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Radiation Therapy for Liver Tumors: The State-of-the-art
Shahed Badiyan, MD1; Keith R. Unger, MD2; Adeel Kaiser, MD1; Allie Garcia-Serra, MD3; Miguel Perez, MD3; Michael D. Chuong, MD3
1University of Maryland Medical Center; Baltimore, MD
2Georgetown University; Washington, DC
3Miami Cancer Institute at Baptist Health South Florida; Miami, FL
Abstract
Most patients with primary or metastatic liver cancer are not resectable and therefore must be considered for nonsurgical therapies. Although radiation therapy was once being considered not feasible for treating liver cancers, it is now increasingly being utilized due to advancements in radiation technologies that permit high dose to be delivered precisely to liver tumors while simultaneously sparing the normal liver. There are several techniques by which radiation therapy can be delivered to patients with liver cancer, including radioembolization, stereotactic body radiation therapy, and proton beam therapy. Here we review the state-of-the-art in radiation therapy for treatment of liver cancer, including mounting data signaling that radiation therapy will maintain a central role in the management of these patients.
Introduction
The incidence of liver and intrahepatic bile duct cancer is rising in the United States, with the National Cancer Institute estimating 40,710 new diagnoses and 28,920 deaths in 2017.1 Patients who meet strict selection criteria should be offered hepatic resection or transplantation, which remains the gold standard for treatment of primary and metastatic liver cancer for appropriate patients and provides the highest probability of long-term disease control and potentially cure.2 However, fewer than 20% of patients are suitable for surgery; therefore, most patients with liver cancer are considered for nonsurgical treatment such as radiation therapy. The optimal nonsurgical approach remains contested in the absence of high-quality randomized data. In that context, multidisciplinary patient review, including surgical oncology, medical oncology, radiation oncology, and interventional radiology is paramount to discussing and recommending the best treatment strategy for each patient with liver cancer.
Radiation therapy to the liver was considered taboo for many years. In 1954, Phillips and colleagues wrote that radiation therapy to liver metastases had “always been regarded as a hopeless proposition” due to “fear of irreversibly damaging the surviving liver parenchyma.”3 The high incidence of liver injury from radiation, also known as radiation-induced liver disease (RILD), was largely the result of the unsophisticated and antiquated technology that did not allow selective treatment of liver tumors and therefore exposed a substantial volume of the normal liver to high doses.4 Moreover, the radiation experience for treatment of liver tumors during the 1970s and 1980s yielded poor results partially due to lack of understanding of liver tolerance to radiation therapy.5 With modern technology and a more comprehensive understanding of normal organ tolerance to radiation dose, it is possible to safely and effectively treat both primary and metastatic liver tumor patients with radiation.
Radiation oncologists today are well positioned to deliver ablative doses of radiation to the liver accurately and safely through better understanding which patients should be selected for radiation therapy (and equally important, which should not), improvement in liver diagnostics, respiratory motion control, and improvement in radiation delivery techniques such as radioembolization, intensity modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and proton beam therapy (PBT).
Radioembolization
Transarterial radioembolization with Yttrium-90 (Y90) is a well-established treatment strategy for the management of primary and metastatic tumors of the liver. Early clinical experience with the technique dates back to studies from the 1980s.6,7 The procedure involves the administration of Y-90 coated microspheres through hepatic arteries, resulting in deposition of the microspheres in the capillaries of the targeted liver tumors. This permits the delivery of beta radiation at a distance of 2.5 mm from each microsphere.8 The limited range allows for critical sparing of normal liver tissue adjacent to tumor targets.
The benefits of radioembolization have now been recognized within the oncology community. The 2016 guidelines by the European Society of Medical Oncology (ESMO) encourages consideration of radioembolization in the setting of salvage therapy.9 In addition, the 2017 National Comprehensive Cancer Center (NCCN) guidelines support the use of Y90 in highly selected patients with chemotherapy-resistant/refractory disease and predominantly hepatic metastases.10
Radioembolization has been used for a variety of cancer histologies including metastases from neuroendocrine, breast, and colorectal tumors, as well as primary intrahepatic cholangiocarcinoma and hepatocellular cancers.8,11-15 Although new data are emerging regarding the benefit of Y90 for many of these histologies, this review will focus on colorectal metastases and hepatocellular tumors, the most commonly treated cancers using this approach.
Radioembolization for Colorectal Cancer
The salvage setting, following exhaustion of systemic treatment options, remains the most common indication for Y-90 therapy in colorectal cancer. A matched pair analysis conducted by researchers from Germany demonstrated a 5-month improvement in survival (8.3 vs 3.5 months, P< .001) in favor of Y90 compared with best supportive care. The survival benefit was evident both at 3 months (97% vs 59%) and with longer follow-up at 1 year (24% vs 0%). Furthermore, the majority of Y-90– related toxicities in the study were mild grade 1 to 2 events.16
Prospective data also support the use of Y90 for salvage. A multicenter, randomized study of 44 patients showed that Y90 plus chemotherapy could more than double time to tumor progression in colorectal cancer patients with metastases confined to the liver (4.5 vs 2.1 months, P=0.3).17 This resulted in a median overall survival improvement from 7.3 to 10 months (P=0.8). Similar results were observed in a larger, prospective series that included 61 colorectal cancer patients who had received prior chemotherapy. In this study, patients without significant extrahepatic disease received Y-90 treatment without chemotherapy and demonstrated a median survival of 8.8 months following treatment.18
Having established a benefit with Y90 in the salvage setting, investigators have also sought to assess the utility of Y90 during initial treatment. This search led to the inception of the SIRFLOX trial, a randomized study evaluating the safety and efficacy of Y90 as a component of first-line therapy in 530 patients with liver metastases from colorectal cancer.19 Patients in this study were randomized to Y-90 resin microspheres with FOLFOX versus FOLFOX alone. Bevacizumab was optional in both arms.
Notably, 40% of patients in both arms harbored extrahepatic disease, and almost half in each group had the primary tumor site still intact. The primary endpoint of the trial was progression-free survival at any site, which remained largely unchanged with the addition of Y90 (10.2 vs 10.7 months, P=.43). Grade 3 toxicities were higher with Y90 (85% vs 73%) but did not reach statistical significance. The incidence of serious adverse events in the Y-90 arm remained low for duodenal ulcers (3.7%), radiation hepatitis (0.8%), and hepatic failure (1.2%). Despite the absence of progression-free survival at any site, progression-free survival in the liver improved with Y90 from 12.6 to 20.5 months (P=0.002)19.
Given the results of the SIRFLOX study, at present there are no prospective studies demonstrating a survival benefit from improved tumor control in the liver using Y90. However, extrapolation from data involving liver-directed therapy using ablation suggests that management of hepatic disease in properly selected patients may still translate to a survival benefit. The EORTC 40004 CLOCC study based in Europe randomly assigned 119 patients with unresectable colorectal cancer liver metastases to chemotherapy alone or chemotherapy plus radiofrequency ablation (RFA) plus/minus resection20. Trial results demonstrated an impressive 8-year overall survival of 36% vs 9% in favor of combination therapy.21
Interestingly, the CLOCC study lacked many of the “shortcomings” present in the SIRFLOX trial. Patients with intact primary tumors, any extrahepatic disease, 10 or more liver metastases, liver metastases >4 cm, or >50% of liver involvement with tumor were all excluded from the EORTC study20. This resulted in a cleaner examination of the benefits of liver-directed therapy. Researchers hoped to demonstrate a similar survival advantage for Y90, although in a recently published combined analysis of 3 randomized trials of first-line FOLFOX with or without Y90 there was no survival difference (22.6 vs 23.3 months).22 These outcomes signal that the early use of Y90 is not indicated, at least in an unselected population, although it is possible that subsets of patients may still benefit. Recently presented data from 739 patients from the SIRFLOX and FOXFIRE-Global trials show that patients with primary right-sided colon tumors may have improved survival (22 vs 17.1 months; P=.007) over those with left-sided tumors (24.6 vs 25.6 months; P=.279) when Y90 is used in the first-line setting with FOLFOX compared to FOLFOX alone23. The reason for such a difference remains uncertain.
Radioembolization for Hepatocellular Carcinoma
Historically, Y90 has been used for patients with unresectable hepatocellular carcinoma (HCC) who were deemed unfit for transarterial chemotherapy (TACE) due to extensive bilobar disease or portal vein tumor thrombosis (PVT).8 These were patients unlikely to undergo curative liver transplant. However, a recently reported prospective, randomized trial from researchers at Northwestern has questioned this longstanding dogma. In this study, 45 patients were randomized to TACE or Y90 and then examined using an intent-to-treat analysis.24 Inclusion criteria for the trial were Child-Pugh A/B status, no vascular invasion, total bilirubin of 2.0 mg/dL or less, aspartate aminotransferase or alanine aminotransferase below 5 times the normal limit, albumin >3 g/dL, tumor burden <50% of total liver volume, and <70% of tumor involvement of the liver in the setting of infiltrative disease. The TACE group received 75 mg/m2 of drug/lipiodol followed embolic microspheres while the Y-90 group was treated to 120 Gy. Selective treatment was employed in 17 of 24 Y-90 patients and 16 of 19 TACE patients. The remaining patients in each group were treated using a lobar approach. At a median follow-up of 15.7 months, 7 patients in the TACE group underwent transplant in comparison to 13 from the group receiving Y90. The primary endpoint, time to progression (TTP), was significantly different between the two groups. Median TTP was 6.8 months for TACE and was not reached (>26 months) for Y90 (p = 0.0012). Nonetheless, overall survival was similar in both groups (17.7 vs 18.8 months, P=.99).24 Although the improved TTP did not translate to a survival benefit due to competing risks of mortality, improved tumor control may potentially decrease the drop rate from tumor progression while patients remain listed for transplant.
The role of Y90 has been questioned in the context of sorafenib, although recently presented data have provided some much-needed clarity. Outcomes from the SARAH trial, a French multicenter phase 3 trial that randomized 459 patients with hepatocellular carcinoma (HCC) to either SIRT or sorafenib, showed no difference in overall survival (8 vs 9.9;P=.179), although Y90 was much better tolerated and resulted in higher response rates in the liver.25 The SIRveNIB randomized trial, an Asian multicenter phase 3 trial, randomized 360 HCC patients to either SIRT or sorafenib and, like the SARAH trial, failed to show a difference in overall survival (8.5 vs 10.6 months;P=.203), although Y90 did result in high response rates and less toxicity.26
The prognosis for HCC patients with portal vein thrombus (PVT) is quite poor, especially those with main versus segmental PVT. Salem and colleagues reported median survival in Child-Pugh B patients who had PVT of 2.7 months compared with 6.4 months if PVT was not present; in Child-Pugh A patients median survival was 6.3 vs 9.5 months, respectively.27 Generally, the management of such patients has been difficult because PVT is a contraindication to both surgery and TACE. Even with the administration of sorafenib, the overall survival of patients with PVT remains approximately 8 months.28 Results from recent studies have provided more encouraging results. In 2015, researchers from France reported their experience using a dosimetrically guided dose intensification approach. They treated 41 patients with PVT using this strategy and demonstrated that with good PVT targeting, as well as the achievement of a tumor dose >205 Gy, overall survival could be improved from 3 months to 20 months (P<.0001).29 It is important to recognize that these outcomes are more favorable than others in the literature.30 Still, these results have shifted the future focus of Y-90 therapy towards a more targeted, dosimetrically guided, and patient-individualized treatment strategy.31
Stereotactic Body Radiation Therapy
Stereotactic body radiation (SBRT), also known as stereotactic ablative radiation therapy (SABR), is an advanced photon therapy technique that has become an increasingly utilized treatment option for both primary and metastatic liver tumors. With the development of advanced radiation therapy planning and delivery techniques, ablative dose can be safely delivered to tumors within the liver, while simultaneously sparing adjacent normal tissue. By employing hypofractionated schedules, whereby large doses are delivered in 1 to 5 daily fractions, SBRT is able to achieve high rates of local control and with an excellent safety profile32. Because SBRT delivers treatment with rapid dose fall off beyond the target, thus limiting dose to the normal liver tissue, it can be safely delivered to carefully selected patients with or without underlying liver dysfunction. SBRT requires accurate localization and immobilization techniques, which account for respiratory motion to ensure accuracy and precision.33 Motion management strategies include respiratory gating, abdominal compression, active breathing control, and tumor tracking, which will be more extensively discussed below.
While surgery is the preferred treatment for resectable liver metastases, SBRT is a non-invasive option when resection is not possible. Alternative techniques such as image-guided ablation and arterially directed therapies offer acceptable outcomes but can be limited by tumor location and vascular anatomy.34,35 Although there are no randomized data, retrospective reports and phase I/II studies provide clinical evidence for the safety and efficacy of SBRT.
Early studies of SBRT in liver tumors primarily employed single fraction regimens, extrapolating from the stereotactic radiosurgery experiences used in the treatment of brain tumors. In a phase I/II study conducted between 1997 to 1999, 60 patients with liver tumors (4 primary, 56 metastatic) were treated with a single fraction ranging from 14 Gy to 26 Gy.36 The median tumor size was 10 cm3 (range, 1-132 cm3). The actuarial local tumor control rate was 81% at 18 months after SBRT and no major toxicities were reported. Goodman et al conducted a similarly designed phase I dose escalation trial of SBRT for primary (n=7) and metastatic liver tumors (n=19) using doses starting at 18 Gy and increasing to 30 Gy in 4 Gy increments delivered in a single fraction.37 Tumor size was limited to a maximum of 5 cm, and a total of 40 lesions were treated. No dose limiting toxicities were observed, but 2 patients developed late grade 2 gastrointestinal ulcers or bleeds. The 1-year local control rate was 77%, and the median survival was 28.6 months.
Initial work with fractionated SBRT was led by researchers from University of Colorado, who conducted a phase I/II multi-institutional study of a 3-fraction regimen in 47 patients with 63 metastatic liver tumors.38 Extrapolating from the surgical literature, the protocol required that a minimum volume of 700 mL of normal liver receive less than 15 Gy, and the maximum tumor diameter was limited to 6 cm. Doses were escalated from 36 Gy to 60 Gy in 3 fractions, in increments of 6 Gy, without dose-limiting toxicity in the phase I portion;60 Gy in 3 fractions was used in the phase II component. The actuarial rate of local control at 1- and 2-years was 97% and 92%, respectively. The 2-year local control rate was 100% in tumors 3 cm or less and 77% in tumors greater than 3 cm. There were no grade 4 or 5 toxicities.
Several prognostic factors have been associated with outcomes following SBRT for liver metastases. Smaller tumor volumes38,39 and higher doses 36,38,39 have been associated with higher local control. A large pooled analysis of colorectal liver metastasis outcomes demonstrated that total dose, dose per fraction, and biologic equivalent dose correlated with local control.40 The investigators concluded that doses of 46 Gy to 52 Gy in 3 fractions were required to achieve 90% local control at 1 year.
Early phase studies and retrospective series have also demonstrated the efficacy of SBRT for hepatocellular carcinoma (HCC) with acceptable rates of toxicity in Child-Turcotte-Pugh class A patients. Retrospective studies in a North American patient population with HCC have shown local control rates ranging from 87% to 100% with 1- to 2- year overall survival rates of 67-75%. 41-44 A large retrospective study from Japan similarly reported a local control rate of 91%, with 70% of patients alive 3 years following SBRT.45
Similar results have been reported in prospective studies. A pooled analysis from a sequential phase I/II trial conducted at Princess Margaret Hospital treated 102 patients with 6-fraction SBRT. Between 24 Gy and 54 Gy was prescribed based on dose delivered to normal liver tissue, with the goal being to deliver the highest possible dose. 43 All patients had Child-Pugh class A liver disease. Over 60% of patients had multiple liver lesions with a median tumor size of 7.2 cm on cross-sectional imaging. In addition, 55% of patients had tumor vascular thrombosis. The 1-year local control rate was 87% and the median overall survival in all patients was 17 months. Tumor vascular thrombosis was a predictor of worse overall survival.
Combinations of SBRT with other liver-directed therapies, especially TACE, have been associated with improved outcomes for larger tumors that have historically not been well controlled with monotherapy. Jacob and colleagues performed a retrospective study of patients with HCC lesions measuring at least 3 cm, some of whom received TACE alone (n=124) and others who received TACE plus SBRT (n=37). They found reduced local recurrence with the addition of SBRT (10.8 vs 25.8%;P=0.04). Furthermore, overall survival favored the SBRT cohort after censoring for liver transplantation (33 vs 20 months;P=0.02). A retrospective study from China that included HCC patients with median tumor size of 8.5 cm (range, 5.1-21 cm) reported improved 5-year overall survival with the addition of TACE or transarterial embolization (TAE) to SBRT versus SBRT alone (46.9 vs 32.9%;P=0.047). Other studies have demonstrated favorable outcomes of this combination strategy, even when used as a bridge to transplantation to maintain patients within transplantation eligibility.
Radiofrequency ablation (RFA) is well established in the management of HCC, and it remains hotly debated what the role of SBRT should be, given that patient population for each of these modalities overlaps. Emerging data suggest that outcomes of SBRT as a bridge to transplantation are similar to that of RFA with a favorable toxicity profile.46,47 A large retrospective study from the University of Michigan compared outcomes in patients undergoing either radiofrequency ablation (RFA) or SBRT for tumors larger than 2 cm.48 On multivariate analysis, RFA was associated with significantly higher rates of local progression when compared with SBRT.
RFA was frequently used for tumors less than 3-4 cm, while SBRT was typically employed for tumors that were not visible by ultrasonography, abutting vascular structures or the luminal gastrointestinal tract, or had previously failed RFA. However, this study has been widely criticized because criteria differed for determining local progression after RFA versus SBRT. Other criticisms include longer follow up in the RFA cohort (20 vs 13 months) that could have led to a higher recurrence rate, more favorable liver function in the SBRT cohort, and poorer outcomes in the RFA cohort compared with historical control.
There are significantly fewer studies assessing SBRT for intrahepatic, hilar, and extrahepatic cholangiocarcinoma. Mahadevan et al reported the results of 32 patients with hilar and intrahepatic cholangiocarcinomas treated with SBRT to a total dose of 30 Gy in 3 fractions, with approximately half of these patients receiving adjuvant chemotherapy in the form of gemcitabine with or without cisplatin.<49 The 1-year local control and overall survival was 88% and 58%, respectively. Grade III toxicities included 2 duodenal ulcers, 1 liver abscess, and 1 episode of cholangitis. Jung at al reported a study of 58 patients with unresectable intrahepatic and extrahepatic cholangiocarcinoma who were treated with a median dose of 45 Gy in 1-5 fractions either with SBRT alone or as boost to conventional radiation therapy.50 One-year local control was 85%, and the median survival was 10 months. Six patients developed grade 3 or higher late toxicity, 3 of whom had received previous in-field irradiation.
Proton Beam Therapy
Although sophisticated x-ray (photon) therapy techniques such as SBRT can safely treat some patients with liver tumors, others may not be ideal candidates because of factors including excessively large tumor burden, multiple tumors, and suboptimal liver function. Unlike x-ray beams that deposit the majority of their dose just below the skin surface and pass completely through the patient, proton beams have a relatively low entrance dose and deposit the majority of their dose at the end of their predefined range (ie, the Bragg Peak) with no dose beyond that point.51 As such, there is no exit dose within a proton beam, resulting in significantly less radiation exposure to healthy liver parenchyma and other nearby organs like the small bowel. The clinical impact of this unique form of radiation therapy can be profound, both with respect to lowering the possibility of normal tissue injury and also by permitting safe dose escalation to increase tumor control.
A number of dosimetric studies comparing proton beam therapy (PBT) to x-ray techniques (eg, SBRT) have provided evidence for a markedly improved therapeutic ratio favoring PBT. Toramatsu et al compared PBT and x-ray plans in 10 patients and 13 liver tumors prescribed to 60 Cobalt Gray Equivalent (CGE) in 15 fractions.52 They concluded that normal liver dose constraints could be achieved using either radiation modality for tumors ≤6.3 cm in diameter, and that only PBT could successfully provide appropriate tumor coverage and satisfactory normal organ dose for tumors with diameter ≥7.8 cm. In addition, using the Lyman normal tissue complication probability model, they found that the risk of RILD for tumors with a diameter ≥6.3 cm was 94.5% with photon therapy vs 6.2% with PBT. I
In order to determine the importance of tumor location in the liver in relation to tumor size, investigators at the University of Pennsylvania created 6 spherical tumors ranging in size from 1-6 cm in diameter in four separate segments of the liver on one patient's computed tomography scan, leading to 24 different tumors.53 Each tumor was hypothetically treated to 50 CGE in 5 fractions through an assortment of proton and x-ray plans. The authors found no difference for tumors <3 cm at any location or up to 6 cm in the caudal (segment 6) and left medial (segments 2/3) locations. However, in tumors ≥3 cm located in the central (segment 1) and peripheral/dome (segment 7/8), PBT plans delivered a significantly lower mean liver dose and therefore would be associated with a lower risk of RILD.
The early prospective clinical data on PBT for liver tumors has clearly indicated that HCC patients with cirrhosis can be safely and effectively treated. Kawashima et al published a phase II study of 30 patients with liver cirrhosis and solitary HCC who received PBT to 76 CGE in 20 daily fractions.54 Twenty and 10 patients had Child-Pugh A and B disease, respectively. The 2-year local progression-free rate was 96% and 2-year OS was 66%. Acute toxicity was very limited and 4 patients died of liver failure 6-9 months following PBT without tumor recurrence. Investigators at Loma Linda also published a phase II study in which 34 patients with a Child Pugh score of ≤10 received 63 CGE in 15 daily fractions.55 The 2-year local tumor control rate was 75%, and OS was 55%. Toxicity was minimal, and no severe RILD was reported. In patients with a detectable α-fetoprotein level, the levels declined from a pretreatment mean of 1405 to a 6-month post-treatment mean of 35. Six patients went on to have liver transplants, including 2 with no residual HCC in the explanted specimen. The same group updated their results in 2011, with a total of 76 patients.56 The mean tumor size was 5.5 cm, and 11 patients had more than 1 tumor. Forty-six percent of patients were within Milan transplantation criteria, and 65% within San Francisco criteria. The median progression-free survival was 36 months, and 3-year PFS was 60% for patients within Milan criteria and 21% for those outside Milan criteria. Eighteen patients went on to have a liver transplantation and had a 3-year OS rate of 70%. Of those patients, 13 (72%) had a pathological complete response or microscopic residual disease. No patients developed severe RILD. Loma Linda has also recently published data from an interim analysis of a randomized trial of PBT versus transarterial chemoembolization (TACE) in patients with HCC.57 While there was not a difference in overall survival (OS), a trend towards improved 2-year local control (88% vs 45%;P=0.06) and progression-free survival (48% vs 31%;P=0.06) favored receipt of PBT. Furthermore, the analysis suggested reduced toxicity and need for hospitalization favoring PBT (P<0.001).
While clinical trials have focused attention on the role of PBT for patients with HCC, there are emerging data that suggest future studies also include intrahepatic cholangiocarcinoma (ICC). In 2016, Hong and colleagues published results from a phase II multi-institutional study of hypofractionated PBT for patients with HCC or ICC.58 Forty-four patients with HCC, 37 with ICC, and 2 patients with mixed histology tumors received 58 CGE in 15 fractions for tumors within 2 cm of the porta hepatis or 67.5 CGE in 15 fractions for all other tumors. Most patients were Child-Pugh A (79.5%). The median tumor size was 5 cm for HCC patients and 6 cm for ICC patients. Tumor vascular thrombosis was present in nearly 30% of patients, and multiple tumors were present in 27.3% of HCC patients and 12.8% of ICC patients.
Despite these unfavorable tumor characteristics, encouraging 2-year local control (94.8% for HCC and 94.1% for ICC) and 2-year OS were reported (63.2% for HCC and 46.5% for ICC). The NRG Oncology GI-001 randomized trial is currently evaluating the role of radiation therapy (including PBT) after upfront chemotherapy without disease progression (NCT02200042).
Finally, the role of PBT for patients with liver metastasis has not been as extensively studied as in patients with primary liver malignancies and is highly controversial. Given that patients with metastatic liver disease may have exceptionally favorable prognoses and live many years, especially if their liver disease is adequately controlled, some potential benefits of PBT over PT(eg, reduced secondary malignancy risk) provide a rationale for further evaluation of PBT in this population.59-62
Respiratory Motion Management
Respiratory organ motion management is one of the main concerns when planning for radiotherapy treatment since it has the capability of altering tumor position and affecting treatment delivery.63 Tumor motion during respiration can cause errors in delineating margins during treatment planning but can also affect dosimetric calculations increasing the risk of RILD. Several studies have evaluated liver displacement throughout respiration with reports of displacement range of 5-17 mm predominantly in the craniocaudal (CC) direction.64,65 Kirilova et al measured the three dimensional liver tumor motion in relationship to liver motion and observed an average displacement of 15.5 mm (CC), 10 mm anteroposteriorly (AP) and 7.5 mm in the lateral (ML) axis further supporting the need for an intervention to reduce this motion.66
The presence of motion during CT imaging can negatively impact image density and cause image distortions which can render inaccurate target volume delineation resulting in dosimetric errors.67 Booth et al evaluated the effect motion has on CT uncertainty and subsequent dose distributions utilizing a Monte Carlo model to simulate organ translations at the time of imaging. They found that for a 60 Gy treatment, a 4 Gy underdosing in the penumbral region of a single-field dose distribution was seen.68
The American Association of Physicists in Medicine (AAPM) in report 91 concluded that significant artifacts and systematic errors during imaging procedures occur with increased motion. Therefore, they recommended limiting motion to less than 5 mm.69 Bortfeld et al reported the standard deviation is generally insignificant, within 1% of the expected value, for IMRT delivery if motion amplitude <5 mm during a 30 fraction treatment course.70 Three commonly utilized techniques for motion management include deep inspiration breath hold, respiratory gating, and abdominal compression.
Deep Inspiration Breath Hold (DIBH)
DIBH technique can be achieved by 2 options, voluntary breath hold and assisted breath hold. Patients without comorbidities, including lung cancer or respiratory disease that may limit their capacity to hold their breath for a prolonged time, can undergo voluntary breath hold, which does not require the use of a breath hold device and has been shown to have dosimetric benefits in breast and gastric cancer patients.71-73 DIBH has been reported to reduce internal organ motion to up to 2.8 mm.74
Patients who cannot perform voluntary breath hold can undergo assisted active breathing coordinator (ABC) and video-based real-time positioning management (RPM). ABC helps reduce diaphragm-induced liver motion by assisting the patient to temporarily hold deep inspiration while the radiation beam is being delivered to the immobilized tumor.75 Eccles et al evaluated the reproducibility of liver position using ABC for liver cancer and found intrafraction CC reproducibility of 1.5 mm while interfraction CC reproducibility was 3.4 mm.76 Performing a normal tissue complication probability comparison between free breathing and ABC plans, Zhao et al found that the predicted incidences of RILD by Lyman model were 1% compared with 2.5% in favor of the ABC plan due to reduced PTV margins for the ABC plan.77 In addition, Zhong et al treated liver tumors with hypofractionated regimens and evaluated dosimetric effects on the target coverage and normal tissues comparing ABC and free breathing (FB) and found that ABC significantly reduced dose to normal tissues and improved target coverage compared to FB (P<0.05).78 These data support breath-holding techniques for reducing liver motion uncertainties in RT planning and as a feasible option for reduced normal liver irradiation.
Respiratory Gating
Respiratory gating allows patients to breathe freely while the respiratory cycle is monitored and administration of radiation for both imaging and treatment are administered during a certain portion of the cycle. There are 2 variables of gating that are characterized by respiratory motion, displacement or phase gating. The former uses a pre-set window of relative organ positions acquired by measurement of organ displacement during the 2 extremes of breathing motion. During phase gating, a radiation beam is delivered when the phase of respiration signal is within a pre-set window.69
In contrast, internal fiducial markers require a patient to undergo invasive procedures to introduce markers (radiotransmitters, stents, or surgical clips) to the treatment area. Seppenwoolde et al concluded that implanted markers are superior for predicting the tumor position compared to other surrogates if implanted reasonably close to the tumor.79 However, this technique increases costs, time, and risk of complications to the patient due to the invasive nature of the procedure. Hugo et al evaluated composite field dosimetry of respiratory-gated IMRT using a moving phantom with an analytical liver motion function and found that dose delivery error can be reduced with gating. They also reported that dosimetric error between nonmoving and moving deliveries is related to gating window size and could be reduced by reducing the window size.80
Abdominal Compression (AC)
Developed in 1990s by Lax and Blomgren in Stockholm, AC technique utilizes an attached plate which applies pressure to the abdomen to reduce organ motion.81 In order to evaluate its effectiveness reducing tumor motion, Eccles et al evaluated 60 patients using T2-weighted MRI with and without AC and found a mean reduction of 2.3 mm in CC direction.76 Another study by Heinzerling et al reported a mean lung/liver superior/inferior movement reduction from 12 mm to 6.1 mm.82 While encouraging, it is important to assess if the motion reduction with AC is reproducible over the course of a treatment. Case et al evaluated this with 29 patients undergoing liver SRBT and reported that 80% of intra and interfraction changes were <3 mm in any direction.83 A similar study by Shimohigashi et al evaluated liver tumor motion during SRBT treatment using four-dimensional cone beam computed tomography and fiducial markers and found liver tumor motion changes of >3 mm in 10% of the time interfractionally and 2% of the time intrafractionally.84 In addition, Wunderink et al showed a liver mean excursion reduction by AC to <5 mm in patients with liver tumors.85 Abdominal compression has also demonstrated effectiveness in improving liver treatments when utilizing modern arc-based SBRT techniques. A study from the University of Maryland of patients who received liver SBRT delivered with Volumetric Modulated Arc Therapy reported that AC achieved a mean PTV volume reduction of 28.3%, mean liver dose reduction of 12.8%, and mean lung V20 reduction of 39.5% compared with no motion management strategy.86 In summary, numerous studies have supported the reproducibility and effectiveness of the AC technique in reducing and regulating organ motion. Even though data has shown AC to effectively reduce liver motion and OAR risk, not every patient is suitable to undergo such technique, and ideally an alternative motion management method would be available.
Conclusions
Radiation therapy for liver tumors has evolved dramatically over the last few decades. Present-day liver tumor patients now have a number of effective and safe radiation therapy treatment options, including radioembolization, SBRT, and proton beam therapy. Modern technologies such as motion mitigation techniques have allowed for the delivery of precise, high doses of external beam radiation that target tumor while sparing normal liver. Future research will continue to refine these techniques and introduce systemic therapies to combine with radiation therapies to improve systemic disease control or act as radiation sensitizers or radiation protectors to improve tumor control or protect normal tissues, respectively.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted August 14, 2017; accepted September 29 2017.
Address for correspondence: Michael Chuong, MD, Miami Cancer Institute, 8900 N Kendall Dr, Florida, 33176. Email: michaelchuong@baptisthealth.net
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