Is Stereotactic Body Radiation Therapy (SBRT) an Attractive Option for Unresectable Liver Metastases? Early Results From a Phase II Trial

Reporter: Gita Suneja, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 28 de octubre del 2012

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Presenter: Stefano Arcangeli, MD
Affiliation: Istituto Clinico Humanitas, Italy

Background

  • Unresectable liver metastases originating from solid tumors present a therapeutic challenge to treatment providers.
  • Attempts at local control with non-radiation techniques, such as radiofrequency ablation, have not been wholly successful.
  • Several Phase I/II trials have been published investigating the use of conformal radiation therapy for liver metastases with a variety of dose and fractionation schemes.
  • The authors sought to evaluate the feasibility of high-dose stereotactic body radiation therapy (SBRT) in the treatment of unresectable liver metastases.

Methods

  • The authors conducted a single institution phase II trial of SBRT for liver metastases, and enrolled 61 patients with 1-3 liver metastases from a number of primary cancers between February 2010 and September 2011.
  • Inclusion criteria were liver metastases that were unresectable, patients medically unsuitable for surgery, good performance status of patients (KPS > 70), life expectancy greater than 6 months, and tumor size < 6 cm.
  • Patients were simulated in the supine position using 4D CT to measure diaphragmatic excursion from breathing, as well as upper abdominal block to minimize diaphragmatic motion. Tri-phasic contrast-enhanced CT images were obtained to ensure proper visualization of tumor and normal tissue structures.
  • The standard dose delivered was 3 fractions of 25 Gy each, for a total of 75 Gy to the clinical target volume.
  • Dose reductions of up to 30% were allowed in order to meet normal tissue constraints. Normal tissue constraints were developed using data from Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC).
  • SBRT was administered using RapidArc with photon beam energy of 10 MV.
  • Daily image guidance was used to ensure patient positioning prior to delivery of each fraction of treatment.
  • The primary endpoint was infield local control (evaluated by CT/MRI/PET), and secondary endpoints were progression-free survival and overall survival.

Results

  • 79 lesions were treated among the 63 patients enrolled in this Phase II study.
  • Median follow-up was 12 months.
  • Median age was 65 years, and most common primary cancers were colorectal and breast cancer.
  • The majority of patients (79%) had one lesion, and 86% of lesions were treated with full dose.
  • The majority of the cohort (57.4%) had been diagnosed with cancer < 12 months prior to treatment, and 21% had received prior therapy.
  • The majority of patients received full dose, 25 Gy x 3 fractions
  • Local control was 95%, however 30% of patients failed distantly.
  • Acute toxicity was mild with no grade 3-5 toxicity or radiation-induced liver disease. One patient developed grade 3 chest wall pain.
  • 12 month overall survival was 83.5%, and 18 month overall survival was 60%

Author's conclusions

  • SBRT should be considered locally ablative for liver metastases if surgical resection is not feasible.
  • High dose radiation resulted in full ablation of larger lesions (> 3 cm) and radioresistant tumors.
  • A randomized controlled trial is needed to further evaluate the efficacy of SBRT for unresectable liver metastases.

Clinical and Scientific Implications

  • The liver is the most common site of metastatic disease after the lymph nodes, and a large number of primary cancers have a propensity to metastasize to the liver including colon, pancreas, breast, and lung.
  • Treatment options include surgery, ablation (chemoablation, radiofrequency ablation, alcohol ablation, etc.), and radiation therapy.
  • Radiation therapy has historically not been favored due to the low median tolerance of the liver, however advances in conformal therapy have made radiation therapy a more feasible option, particularly for patients with unresectable disease.
  • Several phase I/II studies have demonstrated the feasibility of SBRT for liver metastases. One notable and recent study was a multi-institutional phase I/II study describing 47 patients with lesions < 6 cm treated to maximum dose of 20 Gy x 3 fractions (total 60 Gy). The authors demonstrated excellent local control (Ruthoven, KR, JCO 2009)
  • Several other dose and fractionation schemes have been studied, and local control has been excellent with minimal toxicity.
  • The present study contributes to the literature by demonstrating the safety of further dose escalation, although the median follow-up was short and further follow-up is needed to ascertain the long-term effects of hypofractionation and high total doses.
  • The study also contributes by documenting the efficacy of SBRT in controlling larger lesions (> 3 cm in size).
  • Another interesting aspect of this study was the patterns-of-failure analysis. Although local control was excellent, 30% of patients failed in distant sites. This finding suggests that the addition of chemotherapy to SBRT may provide additional benefit. In fact, Brade et al are presenting the results of a phase I study of Sorafenib and SBRT for liver metastases elsewhere at the ASTRO 2012 Meeting (Presentation # 26).
  • The results presented in this study are encouraging. As primary treatment paradigms for colon, breast, and other cancers improve, management of metastatic disease becomes of critical importance. SBRT is a non-invasive way to safely and effectively treat liver metastases.
  • In spite of the strong points of this study, the results need to the validated in a Phase III clinical trial. As mentioned previously, there are numerous Phase I/II trials demonstrating the efficacy of SBRT in treating liver metastases, however limited randomized data exist comparing SBRT to other non-surgical approaches.

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