Improving Treatment Responses for Hepatic Malignancy
ABSTRACT & COMMENTARY
Synopsis: Treatment of liver malignancy remains only marginally effective. One reason for this is the heretofore limited role of radiation therapy because of the radiosensitivity of normal liver. In this report, a series of patients with hepatic malignancy were treated with high-dose radiation delivered in a focused manner such that normal liver was spared. Responses were impressive when compared to published experience. Future research developing this approach is clearly warranted.
Source: Dawson LA, et al. J Clin Oncol 2000;18:
2210-2218.
Treatment of liver malignancy, whether primary or metastatic, has proven problematic. Historically, radiation therapy has not been a primary modality because it was technically difficult to protect the surrounding radiosensitive normal liver.1,2 However, new three dimensional, conformal techniques have permitted the delivery of higher doses of radiation to localized intrahepatic disease and these have led to significantly higher response rates than would be anticipated from whole liver radiation alone.3,4
In the current phase I/II trial, 43 patients with unresectable intrahepatic cancer (27 with primary hepatobiliary cancer and 16 with metastases from colorectal primaries) were treated with high-dose conformal radiation therapy (RT) and intrahepatic arterial infusion of fluorodeoxyuridine (0.2 mg/kg/d). The radiation was precisely delivered to a target contoured by axial computed tomography using techniques developed at this institution (University of Michigan). Dawson and associates adjusted the dose and schedule by a method they had developed to predict and then deliver an equivalent risk of radiation-induced liver disease (RILD) (5). The starting dose of radiation subjected every patient to an estimated 10% maximal risk of RILD and the doses were adjusted upward in 10% increments. The maximal allowable prescribed dose was 90 Gy to the isocenter. The median tumor size was 10 ´ 10 ´ 8 cm and the median dose of RT was 58.5 Gy (range, 28.5-90 Gy) administered as 1.5 Gy twice daily.
The response rate in the 25 assessable patients was 68% (16 partial and 1 complete response). With a median potential follow-up period of 26.5 months, the median times to progression for all tumors, metastatic (colorectal) lesions, and primary hepatobiliary cancers was six, eight, and three months and overall survival was 16, 18, and 11 months, respectively. Upon further (multivariate) analysis, those that were treated with higher doses had superior outcomes. For example, the survival of patients treated with 70 Gy or more had not been reached by 16.4 months of analysis, whereas the median survival for those that received less was 11.6 months.
Dawson et al suggested that higher-dose, focused radiation is now feasible for the treatment of liver malignancy, either primary or metastatic and that higher dose radiation may result in higher response rates and longer survival.
COMMENT by william b. ershler, MD
Treatment of malignancy in the liver, either primary or secondary, has been very disappointing. In recent years, hepatic resection of metastatic lesions has become more commonplace, and this approach has been predicated on the failure of any other intervention to enhance survival. Whole liver radiation is of limited value because of the radiosensitivity of the normal hepatic tissue. In many cases, surgical excision is not possible due to the size or location of the tumor or to host factors that preclude such extensive surgery. Thus, the new developments in radiation therapy are a welcome advance. Survival in patients treated to higher doses, using a well described technique that allows focused dosing to the tumor without injuring normal liver appears improved. What’s more, it does not appear that the method has been used to the maximum yet. That is, additional doses of RT would have been possible in at least some of these patients.
This was not a randomized or otherwise controlled study, but a series of patients treated by a specific technique; thus, it is hazardous to become too enthusiastic about the results. Nonetheless, it’s hard to hide that enthusiasm because the approach makes sense, it is an application of new imaging and radiation physics advances, and the successes of other approaches have been so marginal. Accordingly, it’s time to subject this approach to a more critical evaluation. Dawson et al will need to define their treatment populations more finely (either primary or secondary lesions) and choose a standard target dose (e.g., 70 Gy). They will also need to justify the hepatic arterial infusion of chemotherapy, inasmuch as this adds significant complexity to the widespread application of this approach. Perhaps a future randomized study could compare intrahepatic arterial chemotherapy vs. focal, high-dose RT vs. a combination of the two.
References
1. Ingold J, et al. Am J Roentgenol 1965;93:200-208.
2. Wharton JT, et al. Am J Roentgenol Radium Ther Nucl Med 1973;117:73-80.
3. Robertson JM, et al. Int J Radiat Oncol Biol Phys 1997;39:1087-1092.
4. Ohara K, et al. Radiother Oncol 1996;41:233-236.
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