The concept of spatially fractionated radiation therapy (SFRT) was conceived over 100 years ago, first in the form of GRID, which has been applied to clinical practice since its early inception and continued to the present even with markedly improved instrumentation in radiation therapy. LATTICE radiation therapy (LRT) was introduced in 2010 as a conceptual 3D extension of GRID therapy with several uniquely different features. Since 2014, when the first patient was treated, over 150 patients with bulky tumors worldwide have received LRT. Through a brief review of the basic principles and the analysis of the collective clinical experience, a set of technical recommendations and guidelines are proposed for the clinical implementation of LRT. It is to be recognized that the current clinical practice of SFRT (GRID or LRT) is still largely based on the heuristic principles. With advancements in basic biological research and the anticipated clinical trials to systemically assess the efficacy and risk, progressively robust optimizations of the technical parameters are essential for the broader application of SFRT in clinical practice.

Although the combination of immune checkpoint blockades with high dose of radiation has indicated the potential of co-stimulatory effects, consistent clinical outcome has been yet to be demonstrated. Bulky tumors present challenges for radiation treatment to achieve high rate of tumor control due to large tumor sizes and normal tissue toxicities. As an alternative, spatially fractionated radiotherapy (SFRT) technique has been applied, in the forms of GRID or LATTICE radiation therapy (LRT), to safely treat bulky tumors. When used alone in a single or a few fractions, GRID or LRT can be best classified as palliative or tumor de-bulking treatments. Since only a small fraction of the tumor volume receive high dose in a SFRT treatment, even with the anticipated bystander effects, total tumor eradications are rare. Backed by the evidence of immune activation of high dose radiation, it is logical to postulate that the combination of High-Dose LATTICE radiation therapy (HDLRT) with immune checkpoint blockade would be effective and could subsequently lead to improved local tumor control without added toxicities, through augmenting the effects of radiation in-situ vaccine and T-cell priming. We herein present a case of non-small cell lung cancer (NSCLC) with multiple metastases. The patient received various types of palliative radiation treatments with combined chemotherapies and immunotherapies to multiple lesions. One of the metastatic lesions measuring 63.2 cc was treated with HDLRT combined with anti-PD1 immunotherapy. The metastatic mass regressed 77.84% over one month after the treatment, and had a complete local response (CR) five months after the treatment. No treatment-related side effects were observed during the follow-up exams. None of the other lesions receiving palliative treatments achieved CR. The dramatic differential outcome of this case lends support to the aforementioned postulate and prompts for further systemic clinical studies.

Lattice radiotherapy (LRT) is a novel technique of delivering heterogeneous doses of radiation to voluminous tumors not amenable to surgery. Built from the conventional two-dimensional grid, LRT utilizes the power of new technology, three-dimensional radiation allowing the delivery of higher doses of radiation to small spheres, also called vertices, inside bulky tumors while limiting exposure to surrounding healthy tissue. The main goals of the study were the evaluation of tumor response and the overall safety of LRT in this cohort of patients with bulky non-small cell lung cancer. During a seven-year period, 10 patients with non-small cell lung cancer (NSCLC), who presented with bulky, unresectable tumors, were treated using a single fraction of LRT followed by conventionally fractionated radiation. Patients received one initial LRT fraction of 18 Gy in the vertices and 3 Gy in the periphery. After the LRT, all patients continued with conventional radiation: 25 to 29 daily fractions of 1.8 Gy to 2 Gy. With a median follow-up of six months (range: one to 71 months), the mean decrease in tumor volume was 42%. The overall survival of the entire group ranged from four to 86 months (mean 22, median 16). There was no mortality related to LRT. No significant acute or chronic toxicity was noted. In this small cohort, LRT appears to be a safe and effective modality to treat bulky NSCLC. Further research is needed to establish its efficacy in the management of voluminous NSCLC.

Despite the unexpectedly high tumor responses and limited treatment-related toxicities observed with SFRT, prospective multi-institutional clinical trials of SFRT are still lacking. High variability of SFRT technologies and methods, unfamiliar complex dose and prescription concepts for heterogeneous dose and uncertainty regarding systemic therapies present major obstacles towards clinical trial development. To address these challenges, the consensus guideline reported here aimed at facilitating trial development and feasibility through a priori harmonization of treatment approach and the full range of clinical trial design parameters for SFRT trials in gynecologic cancer. Gynecologic cancers were evaluated for the status of SFRT pilot experience. A multi-disciplinary SFRT expert panel for gynecologic cancer was established to develop the consensus through formal panel review/discussions, appropriateness rank voting and public comment solicitation/review. The trial design parameters included eligibility/exclusions, endpoints, SFRT technology/technique, dose/dosimetric parameters, systemic therapies, patient evaluations, and embedded translational science. Cervical cancer was determined as the most suitable gynecologic tumor for an SFRT trial. Consensus emphasized standardization of SFRT dosimetry/physics parameters, biologic dose modeling, and specimen collection for translational/biological endpoints, which may be uniquely feasible in cervical cancer. Incorporation of brachytherapy into the SFRT regimen requires additional pre-trial pilot investigations. Specific consensus recommendations are presented and discussed.

Purpose: To report a case of large extremity soft tissue sarcoma (2933 cc), safely treated with a novel approach of interdigitating high-dose LATTICE radiation therapy (LRT) with standard radiation therapy as a neoadjuvant treatment to surgery. Patients and Methods: Four sessions of high-dose LRT were delivered in a weekly interval, interdigitated with standard radiation therapy. The LRT plan consisted of 15 high-dose vertices receiving a dose > 12 Gy per session, with 2– 3 Gy to the peripheral margin of the tumor. The patient underwent surgical excision 2 months after the new regimen of induction radiation therapy. Results and Discussion: The patient tolerated the radiation therapy regimen well. The post-operative assessment revealed a negative surgical margin and over 95% necrosis of the total tumor volume. The post-surgical wound complication was mitigated by outpatient wound care. Interdigitating multiple sessions of high-dose LATTICE radiation treatments with standard neoadjuvant radiation therapy as a neoadjuvant therapy for soft tissue sarcoma was feasible and did not incur additional toxicity in this clinical case. A phase-I/II trial will be conducted to further evaluate the toxicity and efficacy of the new treatment strategy with the intent to increase the rate of pathologic necrosis, which has been shown to positively correlate with the overall survival.

Stereotactic radiosurgery (SRS) has evolved as an accepted treatment for medication resistant trigeminal neuralgia. Initial results are very good but follow-up over three to five years shows a gradual return of pain in up to 50% of treated patients, often requiring further treatment. The results with repeat SRS using the isocentric Gamma Knife (GK) (Elekta, Stockholm, Sweden), especially in patients having initially good results, are very similar to the outcomes after the initial treatment although there is an increased risk of residual facial numbness secondary to the additional radiation dose to the trigeminal nerve. However, after 2000, non-isocentric SRS systems began to be used for treating trigeminal neuralgia including the CyberKnife (CK) (Accuray, Sunnyvale, California) as well as various linear accelerator (LINAC) based systems. This report specifically examines a series of recurrent trigeminal cases treated by the same group of physicians with the CK system. Similar doses and locations on the trigeminal nerve and/or the root entry zone were used for both initial and repeat SRS treatment regardless of system used. Although there are numerous series reporting the use of GK for recurrent treatment for recurrent trigeminal neuralgia, there are no series reviewing the results and long-term effectiveness using CK for repeat SRS for recurrent trigeminal pain. We reviewed 23 cases that had initial treatment for trigeminal neuralgia either surgically or with SRS with either the GK or CK and then a later second procedure only with CK. The follow-up after the second CK SRS ranged from three to 13 years found that the results are very similar to the multiple reports in the literature describing second or third SRS treatments with the GK. Results of repeat radiosurgery treatment of recurrent trigeminal neuralgia appear to be independent of the system used and are primarily based on proper target and dose to the trigeminal nerve.