
==== Front
Adv Radiat Oncol
Adv Radiat Oncol
Advances in Radiation Oncology
2452-1094
Elsevier

S2452-1094(24)00129-5
10.1016/j.adro.2024.101566
101566
Scientific Article
Time-Related Outcome Following Palliative Spatially Fractionated Stereotactic Radiation Therapy (Lattice) of Large Tumors – A Case Series
Studer Gabriela MD gabriela.studer@luks.ch
⁎
Jeller David
Streller Tino PhD
Huebner Dirk
Glanzmann Christoph MD
Radiation Oncology, Lucerne Cantonal University Teaching Hospital (LUKS), Lucerne, Switzerland
⁎ Corresponding author: Gabriela Studer, MD gabriela.studer@luks.ch
09 7 2024
9 2024
09 7 2024
9 9 10156630 9 2023
8 6 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Purpose

Lattice radiation therapy (LRT), a form of spatially fractionated radiation therapy, holds promise for treating large tumors. Despite its introduction in clinical practice around 2010, there remains limited information on its time-related outcomes despite consistently high response rates and tolerability. We assessed the time-related outcome of our palliative LRT cohort.

Methods and Materials

We conducted an analysis of our LRT program, which involved 45 palliative patients with 56 lesions larger than 7 cm, treated between January 2022 and November 2023. Prospectively defined treatment protocols included delivering 20 to 25 Gy/5 fractions to the tumor with a stereotactic simultaneously integrated boost (SIB) of 60 to 65 Gy to lattice vertices (n = 45/56) or, mainly in preirradiated lesions, single fraction stereotaxy with 1 × 15 to 20 Gy to vertices only (n = 11/56). Follow-up (FU) intervals were determined based on clinical considerations, considering the mostly highly palliative situation of included patients. Outcome assessments focused on subjective benefit and objective radiologic FU response.

Results

The mean/median FU was 5.5/4.0 months (0.3-21 months). A total of 25/45 (56%) patients died after a mean/median of 3.9/2.0 months (0.3-14 months). Fourteen of 56 lesions (25%) were previously irradiated, with a mean/median of 18/13 months (4-72 months) prior to LRT. The mean/median gross tumor volume (GTV) measured 797/415 cc (54-4027 cc) and 14/13 cm (7-28 cm). Subjective statements at LRT completion were available from 37 symptomatic patients: 32/37 (87%) reported fast symptom relief, and 5/37 felt no change under LRT or at LRT completion. Early tolerance was excellent (G0-1). FU imaging was available from 40/56 lesions (71%): progression in 3/40 at first exam one at 1.5 and 4 months post-LRT, and stable disease (±10%) in 5/40 assessed at 2, 3, 3, and 4 months post-LRT. First measure shrinkage of 48%/30% (10%-100%) was found in 32/40 lesions (80%) after a mean/median of 2.8/3 months (0.3-7 months). Maximum shrinkage over time based on 21 cases with at least 1 FU imaging measured a mean/median of 62%/60% after 6.2/5.5 months. The duration of radiologic response was a mean/median of 7.4/7.0 months (1-21 months).

Conclusions

Short-course LRT emerged as an effective and well-tolerated palliative option for very large lesions, whether treatment-naïve or previously irradiated. Nearly 90% of symptomatic patients reported significant subjective benefit, and 80% of assessed lesions demonstrated tumor shrinkage ≥10%, with a mean response duration of >6 months.
==== Body
pmcIntroduction

In recent years, there has been a significant increase in awareness and publications related to spatially fractionated radiation therapy (SFRT).1, 2, 3 One promising form of SFRT, known as lattice radiation therapy (LRT), has primarily been used to treat patients with large, inoperable, or metastatic tumors.4 Initial clinical reports on LRT, dating back to around 2010, mostly in palliative care settings, consistently demonstrate unexpectedly high tumor responses and excellent treatment tolerance. Over the past 13 years, data from more than 250 patients with bulky tumors treated with LRT have been published. However, many questions about optimal dose volume, fractionation, and geometric solutions remain unanswered, and several experimental approaches are currently being explored.

A recent systematic review by Iori et al5 in 2023 summarizes clinical results from 81 patients (84 lesions) across 12 selected articles published between September 2015 and September 2022, including case reports, case series, and clinical studies with image-based follow-up (FU) ranging from 1 to 10 months. The authors reported a median lesion reduction of approximately 50% or more when a complete response was not achieved within 3 to 6 months after LRT. An overview of phase 1 LRT trials and case reports (searched in PubMed and Google) is presented in Table 1.6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 Wu et al, in their 2020 paper25, mentioned that since its introduction in 2010, over 150 patients with late-stage bulky tumors have received LRT, primarily at 2 centers: the Innovative Cancer Institute in Miami, Florida, and Fujian Union Hospital in Fuzhou, China.6Table 1 Selected phase 1 trials/case reports/cohort reports (PubMed, Google, July 2023)

Table 1Author<	Publication (Y)	Interval	Type	No. patients	No. lesions	Intention	Schedules	Diagnosis, inclusion	FU	Result	>1 FU imaging (CT, MRI, PET-CT)	
Pollack et al26*
NCT01411319
LEAD	2020	December 2011 to December 2014	Phase 1 trial	25	25	Definitive	Sequential 1 × 12-14 + 76/38 fractions	Prostate	Mean, 66 mo	No G3	-	
Duriseti et al 7 NCT04133415/04553471
LITE SABR M1	2022	October 2019 to August 2020	Phase 1 trial	20	22	12 palliative
5 palliative-progr
3 definitive	SIB 20/66.77 y in 5 fractions	4.5 cm, any (9 sarcoma, 7 NSCLC,
4 carcinoma	NR	47.4% shrinkage at 1 and 4.5 mo in 13 and 11 out of 22 patients, no G3	-	
Larrea et al8
Valencia protocol	2022	December 2019-? (abstract)	Phase 1 trial	21	21	Palliative	1 × 15-18 Gy + RT 2-3.5 Gy/fractions	>45 cc, 1 sarcoma, 20 carcinoma	NR	>50% shrinkage in 9/9 patients 2 wk post LRT	-	
Ferini et al9
Lattice_01 multicenter	2022	June 2020 to December 2021	Phase 1 trial	30	31	Palliative	1 × >10 Gy-27 in 3 fractions, sequential 20/4 fractions-40/15 fractions homogeneous	>5 cm, stage IV bulky, 5 sarcoma,
3 melanoma, 18 carcinoma	Median, 11 mo (range, 6.8-20.5)	Clinical response 89%, 23% CR, symptomatic response in all	-	
Amendola et al10*	2010	-	Case report	1	1	curative	2 × 3 Gy + 20 × 1.8/2.4 Gy + CDDP + S	Cervical Ca	NR	70% shrinkage, histological. CR	-	
Blanco Suarez et al11*	2015	-	Case report	1	1	Palliative	SIB 9/27 Gy in 3 fractions + 20 fractions nRT	Mullerian ovarian tumor	4 mo	>70% shrinkage	-	
Amendola et al12*	2018	-	Case report	1	1	Curative	29 × 2 Gy + 1 × 18 Gy	SC lung	3 mo/6 y	7.5 to 2.8 cm shrinkage/2.8 cm	Yes (n = 1)	
Jiang et al13	2021	-	Case report	1	1	Palliative	1 × 20 Gy	Chest wall	7 mo	CR at 2 mo	Yes (n = 1)	
Schiff et al14	2022	-	Case report	1	1	Palliative	SIB 5 × 4/20 Gy	Endometrial M	4 d	Regression, lysis syndrome	-	
Ferini et al15, 16	2022	-	Case report	1	1	Palliative	1 × 15 Gy
sequential 10 × 3 Gy	Skin SCC M	1/4 mo	Regress/absence of pathological metabolism	Yes (n = 1)	
Dincer et al17	2022	July 8, 2021	Case report	2	2	palliative	SIB 50/30 Gy in 5 fractions	Rectal M/anal M	1/3 mo	Near CR/>50% shrinkage	-	
Larrea et al18	2022	November 2019 to September 2020	Case report	2	2	Curative	1 × 15 Gy + EBRT/CDDP/BT×	Cervical cancer > 45 cc	5 + 14 mo	CR	-	
Borzov et al19	2022	NA	Case report	3	3	Preoperative	1 × 20 Gy + 50 Gy/25 fractions	Sarcoma	NR	CR in 2/3	-	
Iori et al20	2022	-	Case report	1	1	Palliative	SIB 55/20 Gy in 5 fractions	Sarcomatoid lung cancer	3/6 mo	19 × 16 cm to 8 × 4 cm/stable	Yes (n = 1)	
Montero et al21	2023	-	Case report	1	1	Palliative	1 × 20 Gy GRID + 50 Gy/25 fractions + pembrolizumab	Melanoma	2 and 5/12 mo	>75% shrinkage and CR	Yes (n = 1)	
Hatoum et al22	2023	-	Case report	1	1	Preoperative	4 × 1 × >12 Gy/wk + standard 50 Gy	Sarcoma	NR	>95% necrosis, wound complications	-	
Price et al23	2023	-	Case report	2	2	Palliative	SIB 20/66.7 Gy in 5 fractions	Sarcoma and carcinoma	3 mo	88% and 15% shrinkage	-	
Amendola et al28*	2019	7 y	Cohort	10	10	Curative	1 × 18 plus 50 nRT/25-33 fractions	NSCLC	Mean, 10 mo
(range, 1-73)	Mean shrinkage 42%	-	
Amendola et al24	2020	January 2013 to April 2019	Cohort	10	10	Curative	SIB 9/24 Gy/3 fractions
+ 45 Gy in 1,8 Gy + CDDP	Cervical carcinoma > 5.2 cm	2.2 mo (range, 0.2-4.5)	CR in 55%, 45 PR (mean, 63% shrinkage)
All: mean, 54% shrinkage (range, 6-91)	-	
Wu et al25
-Innovative Cancer Institute*
-Fujian Union Hospital	2020	April 2010 to July 2019
April 2017 to December 2020	Cohort
Cohort	56
69	56
69	Mostly
palliative	Vertex dose 2.4-18 Gy
Vertex dose 8-20 Gy/fraction	All > 40 cc
All > 17 cc	NR
NR	NR
NR	-	
Larrea et al6, abstract 2916]	2021	January 2020-2021	Cohort	11	11	Palliative	1 × 25 Gy + 55 Gy/20 fractions	NSCLC > 45 cc	NA	2 CR, 6 >50% shrinkage, 2 SD, 1 PD	-	
This study	2024	January 2022 to November 2023	Cohort	45	56	Palliative	20-25/9-13 in 5 fractions (45)
1 × 20 Gy vertices only (11)	Sarcoma, melanoma, carcinoma, >7 cm	5.5/4.0 mo (range, 0.5-21)	In 40/56 imaged lesions, mean/median of 48%/30% shrinkage (range, 10%-100%)	Yes (n = 21): maximum shrinkage mean/median of 60%/62%	
TOTAL	13 y			∼266	∼270	Mostly palliative						
Abbreviations: BTx = Brachytherapy; CA = carcinoma; CDDP/5-FU = Cisplatin/5-Fluorouracil chemotherapy; CR = complete response; CT = computed tomography; EBRT< = External beam radiation therapy; FU = follow-up; G3 = grade 3; LRT = lattice radiation therapy; M = Metastasis; MRI = magnetic resonance imaging; NR = not reported; nRT = normofractionated radiation therapy; NSCLC = non-small cell lung cancer; PET = positron emission tomography; PR = partial remission; RT = radiation therapy; SC = small cell; SCC = squamous cell carcinoma; SD = stable disease; SIB = simultaneously integrated boost.

⁎ : there may be some patient duplicates included.

However, knowledge regarding the long-term outcomes of LRT, including the extent and duration of its effects, remains limited. Therefore, the aim of this analysis was to evaluate the time-related clinical outcomes of our prospective single-center cohort treated with palliative LRT.

Methods and Materials

We conducted an analysis of our LRT program, which involved 45 palliative patients with 56 lesions larger than 7 cm, treated between January 2022 and November 2023. Treatment concepts and data collected were prospectively defined.

Patients

Inclusion criteria

All patients treated with LRT who were referred for palliative radiation therapy (RT) evaluation of large tumors ≥7 cm. In all cases, surgical intervention was either not feasible or not indicated, and systemic therapy was not indicated/not possible/not effective anymore.

Exclusion criteria

Patients who did not sign the Hospital General Informed Consent or the RT-specific information sheet were excluded (n = 0). Patients who were not willing (anymore) to undergo any RT or considered with terminal stage of disease with an expected life expectance of less than a few weeks were not treated. Cases with a histopathological diagnosis of Morbus Hodgkin disease (MH) or Non-Hodgkin lymphoma (NHL) were excluded.

Patient and tumor characteristics

For several of these patients with exceptionally large tumors, the omission of any palliative RT has been considered on the availability of LRT as an option. Prior to LRT, most patients had undergone one or more systemic treatments. Patient and tumor characteristics are summarized in Table 2. Clinical and radiological FU was conducted on an individualized basis, tailored to the needs of this palliative cohort. FU imaging was not performed solely for analytical purposes, resulting in incomplete radiographic FU for the cohort (40 out of 56 lesions were examined with at least 1 magnetic resonance imaging or computed tomography scan, accounting for 71% of cases), making precise time-related volumetric change analysis unfeasible.Table 2 Patient and tumor characteristics

Table 2Parameter	N	
No. patients	45	
No. treated lesions	56	
Age, mean/median (range), y	64.9/66 (18-93)	
Localization of treated lesions	• 27 abdomino-pelvic/retroperitoneal
• 8 pleuro-pulmonal
• 6 lower extremity
• 4 thoracic wall
• 2 sternal
• 5 axillary/breast
• 1 skin
• 1 upper extremity
• 2 cervical/nodal	
Histopathological diagnosis of lesions	• 24 carcinoma
• 18 sarcoma
• 14 melanoma	
Lesion size, mean/median (range)		
• Diameter	• 14/13 cm (7-28)	
• GTV	• 797/415 cc (54-4027)	
Previous local RT	14/56 lesions (25%) after a mean/median of 18/13 mo (range, 2-72)	
Systemic therapy		
• Previous ± post	• 39/56 lesions	
• During LRT	• 3/56 lesions	
• None	• 14/56 lesions	
LRT schedule		
• 5 × 4-5 Gy/9-13 Gy, simultaneous integrated boost	• N = 45	
• 1 × 20 Gy	• N = 11	
LRT characteristics, mean/median (range)		
• PTV2 whole mass (0-5 mm margin to GTV)	• 1161/777 cc (87-4460)	
• PTV1 vertices	• 5.4/3.3 cc (0.35-36.4)	
• % PTV1 of PTV2	• 0.7/0.5% (0.05%-4%)	
• No. vertices	• 8.6/5 (1-83)	
FU, mean/median (range), mo		
• All patients	• 5.5/4.0 (0.3-21)	
• Alive (n = 20/45)	• 7.5/7.5 (0.5-21)	
• Dead (n = 25/45)	• 3.9/2.0 (0.5-14)	
Abbreviations: FU = follow-up; GTV = gross tumor volume; LRT = lattice radiation therapy; PTV = planning target volume; RT = radiation therapy.

LRT

Among the various dose-volume regimens reported in the specific SFRT literature,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32 our LRT schedule was prospectively decided based on the principles outlined by Duriseti et al7 in 2020-2021 and applied in their LITE SABR M1 phase 1 trial published in 2022.7,29 Our treatment protocols included delivering 20 to 25 Gy in 5 fractions to the tumor with a stereotactic simultaneously integrated boost (SIB) of 60 to 65 Gy to lattice vertices (n = 45/56) or, mainly in preirradiated lesions, a single fraction stereotactic LRT dose with 1 × 15 to 20 Gy to vertices only (non-SIB LRT, n = 11/56).

The lattice stereotactic body radiation therapy (SBRT) prescription was formulated with the goal of delivering a standard 5-fraction palliative dose of 2000 cGy to the tumor planning target volume (PTV) 2. Traditionally, spatially fractionated techniques create a peak-valley dose gradient ranging from approximately 100% to 30%. Consequently, a simultaneous integrated boost of 6670 cGy was selected as the lattice boost dose prescription.

Additionally, especially for LRT administered to previously irradiated lesions or regions deemed at high risk within normal tissues, we adopted the approach described by Jiang et al13 and Dincer et al.17 This involved delivering a single fraction of approximately 20 Gy to the vertices exclusively.13, 17

Volumetric modulated arc therapy lattice SBRT plans were designed to provide a palliative PTV2 dose of 20 to 25 Gy in 5 fractions to the tumor mass (with or without margins). This was achieved while maintaining a peak-to-valley dose gradient of approximately 30% to 100%, resulting in a simultaneously integrated boost PTV1 prescription dose of approximately 13 Gy per fraction to the vertices. The geometric arrangement of the lattice SBRT technique employed spherical vertices with a diameter of approximately 1 to 1.5 cm and a separation distance of roughly 3 cm between vertex centers. A minimum of 2 cm distance was prescribed from PTV1 (vertices) to surrounding normal tissues. Maximum distance between vertices measured 3.2 cm (anatomic reasons).

Besides the geometric constraints, the number of maximal vertices is limited by the tumor volume and shape, the potential mobility of the mass, and the surrounding normal tissue structures. In order to minimize any risks for normal tissue damage, the placement of especially lateral vertices was based on manual edition and individual decisions. Regarding the placement of vertices in different tumor zones, ie, well-oxygenated versus transitional zones versus necrotic areas, we did not take this too much into account (yet) considering the still limited knowledge on these aspects.16

All patients received treatment according to the 2 aforementioned regimens. Volumetric modulated arc therapy was employed as the treatment technique using multiple coplanar and noncoplanar arcs to ensure an appropriate conformal dose gradient between the vertices. PTV1 vertice volumes were maintained at greater than 95% coverage with 95% of the prescribed dose, while the maximum dose remained below 120%.

Statistics

An Excel database was used for the collection and analysis of prospectively defined parameters. The VARIAN ARIA treatment planning system was used to assess tumor volumes using its automatic volume measure tool.

Ethical approval

All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Results

The mean/median FU of the entire palliative cohort was 5.5/4.0 months (0.3-21 months). Twenty-five of 45 (56%) patients passed away after a mean/median of 4.4/2.0 months (0.3-14 months) (Table 2). The mean/median gross tumor volume (GTV) measured 797/415 cc (54-4027 cc), and the tumor diameter measured a mean/median of 14/13 cm (7-28 cm).

Thirty-four of 45 patients had undergone palliative systemic therapy prior to and/or after LRT, and 14/56 lesions (25%) in 14 patients had previously been irradiated at a mean/median of 18/13 months (range, 4-72 months) prior to LRT.

Treatment tolerance

All patients completed the prescribed short-course LRT. Early side effects were limited to G0 to 1, except for 2 patients who experienced G2 to 3 dermatitis because of lesions directly affecting the skin. No late radiation-associated side effects have been observed so far.

Patient-reported outcome

Regarding subjective benefits, 5/45 patients underwent LRT for asymptomatic masses. Three patients’ post-LRT patient-reported outcome statements could not be adequately assessed, primarily because of poor general end-of-life conditions and/or simultaneous analgesic drug therapy; 5 patients did not experience early changes in symptoms at LRT completion. The remaining 32 out of 37 (87%) symptomatic patients able to provide subjective feedback reported rapid and significant symptom relief either during or immediately after LRT completion.

Objective response rate

Radiologic response

Radiologic treatment response data were available in 40 out of 56 lesions (71%). Among these, 21 lesions underwent second to fourth additional FU examinations, totaling 74 radiologic assessments. These assessments were conducted at mean/median intervals of 2.6/2.0 months, 5.1/5.0 months, 8.1/7.0 months, and 9.6/7.2 months from LRT to the first, second, third, and fourth FU, respectively. Stable disease was defined as <10% volumetric change compared with pre-LRT GTV. The following response patterns were identified:• Progression occurred in 3/40 lesions (8%), as evidenced by the first FU exam at 1, 1.5, and 4 months post-LRT.

• Stable disease was found in 5/40 lesions (11%) assessed at 2, 3, 3, and 4 months post-LRT.

• First measure tumor shrinkage of a mean/median of 48%/30% (10%-100%) was found in 32/40 lesions (80%) after a mean/median of 2.8/3 months (0.3-7 months) post-LRT. Maximum shrinkage over time measured a mean/median of 62%/60% after 6.2/5.5 months.

Figure 1 provides volumetric changes in 21 lesions with >1 FU imaging. The graph suggests poorer outcomes when shrinkage was modest in the initial FU imaging (without a specific time reference).Figure 1 Development of tumor volumes over time in 16/36 imaged lesions that underwent >1 follow-up (FU) imaging (ranking according to percentage [%] shrinkage in the first radiologic FU exam, blue bars). The red dotted line indicates the lesions with no or limited shrinkage assessed in the first FU imaging exam that showed mostly progressive disease in a second FU exam (green bars).

Figure 1

Figure 2 illustrates individual volumetric responses over time in the 21 cases with multiple FU imaging sessions. In this subgroup, the mean/median duration of treatment response, defined as either stable disease or tumor size remaining smaller than before LRT, was 7.4/7.0 months (1-21 months). The following patterns were identified:• Volumetric response appeared independent of pre-LRT tumor size; 20 lesions with smaller GTV (mean/median, 161/125 cc [54-310- cc]) versus 20 lesions with the largest GTV (mean/median, 1098/780 cc [337-2352 cc]).

• Notably, substantial LRT response was not solely reflected in shrinkage; 3 cases with former large lytic bony lesions exhibited significant recalcification as a morphological sign of response (Fig. 3A, B) despite no significant volumetric reduction.Figure 3 Six examples of morphologic responders out of 40 lesions with available follow-up imaging. (A, B) Substantial recalcification indicating treatment response despite limited volumetric shrinkage. (C-E) Substantial volumetric response.

Abbreviations: LRT = lattice radiation therapy; SIB = simultaneously-integrated boost; UPS = undifferentiated pleomorphic sarcoma;

Figure 3

• Volumetric response also appeared to vary with histopathologic diagnosis, with melanomatous lesions being less responsive compared with carcinomatous and sarcomatous lesions:- Melanoma (n = 14): mean/median GTV: 317/168 cc (66-4027 cc); mean/median shrinkage of 30%/28% (−10% to 90%) in 10/14 with radiologic FU.

- Sarcoma (n = 18): mean/median GTV: 653/420 cc (88-2105 cc); mean/median shrinkage of 46%/30% (0%-100%) in 11/16 with radiologic FU.

- Carcinoma (n = 24): mean/median GTV: 695/420 cc (141-2352 cc); mean/median shrinkage of 43%/60% (0%-93%) in 15/22 with radiologic FU.

Figure 2 Development of individual tumor volume response over time in 21 lesions with >1 follow-up imaging. The red lines indicate “negative shrinkage,” ie, progression following stable disease or following initial tumor shrinkage dots, and each dot indicates one radiologic imaging.

Figure 2

Furthermore, the volumetric response appeared comparable in previously irradiated and radiation-naïve lesions. Among the 9 out of 14 reirradiated lesions with available FU imaging, 1 displayed progression, 2 showed no change, and 6 (66%) exhibited a mean/median shrinkage of 39% (20%-72%). Forty-five of 56 lesions were treated with the 5-fraction SIB-LRT, and 11/56 with single fraction non-SIB LRT (dose to vertices only); the comparison between the 36/45 SIB-LRT lesions with available FU imaging and 4/11 lesions with FU imaging treated with a single fraction non-SIB LRT is challenging because of the imbalanced sample sizes. Among the 4 lesions irradiated with the 1-fraction schedule and having radiologic FU data so far, 1 exhibited no change, while 3 displayed shrinkage of 28%, 100%, and 100%, respectively.

Discussion

The aim of this study was to evaluate the subjective and objective tumor response over time following short-course LRT. Our findings indicate that ∼90% of symptomatic patients experienced a rapid and substantial benefit. This observation, combined with excellent treatment tolerance, suggests that LRT fits the profile of an ideal palliative therapy, especially for patients with a limited life expectancy. Objective treatment response, averaging approximately 50%, was observed in 80% of lesions as determined by FU imaging, regardless of their initial size. Notably, lesions that shrank quickly and those of sarcomatous and carcinomatous origin responded more favorably compared with melanoma lesions. The interim analysis showed a response duration of approximately 6 months in cases with multiple radiologic assessments.

However, this analysis has limitations, including a small sample size, a relatively short FU period, and a lack of direct comparisons with other LRT data or conventional palliative radiation schedules for very large lesions.

Comparisons with time-related LRT data

Existing time-related LRT data are scarce, primarily limited to a few case reports (Table 2), which, being selected cases, may not represent general response patterns. Cohort reports providing response-over-time data were not found. The observation of a rapid subjective benefit following LRT aligns with reports from other authors. With an average morphologic response duration of approximately 6 months, LRT may be suitable for patients with both short and longer life expectancies. It may also serve as an effective and safe reirradiation option, resulting in a shrinkage of approximately 40% in about two-thirds of cases. However, there is no available LRT data for preirradiated lesions. The lower responsiveness of melanomatous lesions compared with carcinoma or sarcoma may be suggestive but requires larger sample sizes for reliable conclusions. We found one case report22 and 3 melanoma cases out of 30 cases in a phase 1 trial8 with no separate diagnosis-related outcome analysis.

Comparison of shrinkage following LRT

Comparing shrinkage with the existing literature presents some challenges because of variations in the timing of assessments and imprecise reporting of methods (eg, the inclusion of all cases vs responders only, assessments at the first FU imaging, or assessments at the point of maximum response across multiple images). However, on the whole, most authors consistently report approximately a 50% shrinkage, irrespective of the cases included or treatment schedules, a trend similarly observed in our own cohort.

Regarding the available phase 1 trial (as listed in Table 1), our data align with the findings of Pollack et al6 and Duriseti et al7, indicating the absence of grade 3 side effects following LRT. Notably, Pollack et al6 reported early shrinkage of 47% in their cohort of 20 patients (excluding melanomas) with lesions measuring ≥4.5 cm, which is comparable to the ∼48% (first imaging) and ∼60% (further FU images) shrinkage observed in our cohort, where larger tumors (≥7 cm) and 1/3 melanomas were included. Furthermore, Larrea et al8 observed an early shrinkage of approximately 50% in all 9 out of 20 mainly carcinoma patients with lesions measuring ≥45 cc. Similarly, Ferini et al9 reported on 31 lesions (including 3 melanomas) larger than 5 cm with a clinical response rate of 89%, including a 23% complete response rate, and a symptomatic response observed in all cases. These findings collectively contribute to the growing body of evidence supporting the effectiveness and safety of LRT in various patient populations.

Comparison attempts with time-related non-LRT data

Comparing LRT data with palliative hypofractionated non-lattice RT schedules is challenging, as subjective responses are mostly reported and specific attention to large tumors is lacking. Different approaches to describe subjective outcomes have been reported in Table 3.32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 In general, the listed non-LRT data suggest longer treatment duration, higher doses, and, consequently, higher rates of side effects.Table 3 Selected reports on palliative hypofractionated nonlattice radiation therapy over the past 15 years (no stereotactic techniques)

Table 3Author [ref]	Year	Type	Diagnosis	No. patients	Schedule	TTT	Palliative response/PROM	Objective outcome	G3, %	Median survival (mo)	
Chen et al32	2008	Retrospective	H&N	23	Quad shot	2 d to ∼4-6 wk	Palliative response 83%	NA	9 G3+	4	
				12	30 Gy/10 fractions	2 wk	67%	NA	37 G3+	8	
				7	37.5 Gy/15 fractions	3 wk	68%	NA	37 G3+	5	
				5	20 Gy/5 fractions	1 wk	60%	NA	37 G3+	3	
Ghoshal et al33	2009	Pilot	H&N	15	Quad shot	2 d to ∼4-6 wk	13/15 > 50% response	NA	0	Mean 6	
Lok et al34	2015	Retrospective	H&N	75	Quad shot	2 d to ∼4-6 wk	65%	NA	7	5.7	
			(SCC 55%)								
Fortin et al35	2016	Phase 2	H&N	32	25 Gy/5 fractions	1 wk	∼60% same or better at 1-6 mo	NA	13	6.5	
							∼30% worse at 1-6 mo				
Finnegan et al36	2016	Retrospective	H&N	70	Quad shot	2 d to ∼4-6 wk	61% pain response	NA	9	3.8	
			(SCC 100%)								
Veluthattil et al37	2009	Prospective trial	H&N	25	52.5 Gy/15 fractions	3 wk	Overall response rate 47%:	NA	73	5.1	
			OCC				CR/PR 12%/35%				
Hartsell et al38	2003	Phase 3	Bone M	454	8 Gy/1 fraction	1 d	CR/PR 15%/50% at 3 mo	NA	24 (all)	9	
				443	30 Gy/10 fractions	2 wk	CR/PR 18%/48% at 3 mo	NA		9	
Roos et al39	2005	TROG 96.05	Bone M	137	8 Gy/1 fraction	1 s	53%, CR 26%, TTF 2.4 mo	NA	NA	4.8 (all)	
		Phase 3		135	20 Gy/5 fraction	1 wk	61%, CR 27%, TTF 3.7 mo				
Strøm et al40	2014	Phase 3 subset analysis	NSCLC	94	42 Gy/15 fractions	3 wk	HRQOL maintained	NA	30	13.4	
Soyfer et al41	2010	Retrospective	Sarcoma	15	39 Gy/13 fractions	2.5 wk	12/15 durable pain control	NA	NA	NA	
Jacbson et al42	2021	Retrospective	Breast CA	9	8 Gy/1 fraction	1 d	Durable response in all 53 parts	NA	∼5	NA	
				44	39 Gy/13 fractions,
45 Gy/15 fractions,
50 Gy/25 fractions	2.5-5 wk					
Maity et al43	2021	Phase 1	Melanoma	22	2-3 × 6 or 8 Gy	1 wk	PR/SD 22.7%/13.6%	NA	50	10.7	
					4 cycles ipilimumab post						
Funk-Brentano et al44	2020	Retrospective	Melanoma	26	20-26 Gy/3-5 fractions	NA	CR/PR 46%/12%	NA	0	NA	
Abbreviations: CA = carcinoma; G3 = grade 3; CR = complete response; H&N = head and neck cancer; HRQOL = health-related quality of life; NA = not assessed; NSCLC = non-small cell lung cancer; PR = partial remission; PROM = patient-reported outcome; Quad shot = 14 Gy in 2 × /d 3.8 Gy over 2 days, 1 to 3 × at 2- to 3-week intervals (RTOG 85-02); SCC = squamous cell carcinoma; TTF = time to failure; TTT = total treatment time.

Lesions treated with LRT seem to shrink more quickly, and retrospective comparison with historical data remains difficult.

Outlook

Further clinical evaluations are needed to refine optimal dose-volume schedules in LRT. Future comparative analyses, including a comparison between the 5-fraction SIB schedule and the 1-fraction high dose to vertices-only schedules, are planned in order to optimize treatment efficacy for patients and address institutional economics.

Conclusions

In summary, short-course LRT emerges as an effective and well-tolerated palliative treatment for both large, untreated lesions and previously irradiated ones. Approximately 90% of symptomatic patients reported a rapid onset of subjective benefit, and objective radiologic response was observed in 80% of assessed lesions with an average response duration of around 6 months.

Disclosures

None.

Acknowledgments

Author responsible for statistical analysis: Gabriela Studer.

Declaration of AI and AI-Assisted Technologies in the Writing Process

Declaration of generative AI and AI-assisted technologies in the writing process:

During the preparation of this work, the first author used Chat GPT exquisitely to improve language and readability. After using this tool/service, the author reviewed and edited the content as needed and take full responsibility for the content of the publication.

Sources of support: None.

Research data are stored in an institutional repository undergoing permanent updates; most recent data will be shared on request to the corresponding author.
==== Refs
References

1 Grams MP Deufel CL Kavanaugh JA Clinical aspects of spatially fractionated radiation therapy treatments Phys Med 111 2023 102616
2 Zhang H Wu X Zhang X Photon GRID radiation therapy: A physics and dosimetry white paper from the radiosurgery society (RSS) GRID/LATTICE, microbeam and FLASH radiotherapy working group Radiat Res 194 2020 665 677 33348375
3 Mayr NA Snider JW Regine WF An international consensus on the design of prospective clinical-translational trials in spatially fractionated radiation therapy Adv Radiat Oncol 7 2022 100866
4 Ferini G Valenti V Tripoli A Lattice or oxygen-guided radiotherapy: What if they converge? Possible future directions in the era of immunotherapy Cancers (Basel) 13 2021 3290 34209192
5 Iori F Cappelli A D'Angelo E Radiation therapy in clinical practice: A systematic review Clin Transl Radiat Oncol 39 2022 100569
6 Larrea L Gonzalez V Antonini P Lopez E Banos MC. Lattice radiotherapy (LRT)-spatially fractionated radiotherapy (SFRT): Advanced non-small cell lung cancer (NSCLC): Early experience [abstract] Int J Radiat Oncol Biol Phys 111 2021 E443
7 Duriseti S Kavanaugh JA Szymanski J LITE SABR M1: A phase I trial of lattice stereotactic body radiotherapy for large tumors Radiother Oncol 167 2022 317 322 34875286
8 Larrea L Gonzalez V Lopez E Antonini P. Lattice radiotherapy (LRT) protocol: Valencia protocol [abstract] Cureus 14 2022 a730
9 Ferini G Parisi S Lillo S Impressive results after “Metabolism-Guided” lattice irradiation in patients submitted to palliative radiation therapy: Preliminary results of LATTICE_01 multicenter study Cancers (Basel) 14 2022 3909 36010902
10 Amendola BE Perez N Amendola MA Lattice radiotherapy with RapidArc for treatment of gynecological tumors: Dosimetric and early clinical evaluations Cureus 2 2010 1 6
11 Blanco Suarez JM Amendola BE Perez N Amendola M Wu X The use of lattice radiation therapy (LRT) in the treatment of bulky tumors: A case report of a large metastatic mixed Mullerian ovarian tumor Cureus 7 2015 e389 26719832
12 Amendola BE Perez NC Wu X Blanco Suarez JM Lu JJ Amendola M Improved outcome of treating locally advanced lung cancer with the use of lattice radiotherapy (LRT): A case report Clin Transl Radiat Oncol 9 2018 68 71 29594253
13 Jiang L Li X Zhang J Combined high-dose LATTICE radiation therapy (HDLRT) and immune checkpoint blockade for advanced bulky tumors: The concept and a case report Front Oncol 10 2021 548132
14 Schiff JP Spraker MB Duriseti S Tumor lysis syndrome in a patient with metastatic endometrial cancer treated with lattice stereotactic body radiation therapy Adv Radiat Oncol 7 2022 100797
15 Ferini G Valenti V Viola A First-ever clinical experience with magnetic resonance-based lattice radiotherapy for treating bulky gynecological tumors Anticancer Res 42 2022 4641 4646 36039437
16 Ferini G Castorina P Valenti V A novel radiotherapeutic approach to treat bulky metastases even from cutaneous squamous cell carcinoma: Its rationale and a look at the reliability of the linear-quadratic model to explain its radiobiological effects Front Oncol 12 2022 809279
17 Dincer N Ugurluer G Korkmaz L Magnetic resonance imaging-guided online adaptive lattice stereotactic body radiotherapy in voluminous liver metastasis: two case reports Cureus 14 2022 e23980 35541303
18 Larrea L Antonini P Gonzalez V Lopez E Banos MC. Lattice radiotherapy (LRT): Case report of bulky cervical cancer (CC) Cureus 14 2022 a728
19 Borzov E Bar-Deroma R Lutsyk M. Physical aspects of a spatially fractionated radiotherapy technique for large soft tissue sarcomas Phys Imaging Radiat Oncol 22 2022 63 66 35572042
20 Iori F Botti A Ciammella P How a very large sarcomatoid lung cancer was efficiently managed with lattice radiation therapy: A case report Ann Palliat Med 11 2022 3555 3561 35871277
21 Montero A Prado A Ciervide R Efficacy of VMAT-lattice spatially fractionated radiation therapy (SFRT) for the treatment of large abdominal sarcoma Oncol Radiother 17 2023 82 86
22 Hatoum GF Temple HT Garcia SA Neoadjuvant radiation therapy with interdigitated high-dose LRT for voluminous high-grade soft-tissue sarcoma Cancer Manag Res 15 2023 113 122 36776730
23 Price AT Schiff JP Zhu T First treatments for Lattice stereotactic body radiation therapy using magnetic resonance image guided radiation therapy Clin Transl Radiat Oncol 39 2023 100577
24 Amendola BE Perez NC Mayr NA Wu X Amendola M. Spatially fractionated radiation therapy using lattice radiation in far-advanced bulky cervical cancer: A clinical and molecular imaging and outcome study Radiat Res 194 2020 724 736 32853384
25 Wu X Perez NC Zheng Y The technical and clinical implementation of LATTICE radiation therapy (LRT) Radiat Res 194 2020 737 746 33064814
26 Pollack A Chinea FM Bossart E Phase I trial of MRI-guided prostate cancer lattice extreme ablative dose (LEAD) boost radiation therapy Int J Radiat Oncol Biol Phys 107 2020 305 315 32084522
27 Boustani J Grapin M Laurent PA Apetoh L Mirjolet C. The 6th R of radiobiology: Reactivation of anti-tumor immune response Cancers (Basel) 11 2019 860 31226866
28 Amendola BE Perez NC Wu X Amendola MA Qureshi IZ Safety and efficacy of lattice radiotherapy in voluminous non-small cell lung cancer Cureus 11 2019 e4263 31139522
29 Griffin RJ Prise KM McMahon SJ Zhang X Penagaricano J Butterworth K. History and current perspectives on the biological effects of high-dose spatial fractionation and high dose-rate approaches: GRID, Microbeam & FLASH radiotherapy Br J Radiol 93 2020 20200217
30 Ferini G Zagardo V Pergolizzi S. To answer Spałek's question: lattice radiotherapy is more hope than hype Ann Palliat Med 12 2023 1106 1108 37303217
31 Duriseti S Kavanaugh J Goddu S Spatially fractionated stereotactic body radiation therapy (Lattice) for large tumors Adv Radiat Oncol 6 2021 100639
32 Chen AM Vaughan A Narayan S Vijayakumar S. Palliative radiation therapy for head and neck cancer: toward an optimal fractionation scheme Head Neck 30 2008 1586 1591 18798313
33 Ghoshal S Chakraborty S Moudgil N Kaur M Patel FD. Quad shot: A short but effective schedule for palliative radiation for head and neck carcinoma Indian J Palliat Care 15 2009 137 140 20668593
34 Lok BH Jiang G Gutiontov SI Palliative head and neck radiotherapy with the RTOG 8502 regimen for incurable primary or metastatic cancers Oral Oncol 51 2015 957 962 26282714
35 Fortin B Khaouam N Filion E Nguyen-Tan PF Bujold A Lambert L. Palliative radiation therapy for advanced head and neck carcinomas: A phase 2 study Int J Radiat Oncol Biol Phys 95 2016 647 653 27020111
36 Finnegan TS Bhatt NH Shaughnessy JN Cyclical hypofractionated radiotherapy technique for palliative treatment of locally advanced head and neck cancer: Institutional experience and review of palliative regimens J Community Support Oncol 14 2016 29 36 26870840
37 Veluthattil AC Sudha SP Kandasamy S Chakkalakkoombil SV. Effect of hypofractionated, palliative radiotherapy on quality of life in late‑stage oral cavity cancer: A prospective clinical trial Indian J Palliat Care 15 2009 137 140 20668593
38 Hartsell WF Scott C Bruner DW Phase III randomized trial of 8 Gy in 1 fraction vs. 30 Gy in 10 fractions for palliation of painful bone metastases: Preliminary results of RTOG 97-14 Int J Radiat Oncol Biol Phys 57 2003 S124 14535238
39 Roos DE Turner SL O'Brien PC Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05) Radiother Oncol 75 2005 54 63 15878101
40 Strøm HH Bremnes RM Sundstrøm SH Helbekkmo N Aasebø U. Poor prognosis patients with inoperable locally advanced NSCLC and large tumors benefit from palliative chemoradiotherapy: A subset analysis from a randomized clinical phase III trial J Thorac Oncol 9 2014 825 833 24807158
41 Soyfer V Corn BW Kollender Y Tempelhoff H Meller I Merimsky O. Radiation therapy for palliation of sarcoma metastases: A unique and uniform hypofractionation experience Sarcoma 2010 2010 927972
42 Jacbson G Kaidar‑Person O Haisraely O Palliative radiation therapy for symptomatic advance breast cancer Sci Rep 11 2021 5282 33674709
43 Maity A Mick R Rengan R A stratified phase I dose escalation trial of hypofractionated radiotherapy followed by ipilimumab in metastatic melanoma: long-term follow-up and final outcomes OncoImmunology 1 2021 1863631
44 Funck-Brentano E Baghad B Fort M Efficacy of late concurrent hypofractionated radiotherapy in advanced melanoma patients failing anti-PD-1 monotherapy Int J Cancer 147 2020 1707 1714 32083739
