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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 1  |  Page : 169-175

Role of stereotactic body radiation therapy in liver metastasis: A pilot study from tertiary cancer institute in India


1 Department of Radiotherapy, PGIMER, Chandigarh, India
2 Department of Radiotherapy, Nehru Hospital, PGIMER, Chandigarh, India
3 Department of Radiodiagnosis, PGIMER, Chandigarh, India
4 Department of Hepatology, PGIMER, Chandigarh, India

Date of Web Publication13-Mar-2019

Correspondence Address:
Dr. Rakesh Kapoor
Department of Radiotherapy, Ground Floor, B-Block, Nehru Hospital, PGIMER, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_647_16

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 > Abstract 


Purpose: This trial studies the feasibility and potential utility of stereotactic body radiation therapy in patients with unresectable liver metastasis.
Aims: (1) The aim of this study is to assess the local response of the liver lesions poststereotactic body radiation therapy regarding number and size of lesions and (2) to evaluate the toxicity to organ (s) at risk.
Materials and Methods: A total of 15 patients were enrolled in this study from November 2014 to October 2015. The inclusion criteria for this study were patients having 1–3 liver metastasis from any solid tumor except germ cell tumor or lymphoma with no evidence of progressive disease (PD) outside the liver. A planning four dimensional-computed tomography (CT) scan was taken. Planning target volume was generated by giving margin of 5 mm. Dose prescribed was 36 Gy in 3#. Response was defined by CT abdomen done at 3 and 6 months poststereotactic body radiation therapy as per RECIST guideline (v1.1).
Results: At 3 months poststereotactic body radiation therapy, five patients had partial response, five patients had stable disease, and five patients had PD as per RECIST criteria. Out of 20 assessable lesions, 16 were controlled at 3 months poststereotactic body radiation therapy. The actuarial local control rate was 86% at 3 months and 77% at 6 months poststereotactic body radiation therapy. The median progression free survival was 7 months. Two patients experienced Grade 2 gastric toxicity and one patient experienced Grade 2 small bowel toxicity. No cases of radiation-induced liver disease were observed.
Conclusions: This trial examines the feasibility of stereotactic body radiotherapy to liver metastasis in the Indian scenario. It shows excellent tolerability and is a safe therapeutic option for inoperable patients, showing good local control.

Keywords: Indian, liver metastasis, prospective study, stereotactic body radiotherapy, unresectable


How to cite this article:
Kumar S, Kapoor R, Oinam AS, Kalra N, Duseja A. Role of stereotactic body radiation therapy in liver metastasis: A pilot study from tertiary cancer institute in India. J Can Res Ther 2019;15:169-75

How to cite this URL:
Kumar S, Kapoor R, Oinam AS, Kalra N, Duseja A. Role of stereotactic body radiation therapy in liver metastasis: A pilot study from tertiary cancer institute in India. J Can Res Ther [serial online] 2019 [cited 2019 Aug 20];15:169-75. Available from: http://www.cancerjournal.net/text.asp?2019/15/1/169/247038




 > Introduction Top


Liver metastasis is a common cause of morbidity and mortality. This can occur in patients with tumors of many common cancer types and are often difficult to treat. They also shorten survival time. The liver is also protected from some cytotoxic agents because of its natural detoxification function and its relatively hypoxic state. In contrast to the 80% perfusion of the normal liver by the portal venous system, most liver tumors obtain blood flow almost exclusively through the hepatic arterial system. This phenomenon necessitates novel interventional radiologic techniques for treating neoplastic involvement of liver. Likewise, advances in imaging have allowed for more definitive anatomic localization of liver metastases, leading to new minimally invasive or noninvasive treatments for these tumors.

Liver metastases are frequently seen in colorectal, breast, lung, neuroendocrine, and gastrointestinal malignancies. With the exception of colorectal cancer, most liver metastases develop late in the course of disease. In the United States, the most likely type of metastases to the liver originates from a colorectal primary lesion. Approximately 50% of patients with colorectal cancer eventually develop metastatic disease to the liver. Surgical series demonstrate that the completeness of surgical resection of isolated hepatic metastases can vary, depending on patient selection. Patients with isolated colorectal lesions and favorable prognostic factors may experience a 5-year survival of 40%–60%. The prognosis of patients with untreated liver metastases, however, can be poor, with a 3-year survival of <5% and median survival of 5–8 months.

Whereas resection of limited number of isolated liver metastases from colorectal cancer has been associated with improved survival,[1],[2],[3],[4],[5] the data demonstrating a survival benefit in the resection of liver metastases from noncolorectal malignancies are scant. However, long-term survival has been reported in select patients with oligometastases from breast, ovarian, renal, and gynecologic cancers as well as melanoma and sarcomas.[5],[6],[7] The achievement of local control, therefore, represents an important treatment goal in such patients with a well-defined, isolated number of liver metastases.

Surgical resection of limited metastatic disease in the liver is known to be associated with favorable outcome in well-selected patients, suggesting a clinical benefit from metastectomy in some patients. Unfortunately, the majority of patients (up to 80%–90%) are not resectable at diagnosis.[8],[9],[10],[11],[12]

Stereotactic external-beam radiation is an increasingly attractive modality for patients with a limited number of unresectable liver metastases requiring treatment, adequate normal liver reserve, and tumors smaller than 6–8 cm, because most of the similar patient- and tumor-related factors that exclude surgery as a first-line treatment for isolated liver metastases can also limit the applicability of alternative treatments. The goal of stereotactic body radiotherapy (SBRT) is to deliver a high dose to the target, thereby providing better local tumor control, while limiting dose to surrounding healthy tissue, thereby potentially decreasing complication rates.

In colorectal patients with focal unresectable liver metastases, dose escalation to these lesions have demonstrated improved response rates, symptom control, and survival rates compared with patients treated with lower doses, independent of tumor size.[13],[14],[15]

The purpose of this study was to evaluate the role of stereotactic body radiation therapy in our institute. Patients with limited liver metastasis (1–3) were subjected to image-guided high-dose radiation in three fractions. They were followed up to assess the control of the liver lesions and to assess the development of toxicity to the normal liver and other surrounding organs, if any.


 > Materials and Methods Top


Eligibility

The study protocol was approved by an institutional review board. The inclusion criteria for the study were patients with 1–3 liver metastases from any solid tumor except a germ cell tumor or lymphoma, with maximum tumor diameter <6 cm, with tumor located preferably away from major vessels i: e portal vein/hepatic artery, and patients having adequate liver/kidney function (defined as total bilirubin <3 mg/dL, serum levels of liver enzymes less than three times the upper limit of normal, and normal prothrombin time and partial thromboplastin time unless the patient was receiving anticoagulant medication, serum creatinine <1.8 mg/dl). The Karnofsky performance status had to be more than 60%. Patients were excluded if they had any history of prior radiotherapy to the liver, had received chemotherapy within 2 weeks of SBRT and if they had gross extrahepatic disease which was either progressive/untreated. All patients signed the review board approved informed consent before enrollment in the study.

Study design

This study is a pilot project to determine the efficacy and safety of SBRT in patients with liver oligometastases. The primary aim of the study is to assess the local response of the liver lesions poststereotactic body radiation therapy regarding number and size of lesions. The secondary aim is to evaluate the toxicity to organ at risk (liver, right kidney, duodenum, and spinal cord).

Treatment

Patients were positioned supine during CT simulation and treatment using a customized vacuum-type immobilization bag (vac-lok) or using an abdominal orfit cast. Before the four-dimensional (4D)-CT simulation, patients were trained to breathe regularly. No attempt was made to control breathing pattern (i.e. Active breathing control/abdominal compression). The RPM™ (Respiratory position management) system (Varian Medical Systems, Palo Alto, USA) with infrared marker was used to track the breathing pattern of the patient. To enhance the visibility of tumors on 4D-CT, 100 ml of contrast at a concentration of 300 mgI/ml was injected along with 4D-CT image acquisition. After initiating contrast injection, the liver was scanned with a 45 s time delay so as to image the liver in the portal venous phase.

Tumor volume delineation of gross tumor volume (GTV), clinical target volume, and planning target volume (PTV) were done. The GTV included the hypodense areas visible in the liver on the planning CT images. GTV was contoured on all the respiratory phases (0–90). Thus, a 4D structure set was created by merging GTV 0–90. This internal target volume was expanded by giving a minimum margin of 5 mm in all directions to create the PTV.

SBRT was planned and administered using multiple noncoplanar arc beams (5–7)/Rapid-Arc (Varian Trilogy™) using 6MV photons. All patients were treated with three fractions at 12 Gy per fraction to a total dose of 36 Gy. The prescription dose mentioned above was prescribed to the isodose line (80%–90%) covering the PTV. Normal tissue dose constraints were met for each patient, with at least 700 ml liver receiving <15 Gy, dose to stomach and small bowel not exceeding 30 Gy/3 fractions or 10 Gy/fraction, dose to spinal cord within 18 Gy/3 fractions or 6 Gy/fraction, and dose to 2/3rd of the right kidney being <15 Gy/3 fractions or 5 Gy/fraction.

Before each fraction, IGRT was performed by acquiring a cone-beam CT with the patient in the treatment position using the onboard kVCBCT (kilo-voltage cone beam CT) imaging system. The planning CT image and current cone-beam CT image were matched using soft tissue/bony landmarks as reference points, and repositioning was performed.

Assessment

All patients had a baseline contrast CT abdomen/pelvis. Patients were followed up with an ultrasound abdomen at 2 weeks post-SBRT completion. This was followed by a contrast enhanced CT abdomen at 6 weeks, 3 and 6 months post-SBRT completion. At each follow-up, physical examination of the abdomen was performed. Routine blood investigations including liver function tests were performed at each visit. Local response was defined using RECIST criteria (version 1.1) (Response Evaluation Criteria in Solid Tumors) to describe the change in the irradiated liver metastases.


 > Results Top


Patient profile

A total of 15 patients were enrolled in this study from November 2014 to October 2015, 5 men, and 10 women. The median age of the patients at the time of enrollment was 50 years (range 30–68 years). Of these 15 patients, there were 5 primary hepatobiliary cancers, three colorectal, two pancreatic, two esophageal, two unknown primaries with liver metastasis, and 1 patient of carcinoma breast. The median time since primary tumor diagnosis was 6 months. Twelve patients had received one line of chemotherapy regimen before being enrolled in the study; three patients were chemotherapy-naïve. One patient had received prior local therapy for the liver lesion (Transarterial chemoembolization). None of the other patients received any prior local therapy for the liver lesions.

A total of 20 metastatic liver lesions were evaluated. The mean GTV volume was 21.7cc (range 0.83–95 cc). The median maximum lesion diameter was 4.4 cm (range 1–6 cm). Nine patients had the presence of active extrahepatic disease (4 stable/5 progressive), six patients had disease confined only to the liver [Table 1].
Table 1: Patient characteristics

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Response and local control

The median follow-up period of the patients was 8 months post-SBRT (range 3–24 months).

An ultrasound abdomen was performed at 2 weeks post-SBRT to detect any early transient changes in the irradiated high-dose region. An intriguing observation was seen in the patients who later went on to achieve partial response (PR) as per RECIST criteria. In the ultrasound imaging obtained at 2 weeks in these patients (5 out of 15 in total), 4 patients demonstrated an interval increase in the size of the lesion [Table 2].
Table 2: Ultrasonography abdomen at 2 weeks poststereotactic body radiotherapy

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At 3 months post-SBRT, five patients achieved PR as per RECIST criteria, 5 patients had stable disease (SD), and 5 patients developed progressive disease (PD) [Figure 1], [Figure 2], [Figure 3], [Figure 4].
Figure 1: Contrast-enhanced computed tomography abdomen of the patient Mrs. M prior to stereotactic body radiotherapy showing hypodense lesion in segment 7 of liver, measuring 2.4 cm in short axis diameter (SAD)

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Figure 2: Contrast-enhanced computed tomography abdomen of the patient 3 months poststereotactic body radiotherapy showing same lesion now measuring 1.3 cm in SAD, indicating partial response as per RECIST criteria

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Figure 3: Planning computed tomography scan of the above patient. Gross tumor volume, planning target volume, and organ at risk's contoured

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Figure 4: Rapid-ArcTM plan showing dose color wash. Dose prescribed – 36 Gy/3#

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Out of 20 metastatic liver lesions, 16 lesions were controlled at 3 months post-SBRT (i.e. PR/SD). No patient achieved complete response (CR). The actuarial local control rate was computed with the Kaplan–Meier method. The local control rate was 86% at 3 months and 77% at 6 months post-SBRT [Figure 5].
Figure 5: Kaplan–Meier plot demonstrating local control of liver lesion plotted against time in months, i.e., local control rate

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Survival

Fourteen patients remained alive at the time of analysis; one patient died as a result of preexisting medical comorbidities unrelated to SBRT. The median PFS (progression-free survival) was 7 months (range 1–21 months).

Toxicity

Acute toxicity was graded based on radiation therapy oncology group toxicity grading charts. Overall, the treatment was very well tolerated. Two patients developed Grade 2 gastric toxicity, with nausea and vomiting. They were managed conservatively with anti-emetics. One patient developed Grade 2 small bowel toxicity, which was managed conservatively with parasympatholytic drugs. There were no instances of Grade 3/4/5 toxicity. No cases of radiation-induced liver disease (RILD) were observed.


 > Discussion Top


This study was undertaken to examine the feasibility, efficacy, and safety of stereotactic body radiation therapy to liver metastases in the Indian population. A number of retrospective and prospective studies of SBRT in the treatment of liver metastases have been reported in literature.[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26] However, to date, there is no available phase 3 data to support the use of SBRT in liver metastases. There is also a considerable heterogeneity in SBRT planning and delivery. There is no consensus on the optimal dose fractionation schedule. However, in general, the local control rates have been high, ranging from 70% to 100% at 1 year. Interpretation of the overall survival has many confounding factors, as there is considerable heterogeneity in patient selection, with patients having different primary tumors. Moreover, many of these patients have received various local/systemic therapies before being selected for SBRT.

In general, it has been observed that local control corresponds to two main factors. One is a smaller tumor volume, and the other is higher overall prescribed dose.[23],[27],[28] In a recent pooled analysis by Chang et al.,[28] which combined the experience from Stanford, Princess Margaret Hospital, and the University of Colorado which included 65 patients with a total of 102 individual liver metastases, it was calculated that the estimated dose range needed for 1-year local control >90% was 46–54 Gy in 3 fractions, or a BED of 117 Gy10 (EQD2 = 98 Gy). Sustained local control after SBRT was closely associated with improved survival on multivariate analysis.

In studies which have included patients with large median GTVs, the documented local control rate has been inferior. Lee et al.[29] reported on a phase 1–2 study, which included 68 patients with a median tumor volume of 75.9 cc. Individualized dose fractionation schedule was followed, with total dose ranging from 27.7–60 Gy in 6 fractions. The 1-year local control rate was 71%. In another study by Aitken et al.,[30] 34 patients were treated with tumor volumes ranging from 2 to 614 ml. The dose prescribed was 30–60 Gy in 10 fractions. The local control rate observed at 1 and 2 years was 65% and 45%.

In our study, the total dose was limited to 36 Gy in three fractions, as this was the initial fractionation regime of choice in the phase 1 study by Schefter et al.[20] We did not escalate the total dose beyond 36 Gy, as this was a pilot study to establish the safety and efficacy of SBRT in our setup. Furthermore, the median tumor volume in our patient population was high (mean GTV volume 21.7 cc, median lesion diameter 4.4 cm). This might explain the lower local response rates seen in our study, as there were no documented CRs, and only 5 out of 15 patients achieved PR as per RECIST criteria. The appearance of a new lesion is characterized as PD as per these criteria. In our study, nine patients had documented active extrahepatic disease, which might explain the occurrence of PD in 5 patients post-SBRT. However, when the local response of the individual lesion to SBRT is considered, out of 20 assessable lesions, and 16 lesions were controlled at 3 months post-SBRT (80%).

The interval increase in the size of the liver lesion documented on ultrasound abdomen at 2 weeks post-SBRT in four patients was noted. This is an interesting finding, which has not been reported in the literature so far. A possible explanation for this observation could be radiotherapy induced tumor edema; however, this is purely hypothetical. The clinical significance of this finding also remains uncertain, given that the response to SBRT is typically assessed at least 3 months posttreatment, with continued imaging till 1–2 years.

The excellent toxicity profile seen in our study might be explained by the strict adherence to normal tissue dose constraints, which were met in all patients. The normal tissue dose constraint for uninvolved liver as described by Schefter et al.[20] is that 700 cc of normal liver should receive <15 Gy. In our study, the mean dose to 700cc of uninvolved liver was 2.28 Gy (Range 0.2–6.4 Gy). This corroborates with the clinical observation that no cases of RILD were observed on follow-up.

Following SBRT to the liver, a consistent feature seen in the first few months is a zone of hypodensity on follow-up CT scans corresponding to the volume that initially received 30 Gy or higher. This phenomenon is likely due to the venoocclusive effects, and this was first described by Herfarth et al. following single-dose liver SBRT.[31] He described three different types of reaction. The Type 1 reaction occurred at a median time of 1.8 months post-SBRT and was characterized by hypodensity on portal venous phase and isodense on late phase. The Type 2 reaction occurred at a median time of 1.6 months post-SBRT and was characterized by hypodensity on portal venous phase and hyperdensity on late phase. The underlying pathophysiology for the Type 2 reaction is that the sinusoids in the irradiated area receive the contrast agent later than in the normal liver (which causes the hypodensity in the portal venous phase) because of the congestion and therefore, reduced blood flow in this area. Contrast clearance is also reduced because of the obstruction of the central veins (which causes the hyperdensity in the late phase). The Type 1 reaction might be explained as an early “Type 2” reaction. The congestion of the small hepatic veins might have already influenced the contrast inflow (which leads to the hypodensity in the portal-venous phase). However, the efferent veins still might clear the contrast agent fast enough for an isodense appearance in the late phase. The Type 3 reaction occurred later at a median time of 3.9 months post-SBRT, which presented with a iso/hyperdense picture in the portal venous phase and a hyperdense appearance in the late phase. This is believed to be due to chronic liver damage.

There are no known clinical consequences of these findings. However, importantly, they can cloud the assessment of tumor response in the first few months post-SBRT. These radiographic changes usually recover at 6–9 months. Hence, posttreatment imaging should be repeated at least every 3 months post-SBRT until 1 year.

In our study, the RECIST criteria (v1.1)[32] were used in assessing treatment response. These criteria are the most commonly used international standard. However, they have certain shortcomings. They are based on the assessment of change in tumor size after treatment. Following local therapy such as SBRT, hepatic tumors show certain unusual characteristics, such as development of thin rim enhancement or local necrosis, which is indicative of local control. An increase in the size of the lesion is deemed as PD according to RECIST criteria, but in many cases this can be attributed to necrosis, cystic degeneration, edema, or hemorrhage. Therefore, it is sometimes necessary to use more diverse criteria based on the aforementioned morphological characteristics of the lesion rather than relying solely on the tumor size as an indicator of response to therapy, as described by Jarraya et al.[33] They have proposed a set of combined criteria (CC) based on lesion size, contrast enhancement, and tumor necrosis. The PR and SD criteria remain unchanged from the RECIST criteria. For CR, the recommendation is disappearance of lesion OR total necrosis, regardless of its size. PD is labeled when there is a ≥20% increase in size or the occurrence of lobulated enhancement pattern around the lesion.


 > Conclusions Top


Our study has demonstrated that SBRT is safe, well tolerated, and effective in the treatment of unresectable liver metastasis in the Indian patient scenario. It has corroborated the findings of previously published prospective trials in this regard. Further studies in the form of well designed, phase 3 trials are needed to establish the role of SBRT. Application of stricter and homogenous selection criteria is essential to understand the real impact of SBRT on overall survival. Further studies are needed to find the optimal sequence and combination of liver SBRT with other systemic therapies, given the fact that most patients fail at distant sites after SBRT. Combination of SBRT with concomitant systemic therapy/hypoxia modifying agents is another area that needs active investigation in an effort to further improve on the results obtained with the use of SBRT alone.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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