Treatment of a well-differentiated hepatocellular carcinoma with CyberKnife stereotactic radiation therapy

The patient, an 11-year-old FS Golden Retriever, presented to a referral hospital where she was diagnosed with a low grade hepatocellular carcinoma (HCC). The only clinical sign present was an increase in ALT of 137 (reference range ALP 0-120) and ALP of 427 (reference range 0-140) which was found on routine bloodwork. An ultrasound revealed a 13 x 8 cm isoechoic mass occupying the right medial and portions of the right lateral liver lobes. The mass was mostly solid but with an approximately 5 x 6 cm hypoechoic region which appeared cavitated. Tru-cut biopsies were obtained of the mass and histopathology confirmed low grade HCC. Thoracic radiographs were free of metastatic disease. Due to the location and size of the mass within the liver, surgical resection was not deemed a reasonable treatment option. Other pertinent medical history included complete resection of a low grade mammary carcinoma nine months prior to diagnosis with HCC.

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The patient was referred to a second specialty hospital for stereotactic radiation therapy in the form of CyberKnife. This type of radiation therapy is the delivery of a highly conformal dose of radiation therapy to a target with steep dose gradients resulting in a very low dose of radiation being delivered to surrounding normal tissue. This form of therapy relies on highly accurate target localization and precise delivery of radiation. The accuracy associated with this type of RT results in the ability to deliver a higher dose of radiation more rapidly with less normal tissue toxicity.

Prior to treatment with radiation, the patient underwent ultrasound-guided fiducial marker placement in the solid portions of the tumor to allow accurate localization of the tumor during the radiation treatments and a planning CT scan in order to define the tumor and surrounding healthy tissue such as the GI tract, lungs, spinal cord and kidneys. The patient received 3 treatments of CyberKnife stereotactic radiation therapy for a total dose of 30 Gy within a one week time period. Due to motion of the tumor with each phase of respiration, tracking was used in the form of Synchrony cameras which can track the motion of the tumor in “real time” and continuously deliver radiation as the tumor moves. The patient did well for each of her treatments and was discharged from the hospital successfully.

Three months after treatment, the patient had a repeat abdominal ultrasound performed which revealed that the tumor had decreased in size to 5 x 5 cm. Bloodwork at that time revealed an ALT of 242 (reference range 18-121 U/L) with all other values being within normal limits. Another repeat ultrasound was performed in 6 months after treatment which revealed that the tumor had further decreased in size to 3.7 x 4.1 x 4.1 cm. Bloodwork at this point showed that ALT had decreased to 180 (reference range 18-121 U/L). All other values were within normal limits.

In human medicine, stereotactic radiation therapy is becoming more routinely used for non-resectable HCC. Doses of 30-60 Gy are typically used over 3-6 treatments. 1-4 In these cases, other options for treatment include arterial chemoembolization or conformal fractionated external beam radiation therapy. The latter treatment modality has been limited in the past due to the risk of radiation-induced liver disease (RILD). RILD is a sub-acute form of liver injury due to radiation damage to normal, healthy liver tissue surrounding the tumor. It typically occurs 4-8 weeks after completion of RT but has been described in humans as late as 7 months after radiation. Clinical signs of classical RILD include fatigue, abdominal pain, hepatomegaly, ascites and elevation of alkaline phosphatase out of proportion to other liver enzymes. A second form of RILD (non-classical) include jaundice and markedly elevated serum transaminase. 5 In the patient being currently described, the decision to use a radiation dose at the low end of typical human doses was due to the proximity of the mass to the stomach and our attempt to avoid normal tissue toxicity. A moderate elevation in ALT was noted after therapy, which may have correlated with a low grade RILD, however, other abnormal clinical signs associated with typical RILD were not observed.

In veterinary medicine, to the author’s knowledge, there are no studies evaluating the use of stereotactic radiation therapy to treat HCC, however, one study exists which evaluates a more traditional form of radiation therapy in the form of 3D conformal external beam radiation therapy. This modality is capable of delivering equivalent doses of radiation, however, the precision and accuracy of stereotactic radiotherapy is lacking, resulting in a greater possibility of RILD due to the inclusion of larger amounts of normal tissue in the radiation field. However, in the aforementioned study, only 1 of 6 dogs included in the study developed RILD. Individual fraction sizes ranged from 6-10 Gy with the total dose administered being 18-42 Gy over several weeks. Five of 6 dogs had an objective response and median follow-up time was 534 days.6

The tumor tracking capability of CyberKnife Synchrony cameras has been shown in human medicine to significantly reduce the volume of normal liver tissue included in the radiation field, while maintaining high precision in tumor localization, conformity and tumor coverage. This may be especially useful in patients with preexisting liver disease or poor liver function in which they are at a higher risk for developing RILD. 1

This case report demonstrates the successful treatment of a dog with non-resectable low grade HCC with stereotactic radiation therapy. Consideration can be given in the future to dose escalation in which a higher dose of radiation can be given over 3 doses, or more doses can be added to the treatment protocol for a higher cumulative dose.

Submitted by Siobhan Haney, VMD, MS, DACVR (RO)

 

References:

1. Gated Volumetric-Modulated Arc Therapy vs. Tumor-Tracking CyberKnife Radiotherapy as Stereotactic Body Radiotherapy for Hepatocellular Carcinoma: A Dosimetric Comparison Study Focused on the Impact of Respiratory Motion Managements. Yoon K, Kwak J, Cho B, Park JH, Yoon SM, Lee SW, Kim JH. PLoS One. 2016 Nov 22;11(11):e0166927. doi: 10.1371/journal.pone.0166927https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119818/

2.Stereotactic body radiotherapy for primary hepatic malignancies – Report of a phase I/II institutional study. Weiner AA, Olsen J, Ma D, Dyk P, DeWees T, Myerson RJ, Parikh P. Radiother Oncol. 2016 Oct;121(1):79-85. doi: 10.1016/j.radonc.2016.07.020. http://www.thegreenjournal.com/article/S0167-8140(16)31236-1/abstract

3Stereotactic Body Radiotherapy for Hepatocellular Carcinoma. McPartlin AJ, Dawson LA. Cancer J. 2016 Jul-Aug;22(4):296-301. doi: 10.1097/PPO.0000000000000201.  http://journals.lww.com/journalppo/Abstract/2016/07000/Stereotactic_Body_Radiotherapy_for_Hepatocellula r.10.aspx

4.Stereotactic Body Radiotherapy for Hepatocellular Carcinoma Resulting in a Durable Relapse-Free Survival: A Case Report Monitoring Editor: Alexander Muacevic and John R Adler Samual Francis,1 Ned Williams,1 Christopher J Anker,2 Akram Shaaban,3Robin Kim,4 Dennis Shrieve,1 and Jonathan Tward1Cureus. 2016 Oct; 8(10): e841. Published online 2016 Oct 24. doi:  10.7759/cureus.841 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120964/

5. Radiation induced liver disease: A clinical update R. BensonaR. Madana, , R. KilambibS. Chandera Journal of the Egytial National Cancer Institute. 2016 March 28 (1) 7-11 http://www.sciencedirect.com/science/article/pii/S1110036215000849

6.Three-dimensional conformal radiation therapy for inoperable massive hepatocellular carcinoma in six dogs. J Small Anim Pract. July 2015;56(7):441-5. T Mori 1, Y Ito 1, M Kawabe 1, R Iwasaki 1, H Sakai 2, M Murakami 1, K Maruo 1http://onlinelibrary.wiley.com/doi/10.1111/jsap.12352/abstract

 

 

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