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A Contemporary Update on the Role of Stereotactic Body Radiation Therapy (SBRT) for Liver Metastases in the Evolving Landscape of Oligometastatic Disease Management
A Contemporary Update on the Role of Stereotactic Body Radiation Therapy (SBRT) for Liver Metastases in the Evolving Landscape of Oligometastatic Disease Management Tyler P. Robin, MD, PhD, David Raben, MD, and Tracey E. Schefter, MD Metastases to the liver are common, and stereotactic body radiation therapy (SBRT) is a recognized tool for ablation of liver metastases. Colorectal cancers commonly metastasize to the liver, and long-term survival is possible after metastasectomy. However, many patients are not candidates for surgical resection, which opened the door to early studies investigating noninvasive techniques such as liver SBRT. Multiple prospective trials have demonstrated excellent local control with this approach coupled with an excellent safety record. The oligometastatic disease state is now appreciated across many histologies, and treatment of liver metastases as a component of oligometastatic disease management has emerged as a rational and relevant strategy. To this end, recent randomized studies in oligometastatic non small-cell lung cancer demonstrated improved progression-free survival with consolidative local therapy, and this approach is the topic of ongoing cooperative group studies inclusive of patients with an array of primary histologies. Further, there is a push to explore the role of radiation as a means to enhance the efficacy of immune enabling drugs. Recent prospective data evaluating the safety and response of SBRT with anti-CTLA4 therapy for patients with lung or liver metastasis demonstrated clinical benefit (out of field immune-related partial response or immune-related stable disease 6 months) in about a quarter of enrolled patients. Interestingly, SBRT to liver metastases was found to elicit a greater systemic immune response than SBRT to lung metastases. Classic management paradigms for metastatic disease are rapidly being supplanted by approaches that are improving outcomes for patients previously offered best supportive care or palliation alone. In this article, we will review the established and emerging potential indications for liver SBRT in this new era of oncologic care. Semin Radiat Oncol 28:288 294 Ó 2018 Published by Elsevier Inc.
Introduction Department of Radiation Oncology, University of Colorado Cancer Center, Aurora, CO Financial support: No relevant financial support to disclose. Conflicts of interest: Tyler Robin: None. David Raben: Consultant: Astra Zeneca; Advisory Boards: Merck and EMD Serono and Genentech. Tracey Schefter: None. Address reprint requests to Tracey E. Schefter, MD, University of Colorado Cancer Center, 1665 Aurora Court, Suite 1032 MS F706, Aurora, CO 80045. E-mail: [email protected]
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raditional teaching dichotomizes malignancies into localized or locoregionally advanced disease (appropriate for local therapy and potentially curable) and metastatic disease (incurable and best managed with systemic therapy or best supportive care alone). However, this historical dogma was first challenged many years ago primarily in sarcoma patients with lung metastases,1-3 and later in the setting of colorectal cancers metastatic to the liver and lung, with multiple series demonstrating notable long-term survival with resection of metastatic disease.4-14 In the mid-1990s, Hellman and Weichselbaum coined the term, oligometastases, to describe https://doi.org/10.1016/j.semradonc.2018.06.009 1053-4296/© 2018 Published by Elsevier Inc.
Radiotherapy for Liver Metastases the intermediate state of limited metastatic disease, where curative strategies may be effective for some patients.15 Importantly, current national guidelines now support aggressive local therapy to sites of colorectal cancer metastases.16 Arguably, the most robust data for local management of metastatic disease come from the colorectal cancer and sarcoma literature,1-14 but there is precedent for this management paradigm in other histologies as well. For example, series have demonstrated long-term survival after pulmonary metastasectomy in breast cancer, as well.17,18 Understanding the role of liver stereotactic body radiation therapy (SBRT) in the contemporary management of oligometastatic disease is germane to understanding future steps and strategies to alter disease outcomes. We will briefly review the role of liver SBRT in colorectal cancer liver metastases, then shift our focus to existing data and ongoing studies of metastasis-directed local therapy, specifically SBRT, in noncolorectal histologies. Finally, we will address the excitement surrounding the potential for liver SBRT to augment immunotherapy and improve responses.
SBRT for Colorectal Cancer Liver Metastases Metastasectomy remains the gold standard for resectable liver metastases from colorectal cancers, but SBRT is an option for unresectable disease and for medically inoperable patients, with multiple phase II studies reporting excellent local control (LC). A few of the larger studies will be briefly reviewed. Hoyer et al conducted a phase II study of SBRT in this setting.19 Patients with 1-6 metastases (maximum diameter of the largest tumor <6 cm) from colorectal cancer were included. Patients were required to have undergone radical resection of the primary tumor, and the metastases had to be determined to be inoperable. Sixty-four colorectal cancer patients were treated to 141 metastases, of which 44 were liver metastases. The SBRT dose was 45 Gy in 3 fractions and 2-year tumor specific LC was 79% (because patients could receive SBRT to more than 1 site, patient-based LC could be lower and was 64%). The following major treatment-related gastrointestinal (GI) toxicities were reported: death from hepatic failure (1 patient), colonic ulceration requiring surgery (1 patient), and duodenal ulceration managed conservatively (2 patients).19 In a single institution phase I and/or II study from The Netherlands, patients with either primary or metastatic liver tumors not suitable for other forms of local therapy were enrolled in a study of liver SBRT.20 Of 25 total participants, 17 patients were treated to 34 metastatic liver tumors. The majority of patients had colorectal primary tumors (14 of 17). The SBRT dose was 30-37.5 Gy in 3 fractions and 2year local tumor control was 86%. There were 3 acute grade 3 toxicities (hepatic toxicity: 2 patients, asthenia: 1 patient), and 1 late grade 3 GI toxicity.20 Rusthoven et al reported a multi-institution phase I/II study of SBRT for liver metastases.21 In phase I, the total dose was escalated from 36 Gy to 60 Gy in 3 fractions, and
289 the phase II dose was 60 Gy. Patients could have 1-3 hepatic metastases with individual tumor diameter of less than 6 cm. Low burden extrahepatic disease was allowed. Forty-seven patients were enrolled and treated with 63 liver metastases. Although patients with colorectal primary tumors were best represented (32% of patients), the remaining patients were treated to liver metastases from an array of primary tumors (lung: 21%, breast: 9%, ovarian: 6%, esophageal: 6%, hepatocellular carcinoma: 4%, and other: 21%). Two-year LC was 92% (100% for tumors less than 3 cm), there was only 1 grade 3 toxicity (soft tissue necrosis), and no reported radiation-induced liver disease.21 Scorsetti et al conducted a phase II study of SBRT for patients with 1-3 unresectable liver metastases with maximum individual tumor diameter less than 6 cm.22 Sixty-one patients were enrolled with 76 liver metastases. Extrahepatic disease was allowed and 34% of patients had stable extrahepatic disease at study entry. Again, colorectal primaries were most frequently represented (48%), but as in the report by Rusthoven et al, noncolorectal histologies constituted a significant proportion of the study population. The SBRT dose was 75 Gy in 3 fractions and 1-year in-field LC was 94%. There was only 1 reported grade 3 toxicity (chronic chest wall pain, late grade 3). Interestingly, in contrast to the study by Rusthoven et al, there was no difference in LC when comparing treatment of tumors 3 cm vs tumors >3 cm (P = 0.90).22 Multiple groups have tried to determine the optimal liver SBRT dose for colorectal cancer metastases.23-25 Chang et al reviewed outcomes for a pooled cohort of 102 lesions (65 patients) treated with liver SBRT at 3 institutions between 2003 and 2009. In their experience, total dose, dose per fraction, and total biologically effective dose (BED), all correlated with LC in multivariate analysis, ultimately recommending a dose of 48 Gy in 3 fractions.23 Joo et al reviewed the outcomes for 70 patients treated with SBRT to 103 colorectal liver metastases, and also demonstrated a dose-response relationship for LC. Two-year LC was 52%, 83%, and 89%, for BED 80 Gy, 100-112 Gy, and 132 Gy (patients in this group received 60 Gy in 3-5 fractions), respectively.24 Further, the Princess Margaret Cancer Centre group recently published on the long-term outcomes of an institutional phase I/II study of 6-fraction SBRT for hepatic colorectal metastases, and observed an association between increasing minimum dose to the gross tumor volume (GTV) and improved LC.25
Considerations for Management of Liver Metastases From Noncolorectal Primaries While the acceptance of liver SBRT as an ablative modality for liver metastases more or less emerged in the context of inoperable colorectal cancer metastases, the oligometastatic management paradigm now applies to many malignant histologies, thus emphasizing the importance of reviewing the
290 existing data for liver SBRT for noncolorectal primary tumors as well. Importantly, 2 of the prospective liver SBRT studies reviewed above (Rusthoven et al and Scorsetti et al) did include a significant proportion of patients with noncolorectal primary tumors.21,22 Scorsetti et al included a subset analysis by histology (comparing what they classified as radioresistant tumors including melanoma, renal cell carcinoma, and pancreatic and biliary duct adenocarcinoma, to all others) and did not see a difference in LC, although the number of events was too low to analyze by multivariate statistics.21,22 Our group reviewed our experience at the University of Colorado with SBRT for melanoma and renal cell carcinoma.26 Thirty patients were treated to 53 metastatic lesions in the lung (n = 39), liver (n = 11), and bone (n = 3), and we found higher dose per fraction, single fraction equivalent dose (SFED),27 and BED, all correlated with improved LC. Two-year LC was 100% for SFED 45 Gy compared with 54% for SFED <45Gy, and tumor control probability (TCP) modeling suggested a prescription dose of 48 Gy in 3 fractions to achieve 90% LC at 2 years.26 Further contributing to our efforts to predict response, investigators at the Moffitt Cancer Center have developed a 10-gene expression radiosensitivity index (RSI), and studied this metric in the context of liver metastases.28 Using 372 metastatic liver tissue samples they show significant differences in RSI by primary tumor histology. In their model, high RSI is associated with radioresistance, and they report median RSI by histology as follows: gastrointestinal stromal tumor—0.57, melanoma—0.53, colorectal neuroendocrine—0.46, pancreas neuroendocrine—0.44, colorectal adenocarcinoma—0.43, breast adenocarcinoma—0.35, lung adenocarcinoma—0.31, pancreas adenocarcinoma—0.31, anal squamous cell cancer—0.22, and small intestine neuroendocrine—0.21 (P < 0.0001). They then reviewed 33 patients treated to 38 liver metastases with SBRT and compared LC for colorectal metastases (22 patients, 27 lesions) to LC for noncolorectal histologies (breast, anal, lung: 11 patients, 11 lesions). All metastatic tumors were treated with 50 or 60 Gy in 5 fractions over 1 week. Importantly, all patients in the noncolorectal SBRT group had tumors with lower RSI than colorectal, and their LC findings were concordant with the RSI, with 2-year LC of 59% for colorectal metastases compared with 100% for noncolorectal metastases.28 Similarly, a German Society of Radiation Oncology database study showed breast cancer liver metastases are more responsive to SBRT than other histologies, with 2-year breast TCP of 90% achievable with BEDmax of 157 + § 80 Gy for patients with prior chemotherapy and only 80 + § 62 Gy for patients without prior chemotherapy, compared with a BEDmax of 257 § 74 Gy needed for a 90% TCP for colorectal liver metastases without prior chemotherapy.29 Another notable study comes from the Dana Farber Cancer Institute.30 They conducted a phase II study of proton-based SBRT for liver metastases enrolling 89 patients of varying histologies (colorectal: 34 patients, pancreatic: 13 patients, esophagogastric: 12 patients, and other: 30 patients). Patients were treated with 30-50 Gray equivalent in 5 fraction regimens (dose was based on effective volume of liver
T.P. Robin et al. irradiated). In this study, LC was associated with genetic alterations, and KRAS mutation was found to be the strongest predictor of poor LC. Further, both mutant KRAS and TP53 was associated with very poor LC of only 20%, compared with LC of 69.2% for the remainder of the cohort.30 These data suggest that there are differences in SBRT outcome by primary tumor histology and genetic profiles, and that future trials might consider histology, genetic alterations and/or RSI-guided dose selection for liver SBRT. While differences in intrinsic radiosensitivity likely drive some of the observed differences in response, it is notable that colorectal cancer patients tend to be heavily pretreated. Perhaps as patients begin to be referred for liver SBRT earlier in their course, we will see less radioresistance in colorectal liver metastases. Although, in the German Society of Radiation Oncology database study described above, it is important to reiterate that colorectal liver metastases were predicted to require higher doses for tumor control even in patients who did not receive chemotherapy prior to SBRT.29
Liver SBRT in Oligometastatic Disease Management Although there are limited additional data specifically dedicated to noncolorectal liver metastases, there are multiple reported and ongoing studies utilizing SBRT for oligometastatic disease inclusive of patients with liver metastases. Milano et al reported their experience of 121 patients with 15 metastatic lesions from any primary histology treated with SBRT on 2 prospective studies at the University of Rochester.31,32 The majority of patients (74%) had noncolorectal primary tumors with breast primaries best represented (32%). Fifty-four of 121 patients had liver metastases. The majority of lesions (72%) were treated with 50 Gy in 10 fractions. For breast cancer patients, the 6-year rates for overall survival (OS), freedom from distant metastases, and LC were 47%, 36%, and 87%, respectively. For patients with nonbreast primary tumors, the 6-year rates for OS, freedom from distant metastases, and LC were 39%, 28%, and 74%, respectively.32 Scorsetti et al have also reported on patients with oligometastatic breast cancer treated with SBRT to 1-3 metastatic sites within the lung and liver.33 Patients with extrapulmonary and/or extrahepatic metastases were excluded. Twentythree of 33 enrolled patients were treated to liver metastases. Multiple liver SBRT regimens were utilized including: 48 Gy in 4 fractions (13 lesions), 75 Gy in 3 fractions (22 lesions), 67.7 Gy in 3 fractions (5 lesions), 61.8 Gy in 3 fractions (4 lesions), and 56.25 Gy in 3 fractions (2 lesions). LC was 98%, 90%, and 90%, at 1, 2, and 3 years, respectively. Median OS was 48 months and 1- and 2-year OS were 93% and 66%, respectively. One- and two-year progression-free survival (PFS) were 48% and 27%, respectively. There was no grade 3 toxicity reported.33 Importantly, 2 randomized controlled phase II trials of consolidative local therapy in non-small cell lung cancer (NSCLC) have recently been published.34,35 In the multiinstitution study by Gomez et al, patients from 3 North
Radiotherapy for Liver Metastases American centers with oligometastatic (3 lesions) NSCLC without progression after first-line systemic therapy, were randomized (1:1) to maintenance systemic therapy (or observation) or to local consolidative therapy (radiation or surgery of all lesions) with or without maintenance systemic therapy.34 Of the 49 enrolled patients, 25 were randomized to local consolidative therapy, though only 2 of these 25 patients were treated for liver metastases. Nevertheless, this is an important positive study with a median PFS in the consolidative local therapy arm of 11.9 months, vs 3.9 months in the maintenance systemic therapy arm.34 Similarly, Iyengar et al completed a single institution randomized phase II study of maintenance systemic therapy alone vs SBRT followed by maintenance systemic therapy, for patients with limited metastatic (primary plus up to 5 metastatic lesions) NSCLC without progression after initial chemotherapy. A total of 29 patients were enrolled. Fourteen patients were enrolled on the SBRT arm with 2 of these patients treated with liver metastases (33 Gy in 3 fractions). This was also an overwhelmingly positive study with a median PFS of 9.7 months in the SBRT arms vs 3.5 months in the maintenance chemotherapy arm. Although liver was an infrequent site of oligometastases on these studies, they nevertheless strongly support aggressive management of oligometastatic disease, including liver SBRT when liver metastases are present. Furthermore, local therapy for oligometastatic disease is now the topic of multiple cooperative group and large multiinstitution studies. Building on the studies by Gomez et al and Iyengar et al, NRG-LU002 (NCT03137771) is a randomized phase II and/or III study of maintenance systemic therapy vs maintenance systemic therapy plus SBRT for limited metastatic (3 discrete sites amenable to SBRT) NSCLC. Patients are randomized 2:1 to the SBRT arm. SBRT doses allowed on this study are 24 Gy in a single fraction, 30 Gy in 3 fractions, and 34 Gy in 5 fractions, and liver metastases are eligible to be treated on study. An analogous study, stereotactic ablative radiotherapy for oligometastatic non-small cell lung cancer (SARON) (NCT02417662), is actively enrolling patients in the UK. Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET; NCT01446744) is an international multi-institutional randomized phase II study that enrolled patients from Canada, the UK, Australia, and the Netherlands.36 Patients with 3 sites of metastatic disease from any primary site were randomized to standard of care or standard of care plus SBRT to all active sites of disease. Liver metastases on the SABR-COMET trial were treated with 45-60 Gy in 3-8 fractions.36 This study completed accrual in 2016 and data are maturing. NRG-BR001 (NCT02206334) is a phase I study of SBRT for the treatment of multiple metastases. Patients with metastatic breast, prostate, and NSCLC, with 4 metastases amenable to SBRT are being enrolled. On this protocol, liver metastases are treated with an “initial starting dose” of 45 Gy in 3 fractions with a planned “decreased dose limiting toxicity dose” of 42 Gy in 3 fractions, if needed. NRG-BR002 (NCT02364557) is a phase IIR/III trial of standard of care
291 with or without SBRT and/or surgical ablation for newly oligometastatic breast cancer. Patients with a controlled (status postsurgery § radiotherapy) primary tumor and 2 distant metastases are eligible to enroll and undergo random assignment (1:1) to either standard of care systemic therapy (arm 1) or standard of care systemic therapy plus ablation of all metastases with SBRT or surgery (arm 2). Liver metastases on NRG-BR002 will be treated with 45 Gy in 3 fractions. Local therapy for oligometastatic disease has shown promise in multiple single institutional and small multi-institution prospective trials, and now this paradigm is being tested in large multi-institution and cooperative group studies. The liver is a common site of metastases for multiple disease histologies, and liver SBRT is likely to continue to play an important role in oligometastatic disease management as this progressive oncologic treatment paradigm continues to evolve.
Combining Liver SBRT With Immunotherapy: An Emerging Concept As discussed in the previous sections, SBRT is an effective ablative modality for liver metastases, and as oligometastatic disease management paradigms continue to evolve, the indications for liver SBRT are likely to continue to expand. Interestingly, liver SBRT may also play a role in the management of patients with widely metastatic disease. Systemic immunotherapeutics have been approved for multiple tumors and ongoing trials are continuing to test various immunotherapies in multiple cancer types. Importantly, there is a growing body of literature supporting a role for radiation therapy to convert cancers into an “in situ tumor vaccine” by inducing release of antigens during cancer cell death, promoting proinflammatory signals within and out of the radiation field, and creating positive microenvironmental changes. Alterations in the tumor stroma as well as within the tumor itself may stimulate the innate immune system to activate tumor-specific T cells and enhance cancer infiltrationis.37 The abscopal effect has gained renewed enthusiasm, although actual documentation of this effect on a wider scale has been lacking. Mediated by the immune system, the abscopal effect occurs when a single lesion treated with a targeted approach such as radiation results not only in local tumor regression but also regression in nonirradiated areas.38 Postow et al sparked intense interest in the use of radiation as an immune “firestarter” when he described a patient with metastatic melanoma with slow progression of disease on maintenance ipilimumab, an anti-CTLA-4 agent, who received palliative SBRT to a paraspinal mass (28.5 Gy in 3 fractions). Ipilimumab was continued, and in addition to regression of the target lesion, regression of lesions not targeted with radiation was observed.39 In another notable case report, a patient with widely metastatic NSCLC received compassionate use ipilimumab and 1 of multiple liver metastases was treated with SBRT to 30 Gy in 5 fractions with the intent to generate an abscopal response. Follow-up imaging showed significant treatment response within the radiation field, but also in
292 unirradiated liver metastases, and at distant sites outside of the liver. This patient went on to receive 4 additional cycles of ipilimumab alone, and a PET/CT 1 year after SBRT was without evidence of disease. The investigators observed a post-treatment increase in absolute lymphocyte and eosinophil counts, as well as increased cytotoxic tumor infiltrating lymphocytes in an unirradiated site of disease.40 The obvious question that emerged initially was whether it was safe to combine checkpoint inhibitors with radiation. Emerging data in the metastatic setting across disease sites suggest that it is quite tolerable.41 Bang et al retrospectively reported on 133 patients, of whom received a CTLA-4 inhibitor alone (n = 28), PD-1 inhibitor alone (n = 88), or combination immune blockade (n = 17). Fifty-six patients received radiation within 14 days of the immune checkpoint inhibitor. Forty-six patients experienced at least 1 immune-related adverse event (ir-AE; 34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P = 0.0008). In general, ir-AEs were manageable and with the limitations of looking backward, not associated with treatment site irradiated. It appeared that ir-AEs were greater when radiation was administered within 14 days of checkpoint inhibition.41 In a prospective study, 22 patients with stage IV melanoma received 4 cycles of ipilimumab combined with radiation to 1-2 sites of metastatic disease started within 5 days after initiation of ipilimumab.42 Patients were required to have at least 1 nonirradiated metastasis for response assessment. The rate of grades 3-4 toxicity was 14% and the combined therapy did not appear to result in an increase in radiation or ipilimumab-associated toxicities. Fifty percent of patients experienced a complete response, partial response, or stable disease. The liver was the only site of SBRT for 2 patients in this study using a fractionated dose of 30 Gy in 5 fractions.42 In contrast, about half of the 35 patients enrolled in the recently published study by Tang et al received liver SBRT.43 This novel phase I study combined ipilimumab and SBRT in patients with metastatic solid tumors refractory to standard therapies with 1 liver or lung lesion and 1 additional nontarget lesion for monitoring.43 Patients were stratified into 4 groups of concurrent or sequential SBRT (50 Gy in 4 fractions) to a liver or lung lesion, with a fifth group receiving sequential radiation (60 Gy in 10 fractions) to either a liver or lung lesion. Clinical benefit (CB) was defined as out-of-field immune-related partial response or immunerelated stable disease lasting at least 6 months. Clinical benefit was achieved in 23% of patients evaluable for clinical response. Only 2 patients experienced dose limiting toxicity. The study also looked at immune marker expression changes, and 1 of the exciting and hypothesis-generating findings from this study as it relates to liver SBRT was that systemic immune activation was greater after liver SBRT than after lung SBRT.43 The reasons for this observation remain unclear and warrant further study; would this observation be similar with anti-PD-1/PD-L1 therapy as it was with antiCTLA-4 therapy? It remains to be seen. Additionally, in a recently published phase I study from the University of Chicago, patients progressing on standard
T.P. Robin et al. treatment received SBRT to 2-4 metastases, and pembrolizumab was initiated within 7 days after completion of SBRT.44 In total, 151 metastases were treated on study including 24 liver metastases. Liver metastases received 45 Gy in 3 fractions. Of 62 patients available for 3 month toxicity evaluation, 6 patients experienced dose limiting toxicity (no dose limiting toxicities were observed in patients that underwent SBRT to liver metastases). The overall objective response rate for nonirradiated lesions was 13.5%.44 In addition, interferon (IFN)-g-associated gene response significantly correlated with nonirradiated tumor response in 8 patients with pre- and post-SBRT biopsy specimens (P = 0.023).44 What is the optimal radiation dose and schedule to enable adequate priming for immunotherapy and what is the extent of the tumor that should be irradiated? Preclinical studies using a colon carcinoma mouse model45 and a clinical study conducted in patients with melanoma46 suggest that fractionated dosing is preferred to a single-dose strategy to elicit an abscopal response when paired with anti-CTLA-4 antibodies. Is it all about the size of the radiation fractionation or does volume play a role as well? Certainly, there is concern that larger volumes and more protracted radiation may lead to a chronic immunosuppressive state and reduce the number of infiltrating effector T-cells needed to enhance immune-based cytotoxicity.47 Hopefully we will continue to explore study designs that attempt to answer these critical radiation questions. The preferred sequence of radiation and immunotherapy remains investigational. Based on current knowledge of cancer immunity and preclinical investigations, radiation prior to immunotherapy, or the 2 therapies administered concurrently, might be optimal, although certainly the type of immune-enhancing agent may dictate the best sequencing.47 With anti-PD-1/PD-L1 therapy, the effects may be different than with anti-CTLA-4, and treating with these checkpoint inhibitors too far after fractionated radiation may not be as effective as a concurrent approach or one shortly after radiotherapy.48,49 Potentially relevant to our discussion are the benefits seen with administration of anti-PD-L1 therapy in the Phase III NSCLC trial (PACIFIC study) after completion of chemoradiation with a doubling of the median PFS.50 This might simplify trials using SBRT for liver metastasis and enable expansion of combination types of strategies with newer immune agents or targeted drugs depending on the underlying molecular nature of the liver metastasis. Will we achieve a greater response to immunotherapy if we treat multiple sites that may have different microenvironments vs only 1 site? Treatment of oligometastases disease is aggressively under investigation with SBRT and is being combined with checkpoint inhibitors in a variety of cancer types and should be tested against single-lesion treatment. Will radiation become the “firestarter rather than the fire” to enhance immune mediated cancer killing in a way that will create wider response, applicability and durability? PD-L1 expression, IFN-g expression, and emerging molecular markers may help predict response to checkpoint inhibition, but the overall response rates across tumor types still appears to be modest. Can radiation convert advanced tumors considered nonresponsive intrinsically such as metastatic
Radiotherapy for Liver Metastases colorectal and pancreatic cancer and change the profiles to enact response? PD-L1 expression may be present; however, tumors are clever enough to downregulate alternative critical immune-related pathways to evade further immune surveillance. Wang et al investigated this phenomenon creating a preclinical tumor model to study anti-PD-1 resistance in a syngeneic host exposed to repetitive dosing with anti-mouse PD-1 antibodies.51 Importantly, although PD-L1 expression did not differ between the resistant and parental tumor cells, IFN-g, MHC class I and II, as well as b2-microglobulin were significantly downregulated in the anti-PD-1-resistant tumors compared with parental tumors and contained fewer CD8+ (CD8a) and CD4+ tumor-infiltrating lymphocytes. Radiation reversed this phenomenon and restored sensitivity to checkpoint blockade.51 Fortunately, many of the important questions outlined above, including optimal timing, dose, fractionation, and sequencing, are being addressed in active and planned clinical trials combining liver radiation with immunotherapy (eg, NCT03007407, NCT02239900, NCT02888743, NCT03101475, NCT03104439, NCT02437071, and NCT02710253).
Summary Liver SBRT plays an important role in the management of patients with unresectable liver metastases from colorectal cancer, but as our understanding of oligometastatic disease management advances and encompasses multiple primary histologies, we are likely to recognize even more indications for liver SBRT. Important cooperative group and large multiinstitution studies are exploring local therapy for oligometastatic disease across multiple histologies and liver SBRT is an important component of these trials for patients with liver metastases. Further, in the era of immuno-oncology, there is unbridled interest in combining radiation with immunotherapy, and numerous studies are combining SBRT to liver metastases with systemic immunotherapy across disease histologies. In summary, multiple studies have established the safety and LC efficacy of liver SBRT, primarily among patients with colorectal cancer metastases, and these pioneering investigations have paved the way for liver SBRT as an important component of modern, progressive oncologic care, across primary tumor types.
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294 30. Hong TS, Wo JY, Borger DR, et al: Phase II study of proton-based stereotactic body radiation therapy for liver metastases: Importance of tumor genotype. J Natl Cancer Inst 2017: 109(1) 31. Milano MT, Katz AW, Muhs AG, et al: A prospective pilot study of curative¡intent stereotactic body radiation therapy in patients with 5 or fewer oligometastatic lesions. Cancer 112:650-658, 2008 32. Milano MT, Katz AW, Zhang H, et al: Oligometastases treated with stereotactic body radiotherapy: Long-term follow-up of prospective study. Int J Radiat Oncol Biol Phys 83:878-886, 2012 33. Scorsetti M, Franceschini D, De Rose F, et al: Stereotactic body radiation therapy: A promising chance for oligometastatic breast cancer. Breast 26:11-17, 2016 34. Gomez DR, Blumenschein GR, Lee JJ, et al: Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non small-cell lung cancer without progression after first-line systemic therapy: A multicentre, randomised, controlled, phase 2 study. Lancet Oncol 17:1672-1682, 2016 35. Iyengar P, Wardak Z, Gerber DE, et al: Consolidative radiotherapy for limited metastatic non small-cell lung cancer: A phase 2 randomized clinical trial. JAMA oncologyOncol. 2017: e173501-e173501. 36. Palma DA, Haasbeek CJ, Rodrigues GB, et al: Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABRCOMET): Study protocol for a randomized phase II trial. BMC Cancer 12:305, 2012 37. Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol 1:1325-1332, 2015 38. Ng J, Dai T. Radiation therapy and the abscopal effect: A concept comes of age. Ann Transl Med 4:118, 2016 39. Postow MA, Callahan MK, Barker CA, et al: Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366:925931, 2012 40. Golden EB, Demaria S, Schiff PB, et al: An abscopal response to radiation and ipilimumab in a patient with metastatic non small cell lung cancer. Cancer Immunol Res 1:365-372, 2013 41. Bang A, Wilhite TJ, Pike LRG, et al: Multicenter evaluation of the tolerability of combined treatment with PD-1 and CTLA-4 immune check-
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point inhibitors and palliative radiation therapy. Int J Radiat Oncol Biol Phys 98:344-351, 2017 Hiniker SM, Reddy SA, Maecker HT, et al: A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma. Int J Radiat Oncol Biol Phys 96:578-588, 2016 Tang C, Welsh JW, de Groot P, et al: Ipilimumab with stereotactic ablative radiation therapy: Phase I results and immunologic correlates from peripheral T Cells. Clin Cancer Res 23:1388-1396, 2017 Luke JJ, Lemons JM, Karrison TG, et al: Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol 36:1611-1618, 2018. JCO.2017.2076.2229 Dewan MZ, Galloway AE, Kawashima N, et al: Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15:53795388, 2009 Chandra RA, Wilhite TJ, Balboni TA, et al: A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab. Oncoimmunology 4:e1046028, 2015 Young KH, Baird JR, Savage T, et al: Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy. PLoS One 11:e0157164, 2016 Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al: Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 74:5458-5468, 2014 Dovedi SJ, Cheadle EJ, Popple AL, et al: Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade. Clin Cancer Res 23:5514-5526, 2017 Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377:19191929, 2017 Wang X, Schoenhals JE, Li A, et al: Suppression of Type I IFN signaling in tumors mediates resistance to anti-PD-1 treatment that can be overcome by radiotherapy. Cancer Res 77:839-850, 2017
Introduction Department of Radiation Oncology, University of Colorado Cancer Center, Aurora, CO Financial support: No relevant financial support to disclose. Conflicts of interest: Tyler Robin: None. David Raben: Consultant: Astra Zeneca; Advisory Boards: Merck and EMD Serono and Genentech. Tracey Schefter: None. Address reprint requests to Tracey E. Schefter, MD, University of Colorado Cancer Center, 1665 Aurora Court, Suite 1032 MS F706, Aurora, CO 80045. E-mail: [email protected]
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raditional teaching dichotomizes malignancies into localized or locoregionally advanced disease (appropriate for local therapy and potentially curable) and metastatic disease (incurable and best managed with systemic therapy or best supportive care alone). However, this historical dogma was first challenged many years ago primarily in sarcoma patients with lung metastases,1-3 and later in the setting of colorectal cancers metastatic to the liver and lung, with multiple series demonstrating notable long-term survival with resection of metastatic disease.4-14 In the mid-1990s, Hellman and Weichselbaum coined the term, oligometastases, to describe https://doi.org/10.1016/j.semradonc.2018.06.009 1053-4296/© 2018 Published by Elsevier Inc.
Radiotherapy for Liver Metastases the intermediate state of limited metastatic disease, where curative strategies may be effective for some patients.15 Importantly, current national guidelines now support aggressive local therapy to sites of colorectal cancer metastases.16 Arguably, the most robust data for local management of metastatic disease come from the colorectal cancer and sarcoma literature,1-14 but there is precedent for this management paradigm in other histologies as well. For example, series have demonstrated long-term survival after pulmonary metastasectomy in breast cancer, as well.17,18 Understanding the role of liver stereotactic body radiation therapy (SBRT) in the contemporary management of oligometastatic disease is germane to understanding future steps and strategies to alter disease outcomes. We will briefly review the role of liver SBRT in colorectal cancer liver metastases, then shift our focus to existing data and ongoing studies of metastasis-directed local therapy, specifically SBRT, in noncolorectal histologies. Finally, we will address the excitement surrounding the potential for liver SBRT to augment immunotherapy and improve responses.
SBRT for Colorectal Cancer Liver Metastases Metastasectomy remains the gold standard for resectable liver metastases from colorectal cancers, but SBRT is an option for unresectable disease and for medically inoperable patients, with multiple phase II studies reporting excellent local control (LC). A few of the larger studies will be briefly reviewed. Hoyer et al conducted a phase II study of SBRT in this setting.19 Patients with 1-6 metastases (maximum diameter of the largest tumor <6 cm) from colorectal cancer were included. Patients were required to have undergone radical resection of the primary tumor, and the metastases had to be determined to be inoperable. Sixty-four colorectal cancer patients were treated to 141 metastases, of which 44 were liver metastases. The SBRT dose was 45 Gy in 3 fractions and 2-year tumor specific LC was 79% (because patients could receive SBRT to more than 1 site, patient-based LC could be lower and was 64%). The following major treatment-related gastrointestinal (GI) toxicities were reported: death from hepatic failure (1 patient), colonic ulceration requiring surgery (1 patient), and duodenal ulceration managed conservatively (2 patients).19 In a single institution phase I and/or II study from The Netherlands, patients with either primary or metastatic liver tumors not suitable for other forms of local therapy were enrolled in a study of liver SBRT.20 Of 25 total participants, 17 patients were treated to 34 metastatic liver tumors. The majority of patients had colorectal primary tumors (14 of 17). The SBRT dose was 30-37.5 Gy in 3 fractions and 2year local tumor control was 86%. There were 3 acute grade 3 toxicities (hepatic toxicity: 2 patients, asthenia: 1 patient), and 1 late grade 3 GI toxicity.20 Rusthoven et al reported a multi-institution phase I/II study of SBRT for liver metastases.21 In phase I, the total dose was escalated from 36 Gy to 60 Gy in 3 fractions, and
289 the phase II dose was 60 Gy. Patients could have 1-3 hepatic metastases with individual tumor diameter of less than 6 cm. Low burden extrahepatic disease was allowed. Forty-seven patients were enrolled and treated with 63 liver metastases. Although patients with colorectal primary tumors were best represented (32% of patients), the remaining patients were treated to liver metastases from an array of primary tumors (lung: 21%, breast: 9%, ovarian: 6%, esophageal: 6%, hepatocellular carcinoma: 4%, and other: 21%). Two-year LC was 92% (100% for tumors less than 3 cm), there was only 1 grade 3 toxicity (soft tissue necrosis), and no reported radiation-induced liver disease.21 Scorsetti et al conducted a phase II study of SBRT for patients with 1-3 unresectable liver metastases with maximum individual tumor diameter less than 6 cm.22 Sixty-one patients were enrolled with 76 liver metastases. Extrahepatic disease was allowed and 34% of patients had stable extrahepatic disease at study entry. Again, colorectal primaries were most frequently represented (48%), but as in the report by Rusthoven et al, noncolorectal histologies constituted a significant proportion of the study population. The SBRT dose was 75 Gy in 3 fractions and 1-year in-field LC was 94%. There was only 1 reported grade 3 toxicity (chronic chest wall pain, late grade 3). Interestingly, in contrast to the study by Rusthoven et al, there was no difference in LC when comparing treatment of tumors 3 cm vs tumors >3 cm (P = 0.90).22 Multiple groups have tried to determine the optimal liver SBRT dose for colorectal cancer metastases.23-25 Chang et al reviewed outcomes for a pooled cohort of 102 lesions (65 patients) treated with liver SBRT at 3 institutions between 2003 and 2009. In their experience, total dose, dose per fraction, and total biologically effective dose (BED), all correlated with LC in multivariate analysis, ultimately recommending a dose of 48 Gy in 3 fractions.23 Joo et al reviewed the outcomes for 70 patients treated with SBRT to 103 colorectal liver metastases, and also demonstrated a dose-response relationship for LC. Two-year LC was 52%, 83%, and 89%, for BED 80 Gy, 100-112 Gy, and 132 Gy (patients in this group received 60 Gy in 3-5 fractions), respectively.24 Further, the Princess Margaret Cancer Centre group recently published on the long-term outcomes of an institutional phase I/II study of 6-fraction SBRT for hepatic colorectal metastases, and observed an association between increasing minimum dose to the gross tumor volume (GTV) and improved LC.25
Considerations for Management of Liver Metastases From Noncolorectal Primaries While the acceptance of liver SBRT as an ablative modality for liver metastases more or less emerged in the context of inoperable colorectal cancer metastases, the oligometastatic management paradigm now applies to many malignant histologies, thus emphasizing the importance of reviewing the
290 existing data for liver SBRT for noncolorectal primary tumors as well. Importantly, 2 of the prospective liver SBRT studies reviewed above (Rusthoven et al and Scorsetti et al) did include a significant proportion of patients with noncolorectal primary tumors.21,22 Scorsetti et al included a subset analysis by histology (comparing what they classified as radioresistant tumors including melanoma, renal cell carcinoma, and pancreatic and biliary duct adenocarcinoma, to all others) and did not see a difference in LC, although the number of events was too low to analyze by multivariate statistics.21,22 Our group reviewed our experience at the University of Colorado with SBRT for melanoma and renal cell carcinoma.26 Thirty patients were treated to 53 metastatic lesions in the lung (n = 39), liver (n = 11), and bone (n = 3), and we found higher dose per fraction, single fraction equivalent dose (SFED),27 and BED, all correlated with improved LC. Two-year LC was 100% for SFED 45 Gy compared with 54% for SFED <45Gy, and tumor control probability (TCP) modeling suggested a prescription dose of 48 Gy in 3 fractions to achieve 90% LC at 2 years.26 Further contributing to our efforts to predict response, investigators at the Moffitt Cancer Center have developed a 10-gene expression radiosensitivity index (RSI), and studied this metric in the context of liver metastases.28 Using 372 metastatic liver tissue samples they show significant differences in RSI by primary tumor histology. In their model, high RSI is associated with radioresistance, and they report median RSI by histology as follows: gastrointestinal stromal tumor—0.57, melanoma—0.53, colorectal neuroendocrine—0.46, pancreas neuroendocrine—0.44, colorectal adenocarcinoma—0.43, breast adenocarcinoma—0.35, lung adenocarcinoma—0.31, pancreas adenocarcinoma—0.31, anal squamous cell cancer—0.22, and small intestine neuroendocrine—0.21 (P < 0.0001). They then reviewed 33 patients treated to 38 liver metastases with SBRT and compared LC for colorectal metastases (22 patients, 27 lesions) to LC for noncolorectal histologies (breast, anal, lung: 11 patients, 11 lesions). All metastatic tumors were treated with 50 or 60 Gy in 5 fractions over 1 week. Importantly, all patients in the noncolorectal SBRT group had tumors with lower RSI than colorectal, and their LC findings were concordant with the RSI, with 2-year LC of 59% for colorectal metastases compared with 100% for noncolorectal metastases.28 Similarly, a German Society of Radiation Oncology database study showed breast cancer liver metastases are more responsive to SBRT than other histologies, with 2-year breast TCP of 90% achievable with BEDmax of 157 + § 80 Gy for patients with prior chemotherapy and only 80 + § 62 Gy for patients without prior chemotherapy, compared with a BEDmax of 257 § 74 Gy needed for a 90% TCP for colorectal liver metastases without prior chemotherapy.29 Another notable study comes from the Dana Farber Cancer Institute.30 They conducted a phase II study of proton-based SBRT for liver metastases enrolling 89 patients of varying histologies (colorectal: 34 patients, pancreatic: 13 patients, esophagogastric: 12 patients, and other: 30 patients). Patients were treated with 30-50 Gray equivalent in 5 fraction regimens (dose was based on effective volume of liver
T.P. Robin et al. irradiated). In this study, LC was associated with genetic alterations, and KRAS mutation was found to be the strongest predictor of poor LC. Further, both mutant KRAS and TP53 was associated with very poor LC of only 20%, compared with LC of 69.2% for the remainder of the cohort.30 These data suggest that there are differences in SBRT outcome by primary tumor histology and genetic profiles, and that future trials might consider histology, genetic alterations and/or RSI-guided dose selection for liver SBRT. While differences in intrinsic radiosensitivity likely drive some of the observed differences in response, it is notable that colorectal cancer patients tend to be heavily pretreated. Perhaps as patients begin to be referred for liver SBRT earlier in their course, we will see less radioresistance in colorectal liver metastases. Although, in the German Society of Radiation Oncology database study described above, it is important to reiterate that colorectal liver metastases were predicted to require higher doses for tumor control even in patients who did not receive chemotherapy prior to SBRT.29
Liver SBRT in Oligometastatic Disease Management Although there are limited additional data specifically dedicated to noncolorectal liver metastases, there are multiple reported and ongoing studies utilizing SBRT for oligometastatic disease inclusive of patients with liver metastases. Milano et al reported their experience of 121 patients with 15 metastatic lesions from any primary histology treated with SBRT on 2 prospective studies at the University of Rochester.31,32 The majority of patients (74%) had noncolorectal primary tumors with breast primaries best represented (32%). Fifty-four of 121 patients had liver metastases. The majority of lesions (72%) were treated with 50 Gy in 10 fractions. For breast cancer patients, the 6-year rates for overall survival (OS), freedom from distant metastases, and LC were 47%, 36%, and 87%, respectively. For patients with nonbreast primary tumors, the 6-year rates for OS, freedom from distant metastases, and LC were 39%, 28%, and 74%, respectively.32 Scorsetti et al have also reported on patients with oligometastatic breast cancer treated with SBRT to 1-3 metastatic sites within the lung and liver.33 Patients with extrapulmonary and/or extrahepatic metastases were excluded. Twentythree of 33 enrolled patients were treated to liver metastases. Multiple liver SBRT regimens were utilized including: 48 Gy in 4 fractions (13 lesions), 75 Gy in 3 fractions (22 lesions), 67.7 Gy in 3 fractions (5 lesions), 61.8 Gy in 3 fractions (4 lesions), and 56.25 Gy in 3 fractions (2 lesions). LC was 98%, 90%, and 90%, at 1, 2, and 3 years, respectively. Median OS was 48 months and 1- and 2-year OS were 93% and 66%, respectively. One- and two-year progression-free survival (PFS) were 48% and 27%, respectively. There was no grade 3 toxicity reported.33 Importantly, 2 randomized controlled phase II trials of consolidative local therapy in non-small cell lung cancer (NSCLC) have recently been published.34,35 In the multiinstitution study by Gomez et al, patients from 3 North
Radiotherapy for Liver Metastases American centers with oligometastatic (3 lesions) NSCLC without progression after first-line systemic therapy, were randomized (1:1) to maintenance systemic therapy (or observation) or to local consolidative therapy (radiation or surgery of all lesions) with or without maintenance systemic therapy.34 Of the 49 enrolled patients, 25 were randomized to local consolidative therapy, though only 2 of these 25 patients were treated for liver metastases. Nevertheless, this is an important positive study with a median PFS in the consolidative local therapy arm of 11.9 months, vs 3.9 months in the maintenance systemic therapy arm.34 Similarly, Iyengar et al completed a single institution randomized phase II study of maintenance systemic therapy alone vs SBRT followed by maintenance systemic therapy, for patients with limited metastatic (primary plus up to 5 metastatic lesions) NSCLC without progression after initial chemotherapy. A total of 29 patients were enrolled. Fourteen patients were enrolled on the SBRT arm with 2 of these patients treated with liver metastases (33 Gy in 3 fractions). This was also an overwhelmingly positive study with a median PFS of 9.7 months in the SBRT arms vs 3.5 months in the maintenance chemotherapy arm. Although liver was an infrequent site of oligometastases on these studies, they nevertheless strongly support aggressive management of oligometastatic disease, including liver SBRT when liver metastases are present. Furthermore, local therapy for oligometastatic disease is now the topic of multiple cooperative group and large multiinstitution studies. Building on the studies by Gomez et al and Iyengar et al, NRG-LU002 (NCT03137771) is a randomized phase II and/or III study of maintenance systemic therapy vs maintenance systemic therapy plus SBRT for limited metastatic (3 discrete sites amenable to SBRT) NSCLC. Patients are randomized 2:1 to the SBRT arm. SBRT doses allowed on this study are 24 Gy in a single fraction, 30 Gy in 3 fractions, and 34 Gy in 5 fractions, and liver metastases are eligible to be treated on study. An analogous study, stereotactic ablative radiotherapy for oligometastatic non-small cell lung cancer (SARON) (NCT02417662), is actively enrolling patients in the UK. Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET; NCT01446744) is an international multi-institutional randomized phase II study that enrolled patients from Canada, the UK, Australia, and the Netherlands.36 Patients with 3 sites of metastatic disease from any primary site were randomized to standard of care or standard of care plus SBRT to all active sites of disease. Liver metastases on the SABR-COMET trial were treated with 45-60 Gy in 3-8 fractions.36 This study completed accrual in 2016 and data are maturing. NRG-BR001 (NCT02206334) is a phase I study of SBRT for the treatment of multiple metastases. Patients with metastatic breast, prostate, and NSCLC, with 4 metastases amenable to SBRT are being enrolled. On this protocol, liver metastases are treated with an “initial starting dose” of 45 Gy in 3 fractions with a planned “decreased dose limiting toxicity dose” of 42 Gy in 3 fractions, if needed. NRG-BR002 (NCT02364557) is a phase IIR/III trial of standard of care
291 with or without SBRT and/or surgical ablation for newly oligometastatic breast cancer. Patients with a controlled (status postsurgery § radiotherapy) primary tumor and 2 distant metastases are eligible to enroll and undergo random assignment (1:1) to either standard of care systemic therapy (arm 1) or standard of care systemic therapy plus ablation of all metastases with SBRT or surgery (arm 2). Liver metastases on NRG-BR002 will be treated with 45 Gy in 3 fractions. Local therapy for oligometastatic disease has shown promise in multiple single institutional and small multi-institution prospective trials, and now this paradigm is being tested in large multi-institution and cooperative group studies. The liver is a common site of metastases for multiple disease histologies, and liver SBRT is likely to continue to play an important role in oligometastatic disease management as this progressive oncologic treatment paradigm continues to evolve.
Combining Liver SBRT With Immunotherapy: An Emerging Concept As discussed in the previous sections, SBRT is an effective ablative modality for liver metastases, and as oligometastatic disease management paradigms continue to evolve, the indications for liver SBRT are likely to continue to expand. Interestingly, liver SBRT may also play a role in the management of patients with widely metastatic disease. Systemic immunotherapeutics have been approved for multiple tumors and ongoing trials are continuing to test various immunotherapies in multiple cancer types. Importantly, there is a growing body of literature supporting a role for radiation therapy to convert cancers into an “in situ tumor vaccine” by inducing release of antigens during cancer cell death, promoting proinflammatory signals within and out of the radiation field, and creating positive microenvironmental changes. Alterations in the tumor stroma as well as within the tumor itself may stimulate the innate immune system to activate tumor-specific T cells and enhance cancer infiltrationis.37 The abscopal effect has gained renewed enthusiasm, although actual documentation of this effect on a wider scale has been lacking. Mediated by the immune system, the abscopal effect occurs when a single lesion treated with a targeted approach such as radiation results not only in local tumor regression but also regression in nonirradiated areas.38 Postow et al sparked intense interest in the use of radiation as an immune “firestarter” when he described a patient with metastatic melanoma with slow progression of disease on maintenance ipilimumab, an anti-CTLA-4 agent, who received palliative SBRT to a paraspinal mass (28.5 Gy in 3 fractions). Ipilimumab was continued, and in addition to regression of the target lesion, regression of lesions not targeted with radiation was observed.39 In another notable case report, a patient with widely metastatic NSCLC received compassionate use ipilimumab and 1 of multiple liver metastases was treated with SBRT to 30 Gy in 5 fractions with the intent to generate an abscopal response. Follow-up imaging showed significant treatment response within the radiation field, but also in
292 unirradiated liver metastases, and at distant sites outside of the liver. This patient went on to receive 4 additional cycles of ipilimumab alone, and a PET/CT 1 year after SBRT was without evidence of disease. The investigators observed a post-treatment increase in absolute lymphocyte and eosinophil counts, as well as increased cytotoxic tumor infiltrating lymphocytes in an unirradiated site of disease.40 The obvious question that emerged initially was whether it was safe to combine checkpoint inhibitors with radiation. Emerging data in the metastatic setting across disease sites suggest that it is quite tolerable.41 Bang et al retrospectively reported on 133 patients, of whom received a CTLA-4 inhibitor alone (n = 28), PD-1 inhibitor alone (n = 88), or combination immune blockade (n = 17). Fifty-six patients received radiation within 14 days of the immune checkpoint inhibitor. Forty-six patients experienced at least 1 immune-related adverse event (ir-AE; 34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P = 0.0008). In general, ir-AEs were manageable and with the limitations of looking backward, not associated with treatment site irradiated. It appeared that ir-AEs were greater when radiation was administered within 14 days of checkpoint inhibition.41 In a prospective study, 22 patients with stage IV melanoma received 4 cycles of ipilimumab combined with radiation to 1-2 sites of metastatic disease started within 5 days after initiation of ipilimumab.42 Patients were required to have at least 1 nonirradiated metastasis for response assessment. The rate of grades 3-4 toxicity was 14% and the combined therapy did not appear to result in an increase in radiation or ipilimumab-associated toxicities. Fifty percent of patients experienced a complete response, partial response, or stable disease. The liver was the only site of SBRT for 2 patients in this study using a fractionated dose of 30 Gy in 5 fractions.42 In contrast, about half of the 35 patients enrolled in the recently published study by Tang et al received liver SBRT.43 This novel phase I study combined ipilimumab and SBRT in patients with metastatic solid tumors refractory to standard therapies with 1 liver or lung lesion and 1 additional nontarget lesion for monitoring.43 Patients were stratified into 4 groups of concurrent or sequential SBRT (50 Gy in 4 fractions) to a liver or lung lesion, with a fifth group receiving sequential radiation (60 Gy in 10 fractions) to either a liver or lung lesion. Clinical benefit (CB) was defined as out-of-field immune-related partial response or immunerelated stable disease lasting at least 6 months. Clinical benefit was achieved in 23% of patients evaluable for clinical response. Only 2 patients experienced dose limiting toxicity. The study also looked at immune marker expression changes, and 1 of the exciting and hypothesis-generating findings from this study as it relates to liver SBRT was that systemic immune activation was greater after liver SBRT than after lung SBRT.43 The reasons for this observation remain unclear and warrant further study; would this observation be similar with anti-PD-1/PD-L1 therapy as it was with antiCTLA-4 therapy? It remains to be seen. Additionally, in a recently published phase I study from the University of Chicago, patients progressing on standard
T.P. Robin et al. treatment received SBRT to 2-4 metastases, and pembrolizumab was initiated within 7 days after completion of SBRT.44 In total, 151 metastases were treated on study including 24 liver metastases. Liver metastases received 45 Gy in 3 fractions. Of 62 patients available for 3 month toxicity evaluation, 6 patients experienced dose limiting toxicity (no dose limiting toxicities were observed in patients that underwent SBRT to liver metastases). The overall objective response rate for nonirradiated lesions was 13.5%.44 In addition, interferon (IFN)-g-associated gene response significantly correlated with nonirradiated tumor response in 8 patients with pre- and post-SBRT biopsy specimens (P = 0.023).44 What is the optimal radiation dose and schedule to enable adequate priming for immunotherapy and what is the extent of the tumor that should be irradiated? Preclinical studies using a colon carcinoma mouse model45 and a clinical study conducted in patients with melanoma46 suggest that fractionated dosing is preferred to a single-dose strategy to elicit an abscopal response when paired with anti-CTLA-4 antibodies. Is it all about the size of the radiation fractionation or does volume play a role as well? Certainly, there is concern that larger volumes and more protracted radiation may lead to a chronic immunosuppressive state and reduce the number of infiltrating effector T-cells needed to enhance immune-based cytotoxicity.47 Hopefully we will continue to explore study designs that attempt to answer these critical radiation questions. The preferred sequence of radiation and immunotherapy remains investigational. Based on current knowledge of cancer immunity and preclinical investigations, radiation prior to immunotherapy, or the 2 therapies administered concurrently, might be optimal, although certainly the type of immune-enhancing agent may dictate the best sequencing.47 With anti-PD-1/PD-L1 therapy, the effects may be different than with anti-CTLA-4, and treating with these checkpoint inhibitors too far after fractionated radiation may not be as effective as a concurrent approach or one shortly after radiotherapy.48,49 Potentially relevant to our discussion are the benefits seen with administration of anti-PD-L1 therapy in the Phase III NSCLC trial (PACIFIC study) after completion of chemoradiation with a doubling of the median PFS.50 This might simplify trials using SBRT for liver metastasis and enable expansion of combination types of strategies with newer immune agents or targeted drugs depending on the underlying molecular nature of the liver metastasis. Will we achieve a greater response to immunotherapy if we treat multiple sites that may have different microenvironments vs only 1 site? Treatment of oligometastases disease is aggressively under investigation with SBRT and is being combined with checkpoint inhibitors in a variety of cancer types and should be tested against single-lesion treatment. Will radiation become the “firestarter rather than the fire” to enhance immune mediated cancer killing in a way that will create wider response, applicability and durability? PD-L1 expression, IFN-g expression, and emerging molecular markers may help predict response to checkpoint inhibition, but the overall response rates across tumor types still appears to be modest. Can radiation convert advanced tumors considered nonresponsive intrinsically such as metastatic
Radiotherapy for Liver Metastases colorectal and pancreatic cancer and change the profiles to enact response? PD-L1 expression may be present; however, tumors are clever enough to downregulate alternative critical immune-related pathways to evade further immune surveillance. Wang et al investigated this phenomenon creating a preclinical tumor model to study anti-PD-1 resistance in a syngeneic host exposed to repetitive dosing with anti-mouse PD-1 antibodies.51 Importantly, although PD-L1 expression did not differ between the resistant and parental tumor cells, IFN-g, MHC class I and II, as well as b2-microglobulin were significantly downregulated in the anti-PD-1-resistant tumors compared with parental tumors and contained fewer CD8+ (CD8a) and CD4+ tumor-infiltrating lymphocytes. Radiation reversed this phenomenon and restored sensitivity to checkpoint blockade.51 Fortunately, many of the important questions outlined above, including optimal timing, dose, fractionation, and sequencing, are being addressed in active and planned clinical trials combining liver radiation with immunotherapy (eg, NCT03007407, NCT02239900, NCT02888743, NCT03101475, NCT03104439, NCT02437071, and NCT02710253).
Summary Liver SBRT plays an important role in the management of patients with unresectable liver metastases from colorectal cancer, but as our understanding of oligometastatic disease management advances and encompasses multiple primary histologies, we are likely to recognize even more indications for liver SBRT. Important cooperative group and large multiinstitution studies are exploring local therapy for oligometastatic disease across multiple histologies and liver SBRT is an important component of these trials for patients with liver metastases. Further, in the era of immuno-oncology, there is unbridled interest in combining radiation with immunotherapy, and numerous studies are combining SBRT to liver metastases with systemic immunotherapy across disease histologies. In summary, multiple studies have established the safety and LC efficacy of liver SBRT, primarily among patients with colorectal cancer metastases, and these pioneering investigations have paved the way for liver SBRT as an important component of modern, progressive oncologic care, across primary tumor types.
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