Use of Multi-Site Radiation Therapy for Systemic Disease Control

Abstract

Metastatic cancer is a heterogeneous entity, some of which could benefit from local consolidative radiotherapy (RT). Although randomized evidence is growing in support of using RT for oligometastatic disease, a highly active area of investigation relates to whether RT could benefit patients with polymetastatic disease. This article highlights the preclinical and clinical rationale for using RT for polymetastatic disease, proposes an exploratory framework for selecting patients best suited for these types of treatments, and briefly reviews potential challenges. The goal of this hypothesis-generating review is to address personalized multimodality systemic treatment for patients with metastatic cancer.

The rationale for utilizing high-dose RT is primarily for local control and immune activation in either oligometastatic or polymetastatic disease. However, the primary application of low-dose RT is to activate distinct antitumor immune pathways and modulate the tumor stroma in efforts to better facilitate T-cell infiltration. We explore clinical cases involving high- and low-dose RT to demonstrate the potential efficacy of such treatment.

We then group patients by extent of disease burden in order to implement high- and/or low-dose RT. Patients with low-volume disease may receive high-dose RT to all sites as part of an oligometastatic paradigm. Subjects with high-volume disease (for whom standard of care remains palliative RT only) could be treated with a combination of high-dose RT to a few sites for immune activation, while receiving low-dose RT to several remaining lesions in order to enhance systemic responses from high-dose RT and immunotherapy. We further discuss how emerging but speculative concepts such as immune function may be integrated into this approach, and examine therapies currently under investigation that may help address immune deficiencies.

The review concludes by addressing challenges in using RT for polymetastatic disease, such as concerns over treatment planning workflows, treatment times, dose constraints for multiple-isocenter treatments, and economic considerations.

INTRODUCTION

Radiation therapy (RT) is one of the most effective means of providing local tumor control in oncology. Ongoing technologic improvements in radiation planning and delivery have the potential to extend RT as a means for systemic disease control.¹ In combination with immunotherapy, the same RT used for local control can potentially convert tumors into a form of in-situ vaccines, as T cells activated by RT can exert effects beyond local disease to enhance systemic control of disease.² Moreover, advances in radiation planning and delivery facilitate more efficient treatment planning, improved dosimetry, and faster delivery, enabling the simultaneous treatment of multiple lesions and sites.³ As the boundaries begin to blur between using RT for local and systemic disease control, clinical strategies are needed to define the appropriate use of systemic RT, identifying which patients, histologies, and metastatic sites are best suited for safe and effective treatment with multi-site RT. As RT becomes increasingly used for systemic as well as local disease control, the principles of personalized medicine should guide the choice of treatment options for metastatic cancer.

Herein, we propose an approach for the use of multi-site RT based on disease burden and endogenous immune function. The suggested approach reflects our experience to date with multi-site RT to treat disseminated disease, including several clinical trials examining abscopal (out-of-field radiation) effects in patients with metastatic disease.^4–6 In this hypothesis-generating article, we explore the role of personalized multi-site RT, in conjunction with immunomodulation, as a means of systemic treatment for disseminated malignancies.

RADIOTHERAPY FOR LOCAL CONTROL AND IMMUNE ACTIVATION

Stereotactic body RT (SBRT, also known as stereotactic ablative therapy [SABR]) is increasingly being used to deliver highly-targeted, ablative doses in fewer fractions and with comparable toxic effects relative to conventionally fractionated RT.⁷ Over the past decade, SBRT, which was originally developed to treat earlier stages of cancer, has revolutionized the treatment of oligometastatic disease, with high rates of local control and significant benefits in terms of overall survival in several randomized phase II trials.^8,9 The advent of targeted agents and immunotherapy has also expanded the treatment options for metastatic cancer patients, with patients living longer and deriving durable benefits from local therapies. Response to immunotherapy given as monotherapy, however, remains low.^10,11 Early clinical findings suggest that the addition of radiation, particularly SBRT, has the potential to improve responses to immune checkpoint inhibitors (ICPIs).^5,12,136 Irradiation of local tumor sites can also upregulate checkpoint receptors such as PD-L1, thereby enhancing the function of ICPIs.¹⁴ Radiation can activate CD8⁺ T cells by causing the release of tumor antigens, damage-associated molecular patterns (DAMPS), and cytokines.¹⁵ The proliferation of antitumor CD8⁺ T cells, in conjunction with upregulation of PD-L1, enables a more robust response to ICPIs.

Analysis of the PACIFIC trial showed that administering the anti-PD-L1 agent durvalumab to patients who had previously received chemoradiotherapy for stage III non-small cell lung cancer led to significantly improved overall survival, regardless of PD-L1 status.¹⁶ In this sequential-therapy approach, radiation may contribute to control of macroscopic sites of disease while T cells and chemotherapy address sites of microscopic, subclinical disease.¹⁷ That radiation can improve T-cell priming may explain in part why the PACIFIC trial showed favorable results for patients with either low or high PD-L1 expression.^18,19

A significant challenge to achieving systemic responses relates to the entry of activated T cells into unirradiated metastatic sites. As discussed below, one major contributor to this challenge is the inhibitory nature of the tumor microenvironment.

OVERCOMING THE INHIBITORY EFFECTS OF THE TUMOR MICROENVIRONMENT

Tumor Stroma

The tumor-associated stroma is a physical barrier consisting of extracellular matrix and various cells including fibroblasts, regulatory T cells (Tregs), myeloid-derived suppressor cells, and tumor-associated macrophages.²⁰ The stroma remains a significant obstacle in eliciting systemic responses to therapy. Stromal cells create an immunosuppressive environment by secreting inhibitory cytokines and recruiting Tregs.²¹ The stroma can be directly toxic to T cells, blunting their activity and causing anergy.^22,23 The stroma also impedes contact between T cells and cancer cells by forming a physical barrier around tumors and by secreting inhibitory chemokines that prevent T-cell infiltration.^24,25 Averting T cell infiltration by the stroma enables cancer cells to continue proliferating despite immune activation. Indeed, the extent of lymphocyte invasion into the tumor microenvironment is essential in eliciting antitumor responses. Meta-analyses of retrospective studies exploring the role of tumor-infiltrating lymphocytes (TILs) show a positive correlation between the presence TILs and overall survival.^26,27 Overcoming the immunosuppressive activity of the tumor stroma is important for achieving systemic responses and is one mechanism by which RT contributes to systemic disease control.

Low-Dose Radiotherapy

Several potential benefits have been proposed in favor of using low-dose RT to modulate the tumor stroma. The first such benefit is that low-dose RT kills relatively few lymphocytes. Lymphocytes are required for antitumor immune responses, and lymphopenia is a negative prognostic factor across several types of cancers.^28–30 Various RT dose and fractionation schedules affect the host immune system differentially; low doses are less likely to be destructive to lymphocytes than are high doses.^31,32 Macrophages and Tregs, on the other hand, are more resistant to radiation.³³ High doses of radiation can cause fibrosis and the increased secretion of TGF-β, which recruits Tregs to tumors.³⁴ Low doses of radiation, however, seem to have the opposite effect by reducing TGF-β,³⁵ which has pleotropic effects on several inhibitory components. Once it is decreased, it creates a ripple effect on several immunosuppressive cell types such as Tregs, MDSCs, M2 macrophages, and cancer associated fibroblasts.³⁶ Depletion of Tregs has been shown to result in improved sensitivity of tumors to radiation and enhanced regression.³⁷ Low doses of radiation may also induce cytokines that have a positive influence on the percentages and activation status of antitumor effector immune cells. For example, delivering whole-body radiation to rodents was shown to increase the number of splenocytes and to boost immunity,^38–40 whereas a localized 2-Gy dose polarized macrophages into the proinflammatory, antitumoral iNOS⁺ M1 phenotype.⁴¹

Another study conducted in an immunocompetent murine model of Lewis lung carcinoma (LLC), demonstrated that the antitumor immunity induced by low-dose RT was attributable to the infiltration of activated NK and T cells, through Th2 to Th1 cytokine polarization.⁴² In a CT26 colon carcinoma model, low-dose RT of 2Gy x 5 has been shown to enhance the outcomes of anti-PD1 checkpoint inhibitor by expanding both tumor-resident T-cells and promoting the recruitment of new effector T-cells from circulation.⁴³ Moreover, researchers have shown that in the 3LL murine lung and 4T1 breast models, delivering 0.5Gy x 4 low-dose RT to primary tumors after a single high-dose of ablative RT helped to slow tumor growth, reduced Tregs, and suppressed pulmonary metastasis.⁴⁴

Our group has been exploring the use of low-dose radiation in preclinical models and in early clinical studies as a means of overcoming the inhibitory stroma and promoting systemic responses. In one study of patients with disease progression on immunotherapy, lesions receiving low-dose RT (the majority of which was a result of scatter from high-dose treated lesions) or no RT to distant tumor sites led to response rates of 58%, compared to 18% for lesions at distant tumor sites receiving no dose²¹ In this study, RT planning techniques included both SBRT and intensity modulated radiotherapy (IMRT), which demonstrated variable dose fall-off geometry with scatter lesions receiving low doses in the range of 1–20 Gy. To study the mechanisms involved in this low-dose effect, we transplanted 344SQ lung adenocarcinoma tumors into 129Sv/Ev mice and irradiated the tumors with low (1 Gy × 2), intermediate (5 Gy x 3), and high (12 Gy x 3) doses of radiation and measured the functionality of CD4⁺ and CD8⁺ T cells isolated from tumor tissue with magnetic beads. The 5-Gy and 12-Gy doses initially eliminated most of the local immune cells, and 7 days was needed for the T cells to replenish themselves before another TIL harvest. Using Isoplexis single-cell analysis technology, we assessed the polyfunctional strength index (PSI) of the isolated T cells after treatment with either high or low-dose radiation. PSI is a measure of the percentage of individual cells that secrete two or more effector or regulatory soluble factors, multiplied by the intensity of such factors and has been validated in the immunotherapy setting as a potential predictor of response.^45,46 The cells were stimulated in vitro with CD3/CD28 overnight to compare the levels of various cytokines and chemokines produced and to assess the activation status on a single-cell level. The radiation dose used had a quite different effect on the observed immune outcomes. High-dose radiation increased the PSI of effector CD8⁺ T cells through the production of IFN-γ, Granzyme B and MIP-1α. Low-dose radiation on the other hand favored the polyfunctional stimulation of CD4⁺ T cells along with upregulation in the activation marker CD137/4–1BB (Figure 1). The primary implication is that high-dose radiation is important for cytotoxic T-cell priming and acquisition of killer effector functions, while low-dose radiation is important to activate and stimulate helper T cells which in turn augment CD8⁺ T cells and help generate immune memory.

Figure 1.

Average single-cell polyfunctional activated topology principal component analysis (PAT-PCA). Polyfunctionality is defined as 2+ cytokines secreted per cell. PSI, or Polyfunctional Strength Index, is defined as the percentage of polyfunctional cells in the sample, multiplied by the intensities of the secreted cytokines.

The second important function of low-dose RT is in modulating the stroma within neoplastic lesions. CD8⁺ T cells primed after high-dose radiation can address disseminated tumor cells. However, low-dose irradiation is being tested as a way to augment infiltration of the otherwise hostile tumor stroma. The reduction in TGF-β from low-dose RT reduces the numbers of Tregs in the tumor microenvironment and also seems to address many other immunosuppressive effects of the stroma.³⁵ Moreover, as noted above, stimulating CD4 T cells with low-dose RT can contribute further to the immune response. Indeed, the rationale for using low-dose RT is not necessarily to ablate or kill the tumor but rather to activate the immune system such that it targets these lesions.

Clinically, low-dose RT has several advantages over high-dose RT. First, low doses are much safer in terms of their potential for damaging normal tissues, which would make meeting dose-limiting normal tissue constraints easier if several lesions (isocenters) within that organ are to be treated with SBRT. As such, treating larger volumes such as whole organs with one isocenter (e.g. clinical liver example in the “Low-Dose Radiotherapy Clinical Cases” section) with low-dose RT might be more dosimetrically feasible in addressing microscopic disease than treating individual lesions with SBRT (each with its own isocenter). Our clinical experience suggests that the addition of low-dose radiation has limited impact on lymphocyte counts, although this data is yet to be reported from prospective clinical trials. Second, low-dose RT also seems to be safer for treating patients with previously irradiated tumors, with minimal concern for exceeding normal tissue dose-constraints in the setting of reirradiation. Finally, low-dose RT can be delivered by means of simple 3-dimensional techniques, which could be adapted more easily by treatment centers lacking the specialized imaging or gating capabilities needed for SBRT.

Another safety issue involves the need for combination therapy (e.g., combinatorial immunotherapy agents), as the use of single agents often leads to the development of treatment resistance. While combinations of systemic agents such as anti-CTLA4 and anti-PD-1 have proven to be quite toxic,⁴⁷ a recent phase I study has demonstrated that high-dose radiation can be safely delivered in patients receiving dual checkpoint inhibition with comparable rates of toxicity.⁴⁸ Our clinical experience of administering low-dose RT in patients who progressed on combined anti-CTLA4 and anti-PD-1 has also demonstrated safe and tolerable treatment (data under review). While long-term implications of low-dose treatments and the use of radiation in dual checkpoint immunotherapy-naive patients are yet to be evaluated, low-dose RT may represent a safe and effective adjunct to combined systemic regimens in the future.

Although the exact mechanisms underlying acquired resistance to immunotherapy are unclear, poor T-cell function or stromal immunosuppressive activity may both be involved. We have developed a novel technique, named RadScopal^™, which combines both high- and low-dose RT to elicit improved systemic responses. With this combination of high- and low-dose RT, we can potentially address two potential mechanisms of resistance simultaneously: high-dose RT stimulates T-cell priming, and low-dose RT modulates the inhibitory stroma, enabling immune cells to enter the tumor environment and elicit an antitumor response.

LOW-DOSE RADIOTHERAPY CLINICAL CASES

In our ongoing phase II clinical trial of high-dose RT with or without low-dose RT in patients progressing on immunotherapy (NCT[XXX BLINDED]), we have now treated over thirty patients with low-doses ranging up to 10 Gy in <2 Gy fractions (most commonly 7 Gy in 5 fractions). Patients continued receiving the same immunotherapy agent (most commonly anti-PD-1) after receiving RT, as it is impossible to independently evaluate the effect of RT on progression if the immunotherapy agent is switched. Preliminary data of lesion-specific responses to low-dose RT (as per immune-related response criteria) have shown response rates of >40%. To offer illustrative examples of the contexts in which low-dose RT may be applicable, brief cases are described below.

1. Low-dose RT can be effective for treating large volume disease

A patient with HPV-positive oropharyngeal squamous cell carcinoma six months status post concurrent chemoradiation developed biopsy-proven metastases in their lung, liver, and peritoneum. The patient was treated with pembrolizumab with initial response, followed by progression in the bilateral lung, mediastinum, and peritoneum (Figure 2a) 10 months after starting treatment. The patient then received 50 Gy in 4 fractions to a 1.9 cm left upper lobe nodule and 6 Gy in 4 fractions to the 5.5 cm peritoneal implant (Figure 2b). Currently, 20 months after treatment, he has no evidence of disease, including a complete response in the large peritoneal implant (Figure 2c). No toxicities were reported.

Figure 2.

Low-dose RT to a 5.5 cm peritoneal lesion. A) CT with contrast before RT. B) Low-dose RT treatment plan (axial). C) CT with contrast after RT.

2. Low-dose RT to large areas of tumor burden can be safe and achieve significant responses

A patient with melanoma metastases in the liver, lung, bone, and brain that progressed over the course of four years on numerous chemo, targeted, and immune therapies, yttrium-90 radioablation to two liver lobes, and T-cell therapy presented to our clinic. Three months after T-cell infusion and one month after resuming combined ipilimumab with nivolumab the patient continued to progress (Figure 3a). He was then treated with 50 Gy in 4 fractions to a lung lesion and 5.6 Gy in 4 fractions to nearly the entire liver (Figure 3b). Given the extent of disease burden (largest liver lesion measuring 9.5 cm) and the risk for radiation-induced hepatopathy, a small portion of the inferior liver was spared, and one fraction was truncated (1.4 Gy x 4 instead of the planned 5). Four months after treatment, the patient had a confirmed partial response in the liver with an 83% reduction in tumor burden. Systemically, this patient also remained stable or responded in non-irradiated regions of the lung. Interestingly, this patient experienced grade 3 lymphopenia and no other grade 2+ toxicities (Common Terminology Criteria for Adverse Events v5.0). ALC decreased from 1.19x10³ to 0.46x10³/μL after treatment but returned to baseline levels within one month. Liver enzymes increased after RT (AST 66→75 U/L; ALT 74→95 U/L), but returned to lower than baseline levels by 4 months after treatment (AST 42 U/L, ALT 27 U/L). Although the patient did not have follow-up coagulation tests or albumin measurements, the platelets decreased after RT (63x10³/uL→33x10³/uL), but improved by 4 months after treatment (95x10³/uL) demonstrating that synthetic function of the liver may have slightly improved. Whether this patient responded due to the cell therapy three months prior, the low-dose RT with dual checkpoint inhibition, or the combination of therapies is yet to be determined. That being said, low-dose RT can be safely administered to the whole liver. Our group has seen a similar response in one other patient treated to the whole liver prior to cell therapy and only experiencing grade 3 neurotoxicity resolving within two days of cell therapy administration.

Figure 3.

Low-dose RT to nearly the whole liver. A) CT with contrast before RT. B) Low-dose RT treatment plan (coronal). C) CT with contrast after RT.

3. Low dose RT can be effective in treating areas that need re-irradiation, especially for smaller sized lesions

A patient with HPV-negative oropharyngeal squamous cell carcinoma isolated to the primary site underwent initial chemoradiation with 70 Gy in 35 fractions to the primary site and 44 Gy in 22 fractions to the bilateral neck (Figure 4a). A year later, restaging PET-CT demonstrated recurrence in the cervical nodes as well as a left lower lobe pulmonary nodule. He was started on pembrolizumab with complete response to therapy. Two years after response, he progressed in the cervical lymph nodes (largest lesions 1.0 and 1.5 cm in shortaxis) and in a right lower lobe pulmonary nodule (1.1 cm in long-axis), which were confirmed to be progressing on repeat scans (Figure 4b). He was treated with 50 Gy in 4 fractions to the lung and 7 Gy in 5 fractions to the cervical lymph nodes (Figure 4c) and continued on pembrolizumab. Currently, three months after treatment, he has had a complete response in all areas (Figure 4d). Although this patient had low disease burden, this patient was an excellent example of how low-dose can be used in areas sensitive to re-irradiation in patients progressing after response to immunotherapy.

Figure 4.

Low-dose RT to previously irradiated neck lymph nodes. A) Initial prophylactic neck irradiation treatment plan. B) PET-CT before RT. C) Low-dose RT treatment plan (axial). D) PET-CT after RT. Red arrow identifies site of cervical lymph node.

CHARACTERIZING IMMUNE FUNCTION

Historically, RT has been used for local control of certain malignancies and for eradicating localized microscopic disease. In addition to providing these benefits, multi-site RT has the potential to be used in conjunction with immunotherapies to achieve abscopal responses (i.e., to address systemic, disseminated disease⁴⁹). Consequently, the relative strength of the immune system may be an important factor in determining the appropriate use of multi-site RT. Indeed, preclinical models have shown that mice with suppressed or depleted immune cells before tumor implantation show a lesser response to combined immunoradiotherapy than mice with intact immune systems.⁵⁰ We propose that considering the following aspects of immune function can help to indicate which patients would experience benefit from multi-site RT.

Absolute lymphocyte count (ALC) can be readily obtained from peripheral blood samples and is relatively well standardized. ALC has been shown to predict clinical response to immunotherapy in several types of cancers.^51–53 Our clinical experience also suggests that ALC is an independent predictor of abscopal responses and progression-free survival after immunoradiotherapy.⁵⁴ In this study, patients with an ALC greater than 1,300/μL prior to RT, 560/μL after RT, or a decrease in ALC of less than 740/μL were associated with improved abscopal responses, although higher than median post-RT ALC was predictive of improved progression-free survival.⁵⁴ Our clinical trial of patients with non-small cell lung cancer demonstrated better abscopal responses in patients receiving 50 Gy in 4 fractions of SBRT than in patients receiving 45 Gy in 15 fractions.⁵⁵ A secondary analysis showed that this difference might reflect the effects of RT on the ALC, in that SBRT did not significantly decrease ALC, but moderately hypofractionated treatment did.⁵³ This finding was likely related to larger margins required for, along with larger treatment volumes in, the latter. Because lymphopenia has been linked with worse prognosis after immunotherapy, presumably patients with low baseline ALC would benefit from treatments associated with minimal reduction in lymphocytes, or from therapies that account for weakened immune function (e.g., cell therapy).

There are several factors that relate to anti-tumor immunity. Characterizing T cell function and strength may offer unique ways of stratifying immune function. This can be done in several ways. First, cell surface markers like ICOS, GITR, OX40, 4–1BB, CD40L and CD44 can indicate T-cell activation.^56–60 Markers of exhaustion, or attenuated T-cell effector function, include PD-1, Tim-3, Lag3, and TIGIT.^61–64 Furthermore, the extent of proliferation after repeated or frequent activation by stimulatory molecules like CD3 and CD28 may offer insight into T-cell strength.⁶⁵

Second, information on T-cell cytokine expression from single-cell polyfunctionality analysis may be another useful predictor of immune status. While the PSI score itself may offer insight into the polyfunctionality of T-cells and has been shown to correlate with response to immunotherapies,^45,46 characterizing polyfunctional T cell populations by the amount and type of cytokines released matters (e.g. pro- vs anti-inflammatory, stimulatory vs inhibitory).^66,67

Lastly, an interesting way of measuring T-cell “fitness”, or capability for expansion, is through assessing mitochondrial function. In chimeric antigen receptor (CAR) T cells, high mitochondrial biomass (measured by microscopy) correlates with T-cell fitness, and therefore proliferative capability.⁶⁸ Other potential means of assessing mitochondrial function are by measuring peroxisome proliferated-activated receptor gamma, coactivator 1 alpha expression in T cells, which correlates with mitochondrial biogenesis and oxidative metabolism⁶⁹ or by targeting key elements of the electron transport chain to assess oxygen consumption rate, which may approximate mitochondrial functional status.⁷⁰ The several aforementioned measures for T-cell function are feasible to test in clinical settings, as T cells can readily be isolated from peripheral blood samples; however, this may add to costs as described in the subsequent “Feasibility and Challenges” section.

While prospectively testing these approximators of anti-tumor immunity is needed, they may offer future potential for quantifying the strength of an individual patient’s immune system. Further efforts will involve finding other factors that more accurately reflect T-cell fitness and can easily and inexpensively be attained in clinical settings. However, at this time a general index of a patient’s immune status (e.g. ALC) can be useful as a decision-making tool for the choice of single-site versus multi-site RT. However, before applying specific cutoffs when constructing randomized trials in these patients, validation is required; as a result, no single ALC cutoff will be suggested herein owing to the overly speculative nature of doing so.

HYPOTHESIS-GENERATING TREATMENT APPROACH

Our experience treating patients with multi-site RT to enhance systemic responses has led us to define a general approach for stratifying patients for such therapy. In this approach, patients are grouped according to extent of disease burden. We will then briefly discuss how more emerging notions such as immune function may be incorporated into this paradigm.

Extent of Disease

Patients classified as having low-volume or oligometastatic disease (although this term is continuing to be defined, currently it most often refers to 1–5 metastatic sites (with the vast majority of data referring to 1–3 lesions) after up-front systemic therapy)^10,11 may be candidates for high-dose RT delivery to all affected areas for immune priming and local control. Such patients may derive further benefit from receiving RT combined with immunotherapy to enhance the ability of T cells to address microscopic disease throughout the body.

An important consideration in this population is the extent to which radiation doses are delivered. Radiation doses could be pushed at each site with the goal of achieving ablation while staying within organ-at-risk dose constraints (or some percentage of the dose constraint, e.g., 85%).⁷⁶ Treatments intended to be “ablative” have classically been defined as a biologic effective dose (BED) in excess of 100 Gy. Whether this BED threshold also applies to the metastatic setting remains unknown, given the low quality and quantity of data.^{77,78 79}

In patients with high-volume or polymetastatic disease, systemic therapies remain the standard of care with radiation administered only for palliation. It is less realistic to give high-dose RT to all lesions owing to the risk of toxicity, although this notion is being tested in randomized trials such as SABR-COMET10 (NCT03721341). However, those with a substantial disease burden could be considered for high-dose RT to one or a few larger lesions to stimulate immune priming, followed by low-dose RT to all other lesions (if feasible) for stromal modulation. Immune priming doses could range from 6–12 Gy per fraction to activate CD8 T cells⁷¹ and should remain below doses (e.g. 12–18 Gy) that would cause DNA degradation and potentially attenuate immunogenicity.^72,73 Such patients would also receive immunotherapy to promote T-cell activity in tumor sites as well as other areas of the body.

Immune function

The up-and-coming (yet still speculative) concept of immune function could also be used to inform treatment (Figure 5). Harboring relatively stronger endogenous immune function (the particular definition of which remains unvalidated to date as mentioned above) may be more compatible with immune priming doses as opposed to more ablative RT in oligometastatic patients (Figure 5a). Conversely, because immunotherapy-related outcomes in patients with poor immune function may be worse^51,52,54, and given that immune cell function plays a role in tumor response to radiation⁷⁵, these patients may benefit from more ablative RT for tumor control (Figure 5d).

Figure 5.

Schematic illustration of a hypothesis-generating treatment approach in patients with metastatic disease, incorporating concepts of disease burden and immune function as well as therapeutic strategies under investigation.

The high- with low-dose RT approach in patients with polymetastatic disease has shown early promise, but it could be further refined by immune function. Patients with stronger endogenous immune function may benefit from this approach, as they have the immune functionality to clear disease (Figure 5b). Conversely, those with poor immune function may not. One modality currently being studied in polymetastatic solid tumors is cell therapy (Figure 5c). Unlike cell therapies for hematologic malignancies, the challenge with respect to using cell therapies in solid tumors is the entry of immune cells into the immunosuppressive tumor environment.⁸¹ As such, a treatment approach currently under investigation in prospective studies (NCT03132922, NCT[XXX BLINDED]) combines adoptive T-cell therapy with low-dose RT, the latter for the purpose of stromal modulation. For patients receiving CAR T cells as opposed to unmodified expanded endogenous T cells, high-dose RT should be limited to areas that require local control, as it would not be needed for immune priming. Essentially, patients without intact immune function, whether from prior therapy or T-cell dysfunction, may benefit from engineering and/or expansion of endogenous immune cells. Natural killer (NK) cell therapy may also be considered, as NK cells do not exclusively rely on tumor antigens and can intrinsically identify tumor cells via their native receptors.⁸² Moreover, low-dose RT activates NK cells, which may further contribute to the effectiveness of this type of combined therapy.⁸³

FEASIBILITY AND CHALLENGES

At present, several limitations complicate bringing multi-site RT into widespread use. The first such limitation is the lack of knowledge of appropriate dose-volume histogram (DVH) (i.e., organ dose-volume) constraints when high RT doses are delivered to multiple isocenters. ⁹¹ Current DVH measurements and constraints provide great detail on the point doses to organs at risk, but in plans with multiple isocenters, scatter dose, and the low-dose cloud (i.e., volumes receiving 5 Gy) become significant issues. These low-dose volumes would be expected to affect circulating immune cells, particularly highly radiosensitive lymphocytes. A patient with good immune function before multi-site RT could experience a significant ALC drop depending on the isocenters being treated, which could lead to T cell depletion; thus, concepts such as total bone marrow dose will need to be defined. While toxicities related to low-dose irradiation of large tumor volumes is yet to be defined, prior studies examining lower-dose irradiation of large tumors volumes may offer insight. For example, conventionally fractionated whole liver irradiation (ranging from 17–30 Gy) is relatively safe with complication rates of less than 16%.^92–94 Our understanding of the extent to which we can safely irradiate lesions is still somewhat limited, in that little information is available as to whether it is better to irradiate a few lesions, most lesions, or all lesions to prompt adequate release of antigens or TILs or to appropriately overcome the tumor stroma.

A second limitation pertains to workflow constraints. Creating and executing a radiation treatment plan for a single site can take hours to days. When three or more sites with several isocenters are to be treated, even with low-dose RT (which limits organ-toxicity concerns), creating and executing treatment plans for several sites becomes even more time-consuming because of the need for repeated simulation, contouring, reviewing, and treatment as well as image review during treatment. Several tools and techniques are being developed for this purpose that can aid in creating a suitable workflow. Tools for auto-contouring, auto-planning, and auto-quality assurance substantially reduce the number of on-hands hours in treatment planning, especially when several sites are to be treated with low-dose RT.^95–99 Indeed, bringing multi-site RT to areas with fewer resources further emphasizes the need for auto-planning tools. Automation, which can enable standardization of treatment parameters, doses, and dose constraints, can make this paradigm practical. Artificial-intelligence-based automation is increasingly being used in the RT setting ¹⁰⁰. With the ability to train and refine algorithms over time such technology may offer significant aid to multi-site treatment planning.

A third limitation in the implementation of multi-site RT is treatment time. Treating 5–10 unique isocenters with high-dose RT or 10+ lesions with low-dose RT is currently not feasible, given the need for about 30 minutes for treatment set-up for each site when onboard imaging is being used; under these conditions, our current linear accelerators are limited to treating around 3–4 unique isocenters per day at most. Moreover, patients may not be able to maintain a particular position for extended periods. Further, for lesions that move with respiration or cardiac activity, the time spent “on the table” can be even longer due to use of gating or breath-hold approaches to limit lung and heart involvement in treatment fields. New technologies in development may allow more rapid treatment of multiple sites including linear accelerators that can treat multiple sites at once, which would reduce planning and treatment time as well as reducing the effects of target motion and uncertainty.

A final consideration in the widespread use of multi-site RT, with or without immunotherapy, is cost. US healthcare spending, particularly for oncologic care, remains disproportionally high relative to the total gross domestic product, and is only projected to increase.¹⁰¹ For example, the annual cost of new cancer medications (such as ICPIs) routinely exceeds $100,000 per patient.^102–106 Regarding the proposed Group 3 patients, novel cellular therapies (such as CAR-T) are even more expensive, with prices of $375,000–475,000 per infusion itself plus $550,000 of associated care (including $50,000 per adverse event), resulting in total expenses of $1 million per patient.^107–109 Furthermore, significant costs would be associated with patient stratification into personalized therapy classes based on immune function and tumor-specific antigen presentation.^110,111

Nonetheless, and amidst the shift towards evaluating therapies based on healthcare value (defined as outcomes per cost), immunotherapy remains cost-effective for many malignancies.^112–115 Similarly, CAR-T cellular therapies justify their value from both the healthcare and societal perspectives for hematologic malignancies,^107,116,117 due to the extensive survival benefit relative to standard-of-care. These costs associated with treatment delivery are also expected to decrease with the reduction in admission lengths and treatment complications.^108,118,119 However, while these prior data offer hope, new models will need to be generated to clarify the cost-effectiveness of these novel treatment paradigms, incorporating data on clinical effectiveness and response durability upon long-term follow-up.

Multi-site RT could further improve the value of these systemic therapies by enhancing response and minimizing relapse through synergistic mechanisms. To put the previous figures into perspective, the cost of an SBRT course is roughly $15,000;^120,121 and despite use in ≥30% of all cancer patients,¹²² RT accounts for <5% of the cumulative cost of oncologic care.^123,124 Indeed, published analyses support the cost-effectiveness of consolidative RT for oligometastatic disease^{121,125 126,127} relative to expensive systemic therapies.¹²¹ Hypofractionated approaches, such as SBRT, further strengthen the high-value proposition of adjunctive multi-site RT to economically improve outcomes.^{120,121,126–128} Furthermore, as personnel expenses are the primary cost driver behind RT delivery,^129–133 novel advancements in auto-contouring^95,96 and auto-planning^97–99 technologies will result in further cost savings with multi-site RT.

CONCLUSIONS

The goal of this hypothesis-generating review aims to address personalized multimodality systemic treatment for patients with metastatic cancer. Emerging clinical and preclinical evidence support the shift from using RT as only a means of local control to one of systemic disease control. Low dose radiation is a potentially meaningful application of RT that can overcome inhibitory stroma and contribute positive immunomodulatory effects, with minimal toxicity. Combined with immunotherapies, RT is integral to creating in-situ vaccines that harness patient immune systems to fight cancer. Patient immune status is an important stratifying factor for deciding whether or not to harness patient immune systems via immunoradiotherapy and/or use ablative RT for systemic control. This approach will evolve over the next few years and is likely to expand the benefits of radiation to many patients as new immunotherapy options become incorporated with radiation oncology. Oncology as a whole has undergone a rapid transformation over the past few decades with the incorporation of genomics and personalized medicine to the current focus on reinvigorating patient immune systems to clear cancer. Radiation oncology is poised to make a similar paradigm shift as advances in molecular immunology are incorporated with automation to bring RT into an era of personalized multimodality systemic treatment. Multi-site RT in combination with immunotherapy is possible but requires consideration of patient immune function, tumor biology, and workflow.

Data Sharing:

Research data are stored in an institutional repository and will be shared upon reasonable request.