.6 cc, respectively; p < 0.001 in all cases). There was no difference between the 2 groups with respect to the V50Gy of the rectum or the dose to 50% of the rectal circumference (p= 0.29 and 0.06, respectively). The V18.3Gy of the bladder was significantly larger with the rectal balloon (19.9 vs 14.5 cc, p= 0.003). In this analysis of patients enrolled on 2 consecutive multi-institutional prospective trials of SBRT for prostate cancer, the injectable spacer gel outperformed the rectal balloon in the majority of the examined and relevant dosimetric rectal-sparing parameters. The rectal balloon did not outperform the injectable spacer gel in any measured rectal dose parameter.

Natural history of 'second' biochemical failure after salvage radiation therapy for prostate cancer: A multi-institution study

To describe the natural history of prostate cancer in men who experience a second biochemical recurrence (BCR) after salvage radiotherapy (SRT) after prostatectomy.

Anatomical patterns of recurrence following biochemical relapse after post‐prostatectomy salvage radiation therapy: a multi‐institutional study

To characterise the frequency and detailed anatomical sites of failure for patients receiving post‐radical prostatectomy (RP) salvage radiation therapy (SRT).

International Symposium on Ion Therapy: Planning the First Hospital-Based Heavy Ion Therapy Center in the United States

Investigation into the use of heavy ions for therapeutic purposes was initially pioneered at Lawrence Berkeley National Laboratory in the 1970s [1, 2]. More recently, however, significant advances in determining the safety and efficacy of using heavy ions in the hospital setting have been reported in Japan and Germany [3, 4]. These promising results have helped to resurrect interest in the establishment of hospital-based heavy ion therapy in the United States. In line with these efforts, world experts in the field of heavy ion therapy were invited to attend the first annual International Symposium on Ion Therapy, which was held at the University of Texas Southwestern Medical Center, Dallas, Texas, from November 12 to 14, 2014. A brief overview of the results and discussions that took place during the symposium are presented in this article.

Safety and efficacy of concurrent immune checkpoint inhibitors and hypofractionated body radiotherapy

ABSTRACT Integration of hypofractionated body radiotherapy (H-RT) into immune checkpoint inhibitor (ICI) therapy may be a promising strategy to improve the outcomes of ICIs, although sufficient data is lacking regarding the safety and efficacy of this regimen. We, hereby, reviewed the safety and efficacy of this combination in 59 patients treated with H-RT during or within 8 weeks of ICI infusion and compared results with historical reports of ICI treatment alone. Most patients had RCC or melanoma. Median follow-up was 11 months. Most patients received either Nivolumab alone or with Ipilimumab; 83% received stereotactic RT and 17% received conformal H-RT. Any grade adverse events (AEs) were reported in 46 patients, and grade 3–4 in 12 patients without any treatment-related grade 5 toxicity. The most common grade 3 AEs were fatigue and pneumonitis. Grade 3–4 toxicities were higher with ICI combination and with simultaneous ICIs. Overall, most any-grade or grade ≥3 AE rates did not differ significantly from historically reported rates with single-agent or multi-agent ICIs. Toxicity did not correlate with H-RT site, dose, fraction number, tumor type, or ICI and H-RT sequencing. Median progression-free survival was 6.5 months. Objective response rate (ORR) was 26%; 10% had complete response (CR). Median duration of response was 9.4 ± 4.6 months. H-RT of lung lesions was more likely to achieve CR than other sites. H-RT of bone lesions had a lower ORR than non-bone H-RT. In conclusion, combining body H-RT with ICIs is safe and promising. Prospective validation is warranted.

Stereotactic Body Radiation Therapy (SBRT) or Alternative Fractionation Schedules

The use of hypofractionated regimens for the treatment of tumors with radiation has come full circle. After the discovery of X-rays and their utilization for cancer treatment, the initial fractionation schemes were primarily hypofractionated in nature. However, due to technical limitations and associated toxicities, more protracted fractionated regimens eventually became the foundation for modern radiation therapy. With the advance of imaging and radiation delivery systems, interest in more hypofractionated approaches was revived. Stereotactic ablative radiation therapy (SABR; also referred as stereotactic body radiation therapy, SBRT) is the most abbreviated form of hypofractionation, typically utilizing 1–5 fractions for treatment. Its strengths include high rates of tumor control via a convenient, noninvasive outpatient procedure. Toxicities related to high, ablative radiation doses still are a potential concern; however, recent clinical trials for a variety of tumor sites have shown good outcomes in properly selected patients. This chapter will discuss the potential for SBRT/SABR to improve the therapeutic response. The use of SBRT/SABR regimens to treat lesions within the lung, liver, spine, and prostate will be reviewed. Due to more mature data in regard to the safety and efficacy, cost-effectiveness of the treatment, and potential for immunomodulatory effects, SBRT/SABR has become more wildly utilized in cancer treatment.