Standard Versus Radiobiologically-Guided Dose Selected SBRT in Liver Cancer

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Primary and secondary (aka liver metastases) hepatobiliary cancer cause substantial morbidity in an increasing number of patients primarily due to the fact that only a minority of patients are suitable for curative treatment; a majority of patients have limited options and have dismal survival rates...

Primary and secondary (aka liver metastases) hepatobiliary cancer cause substantial morbidity in an increasing number of patients primarily due to the fact that only a minority of patients are suitable for curative treatment; a majority of patients have limited options and have dismal survival rates. First, primary cancers of the hepatobiliary tract are one of the most common malignancies internationally. Though they occur less frequently in the industrialized world; however, the incidence of primary hepotobiliary cancer is one of the fastest rising cancers in North America. Treatments for unresectable hepatobiliary cancer, including chemotherapy and hepatic arterial embolization are associated with low response rates and very poor survival. Second, metastatic disease to the liver is common and, like primary hepatobiliary cancer, causes significant morbidity and mortality. Metastatic colorectal cancer to the liver is a common pattern of spread, sometimes as the only site of metastatic disease. Autopsy studies have shown that 40% of colon cancer patients fail with disease confined to the liver. Approximately 50% of metastatic deaths from breast and prostate cancers are associated with liver metastases: 43,000 women and 34,000 men per year. This has led to the hypothesis that not all metastases are diffuse and that "oligometastasis" can occur where aggressive local therapy to the oligometastasis may lead to long-term control of disease. This hypothesis is gaining support over the currently held belief that metastases are always systemic. Evidence for the oligometastasis theory is found in surgical series of treated oligometastases of the colon, sarcoma, melanoma and breast. If metastases were truly confined to the liver, and if effective therapy for the localized intrahepatic disease existed, aggressive local therapy may lead to cure in some patients. Given that patients with liver lesions (both primary and secondary) currently have few options, the potential gains in national cancer survival are substantial if an effective high-dose focal liver radiation treatment regimen could be delivered safely and effectively. Recent technological advances have made it possible to deliver high doses of radiation therapy precisely to small tumours while preserving function in critical structures surrounding the lesion. With these techniques, control rates in excess of 80% have been achieved in patients with metastasis from lung, breast, renal, and other cancers. We hypothesize that similar control rates may be feasible using stereotactic radiotherapy for liver cancers. External beam radiotherapy has long been considered to have a very limited role in the treatment of liver tumours. This has historically been because minimum dose required for local ablation exceeded the dose that would result in liver toxicity which can be morbid and cause death. The technical development of stereotactic body radiation therapy (SBRT) renewed interest in radiation for HCC. For SBRT, advanced techniques are used to very accurately deliver a high total dose to the target in a small number of daily fractions while avoiding dose delivery to surrounding healthy structures. This research in HCC was done mainly by two groups, in Michigan and Stockholm, who demonstrated that the delivery of high doses of radiation to limited volumes of the liver had promising results in terms of local control and survival with acceptable toxicity. SBRT is offered as an ablative radical local treatment as opposed to low palliative doses. In total as of 2015, eleven primary series reported on tumour response and survival of around 300 patients who have been treated with stereotactic body radiation therapy as primary therapy for HCC. The reported percentage of objective responses defined as complete and partial was ?64% in 7 of 8 series. Median survival between 11.7 and 32 months has been observed. Toxicity, based on multiple case series trials, indicate that the treatment is considered safe. The most common CTC grade 3-4 toxicity was elevation of liver enzymes. However, there is no accepted dose or dose regimen. The reason for a lack of liver SBRT's acceptance into practice is this lack of a standard regimen and the fact that most dose selection studies are based on anecdotal experience or small single institution dose escalation studies. Furthermore, known risks of harm, including death, have been shown in dose escalation studies. Given the relative heterogeneity of liver cancer patients, small sample sizes and high risk of harm, a consensus dose regimen that can be tested remains elusive. One solution is to individualize dose selection to decrease the impact of heterogeneity of patient anatomy, type of cancer, size of lesion and motion. The liver tolerance to external beam irradiation depends on the volume treated and the fractionation schedule. Lawrence, et al found that patients who developed grade III or IV radiation induced liver disease (RILD) tended to receive a higher mean dose and have less sparing of normal liver than those who did not. In the original analysis, none of the 45 patients who received a mean dose to the whole liver of less than 37 Gy (in 1.5 Gy per fraction bid) developed RILD, while 9 of 34 patients who received a mean dose of more than 37 Gy developed this complication. Another study from the University of Michigan looked at 26 patients with hepatobiliary cancer treated with radiation doses up to 72.6 Gy, in 1.5 Gy bid and concurrent intrahepatic fluorodeoxyuridine administration. Patients treated with a component of 36 Gy whole liver radiation were more likely to develop RILD compared to those treated with focal high-dose radiation with no whole liver radiation. These studies indicate that by using modern conformal radiation planning it is possible to deliver tumouricidal doses of radiation safely. More recently, we have developed a better understanding of the relationship between dose, volume of liver irradiated and RILD, based on an analysis of over 200 patients with hepatic malignancies treated at the University of Michigan. This analysis demonstrates that for a small effective liver volume irradiated, far higher doses of radiation can be prescribed than previously estimated. In addition to the dose and volume irradiated, several other factors were significantly associated with increased the risk of RILD, including use of BUdR chemotherapy (versus FuDR), primary hepatobiliary cancer diagnosis (versus metastatic cancer diagnosis) and male sex. Excluding 32 patients treated with BudR, leaving 169 patients treated with 1.5 Gy bid with concurrent FudR, the mean liver dose associated with a 5% risk of RILD for patients with metastases and primary hepatobiliary cancer were 37 Gy and 32 Gy, in 1.5 Gy bid. Assuming an alpha/beta ratio for the liver of 2.5 Gy, the corresponding mean liver doses associated with a 5% risk of RILD are 33 Gy and 28 Gy in 2 Gy per fraction, and 28.2 Gy and 25.1 Gy in 10 fractions, for metastases and primary liver cancer respectively. This radiobiological guidance has been used at the London Regional Cancer Program since 2004 with a REB approved, prospectively collected case series. This radiobiologically-guided individualized dose selection is now used routinely in London, has shown a very good tolerability and can be implemented immediately. Doses can be escalated and de-escalated to account for variation in patient anatomy, tumour and normal tissue motion, comorbidities, size of lesion, number of lesions and function of the normal liver. However, the value of this new technique relative to palliative treatment is unknown. In particular, is there a survival advantage to dose escalation based on the oligometastases theory. For unresectable cases, SBRT has been shown to be a safe alternative for patients with few, if any, options. However, neither the appropriate dose regimen nor impact on important clinical endpoints, including survival has been determined; and no randomized trials have been published to guide management. Individualized dose selection based on radiobiological parameters promises a safe dose escalation or de-escalation for each patient. Therefore, a phase III randomized clinical study comparing palliative external beam radiation and a radiobiologically

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