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|CANCER & TREATMENTS FOR CANCER CENTER PATIENTS PREVENTION & RISK ASSESSMENT CLINICAL TRIALS & RESEARCH LIVING WITH CANCER|
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Michigan Oncology Journal Fall 98
Conformal Radiation Therapy for Patients with Intrahepatic Malignancies
---Cornelius J. McGinn, M.D. and Theodore S. Lawrence, M.D., Ph.D.
In 1998, an estimated 13,900 patients in the United States will be diagnosed with hepatocellular carcinoma (hepatoma) and intrahepatic cholangiocarcinoma (1). Only a small subset of these patients present with resectable disease. The median survival in most U.S. series, including those with patients who have undergone potentially curative or palliative resection, is generally in the range of six to ten months (2). Mortality results from local and regional progression of tumor. Although a variety of non-surgical treatment approaches have been investigated, none have been effective enough to be considered standard primary or adjuvant management.
Displayed are the target volume (tumor with an additional margin for uncertainty), the liver, spinal cord and kidneys. Anterior and lateral beams (defined by a multileaf collimator) are shown as well, in this oblique view.
A larger number of patients, however, die from colorectal cancer metastatic to the liver. Aggressive local/regional approaches have been considered for these patients based on clinical information confirming hepatic dissemination as the only site of disease in 20 percent, and surgical series demonstrating long-term survival in patients with solitary or a limited number of liver metastases (3). Among these, only surgical resection can be considered standard, yet is only possible in a select group of patients.
Investigation of non-surgical local/regional treatment modalities for this patient population continues at medical centers across the U.S. Each institution tends to focus on a limited number of approaches from a wide range of options including hepatic arterial chemotherapy, chemoembolization, radioisotope administration, percutaneous ethanol injection, and cryosurgery. At the University of Michigan, we have focused on the use of external beam irradiation combined with hepatic arterial chemotherapy in a series of prospective clinical trials initiated in 1987. Our work represents the only systematic investigation of radiation dose escalation trials in this patient population, as will be discussed below. It is clear, however, that investigation and evaluation of all potential options (including advances in systemic therapy) and potential integration of approaches will be required to improve the outcome for these patients.
The Role of Conformal Radiation Therapy
Using these tools, we initiated a series of clinical trials for patients with intrahepatic malignancies combining high-dose 3D conformal radiation with concurrent hepatic arterial fluorodeoxyuridine (HA FUdR). Concurrent HA FUdR was administered because of its established role in the treatment of colorectal liver metastases (5) and for its potent radiosensitizing properties. In these initial protocols, the dose was based on the amount of normal liver excluded from the high-dose region (defined as the 50 percent isodose line). However, the relationship between volume of liver irradiated and dose that it could safely receive was not well understood. Thus, all patients were divided into only three categories (<33 percent of liver excluded, 33 to 66 percent of liver excluded, and >66 percent of liver excluded), with three corresponding doses (33 Gy, 48 Gy, and 66 Gy, respectively). Compared to whole liver irradiation (+/- HA FUdR), this approach produced a higher response rate and possibly improved survival, par ticularly for patients with primary hepatobiliary cancer (6, 7).
Individualized Dose Determination
We therefore analyzed the entire dose distribution (all isodose lines, rather than just the 50 percent isodose line) across the normal liver for patients with and without RILD in these earlier protocols, and developed parameters for a normal tissue complication probability (NTCP) model that described this clinical experience. We then designed a protocol in which each patient received an individualized, maximum possible dose while being subjected to an estimated fixed probability of RILD. The estimated risk is calculated from the entire dose distribution (once the 3D plan for that patient has been created) using the NTCP model. This contrasts with standard phase I trial design, which delivers a target dose without regard to the volume of normal tissue, and with our previous protocol, which based the dose on the fraction of normal liver receiving < 50 percent of the isocenter dose.
In the first level of this trial, the dose prescribed was
that which subjected each patient to a 10 percent risk of
RILD. Our hypotheses were that this approach would allow safe
delivery of a higher dose than we would have prescribed on
our previous protocol, and that the model would predict the
observed complication probability. In the first 21 patients
who were evaluable for liver toxicity, the mean dose delivered
was 56.6 Gy (range 40.5 to 81 Gy) compared to a mean of 46.0
Gy (range 33 to 66 Gy) if they had been treated according
to the prior study (p<0.01) (8). One of these 21 patients
developed RILD, for a complication rate of 4.8 percent. These
findings supported our initial hypotheses, but also suggested
that the NTCP model may have overestimated risk. As a result,
we are continuing to accrue patients in the second level of
the trial, where each will receive an individualized, maximum
possible dose while being subjected to an estimated 20 percent
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