Official Title
A Phase III Randomized Trial of Standard Dose Stereotactic Body Radiation Therapy (SBRT) Versus Radiobiologically-Guided Dose Selected SBRT In Primary or Secondary Liver Carcinoma (SAVIOR).
Summary:
Radiation is a standard treatment option for patients with liver cancer. Unfortunately, the
tumour grows after radiation in many patients and radiation can harm normal tissues. A new
treatment using a specialized radiation procedure called Stereotactic body radiation therapy
(SBRT) may increase the chance to control liver cancer and reduce the chance of harm to
normal tissues. SBRT allows radiation treatments to be focused more precisely, and be
delivered more accurately than with older treatments. SBRT has become a routine treatment.
Further research has found that specialized computer programs can possibly guide the
selection of an appropriate SBRT dose. This is called radiobiological guidance. However, this
has not yet been proven to improve outcomes and/or reduce toxicity.
Therefore, the purpose of this study is to find out if SBRT at standard dose versus SBRT
guided by radiobiological techniques is better for you and your liver cancer.
Trial Description
Primary Outcome:
- Overall survival
- Treated lesion progression
Secondary Outcome:
- Response rate - Modified RECIST criteria
- Extrahepatic failure
- Time to intrahepatic progression
- Toxicity from the intervention
- Comparison of Quality of Life (QOL) Using a Standardly-Used Validated Instrument. Specifically, measures of physical, social/family, and functional well being. Overall symptoms, function, global health status will also be compared.
- Comparison of Quality of Life (QOL) Using a Standardly-Used Validated Instrument. Specifically, measures of physical, social/family, and functional well being. Overall symptoms, function, global health status will also be compared.
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 radiation therapy for
liver cancers.
External beam radiation therapy 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
View this trial on ClinicalTrials.gov
