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© 2000 American Society for Clinical Oncology Escalated Focal Liver Radiation and Concurrent Hepatic Artery Fluorodeoxyuridine for Unresectable Intrahepatic MalignanciesFrom the Departments of Radiation Oncology, Internal Medicine, and Pharmacology, University of Michigan, Ann Arbor, MI. Address reprint requests to Laura A. Dawson, MD, Department of Radiation Oncology, University of Michigan, UH-B2C447, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0010; email dawson@ umich.edu.
PURPOSE: To evaluate the response, time to progression, survival, and impact of radiation (RT) dose on survival in patients with intrahepatic malignancies treated on a phase I trial of escalated focal liver RT. PATIENTS AND METHODS: From April 1996 to January 1998, 43 patients with unresectable intrahepatic hepatobiliary cancer (HB; 27 patients) and colorectal liver metastases (LM; 16 patients) were treated with high-dose conformal RT. The median tumor size was 10 x 10 x 8 cm. The median RT dose was 58.5 Gy (range, 28.5 to 90 Gy), 1.5 Gy twice daily, with concurrent continuous-infusion hepatic arterial fluorodeoxyuridine (0.2 mg/kg/d) during the first 4 weeks of RT. RESULTS: The response rate in 25 assessable patients was 68% (16 partial and one complete response). With a median potential follow-up period of 26.5 months, the median times to progression for all tumors, LM, and HB were 6, 8, and 3 months, respectively. The median survival times of all patients, patients with LM, and patients with HB were 16, 18, and 11 months, respectively. On multivariate analyses, escalated RT dose was independently associated with improved progression-free and overall survival. The median survival of patients treated with 70 Gy or more has not yet been reached (16.4+ months), compared with 11.6 months in patients treated with lower RT doses (P = .0003). CONCLUSION: The excellent response rate, prolonged intrahepatic control, and improved survival in patients treated with RT doses of 70 Gy or more motivate continuation of dose-escalation studies for patients with intrahepatic malignancies.
THE GREAT MAJORITY of the more than 30,000 patients per year in the United States who develop either hepatobiliary cancer or liver-confined metastases from colorectal cancer have unresectable, incurable disease. Despite the use of aggressive hepatic arterial and systemic chemotherapy, at least one third of patients with liver metastases from colorectal cancer ultimately relapse in the liver1; this figure is higher for patients with unresectable hepatobiliary cancer.2 As the whole-liver tolerance to radiation (RT) is low, RT was originally thought to have a limited role in the treatment of intrahepatic malignancies.3,4 The use of three-dimensional (3D) conformal RT treatment planning has permitted the delivery of higher doses of RT to localized intrahepatic disease, which has led to significantly higher response rates than would be anticipated from whole-liver RT alone.5-8 We hypothesized that the delivery of tumoricidal doses of RT to focal intrahepatic tumors would improve local control and ultimately survival of patients. To test this hypothesis, it would be useful to determine the maximum-tolerated dose (MTD) of RT (as a function of the volume of liver irradiated) that can be delivered to patients with focal intrahepatic malignancies. A prospective phase I/II trial was developed in which patients received the maximum possible dose of RT while being subjected to the same risk of complications, using a normal tissue complication probability (NTCP) model, with parameters derived from our previous experience.9 We recently reported that the use of such an NTCP model has allowed the safe delivery of far greater doses of external-beam photon RT than is possible with other treatment approaches.10 Although the MTD of RT has not yet been reached, the ability to deliver higher RT doses than were previously thought to be possible has allowed us to begin to test our original hypothesis. If our hypothesis were found to be correct, then increased RT doses would produce increased local control and survival independent of tumor size. Such findings would encourage additional efforts to increase focal liver dose as a treatment option for patients with unresectable intrahepatic cancers.
Patients Patients with unresectable intrahepatic primary hepatobiliary cancers and colorectal cancer liver metastases were eligible for the phase I/II trial of focal liver RT and hepatic arterial fluorodeoxyuridine (FUdR), as previously described.10 Patients had to have an estimated life expectancy of at least 12 weeks and an Eastern Cooperative Oncology Group performance status of 2 or less. All patients were required to have normal liver and renal function, adequate bone marrow function, and to be free of serious intercurrent illnesses. Patients with extrahepatic disease were eligible if progression of intrahepatic disease was estimated to be the greatest short-term threat to the patient’s life. At least 10% of normal liver had to be spared from RT for patients to be eligible for treatment with high-dose focal liver RT. Informed consent was obtained from all patients in accordance with the procedures of the Institutional Review Board of the University of Michigan Medical Center.
Treatment
As previously described, each patient was subjected to an estimated equivalent risk of radiation-induced liver disease (RILD) as determined by the Lyman NTCP model, in which NTCP is a function of the RT dose and the volume of liver irradiated.10,12 The starting dose of RT subjected every patient to an estimated 10% maximal risk of RILD, and the RT doses for three volume bins were then escalated independently in nominal 10% increments. The maximal allowable prescribed dose was 90 Gy to the isocenter. The tolerance for dose-limiting organs was respected. The maximal dose to the duodenum and stomach was 68 Gy in 1.5-Gy fractions bid. The maximal allowable dose to the spinal cord was 38.4 Gy in 1.5-Gy fractions bid, 48 Gy in 1-Gy fractions bid, and 50.4 Gy for fraction sizes of 0.6 Gy or less. If one kidney was treated with 20 Gy or greater, then more than 90% of the other kidney was limited to 18 Gy or less. Concurrent continuous-infusion hepatic arterial FUdR 0.2 mg/kg/d was delivered with the first 4 weeks of RT as outlined in Fig 1. Hepatic arterial FUdR was typically delivered through a percutaneous hepatic arterial catheter placed through the brachial artery, as previously described.13 Hepatic artery perfusion was checked with a nuclide hepatic arterial perfusion scintigram with technetium-99m–macroaggregated albumin before FUdR delivery.
Evaluation Patients with measurable disease who had a posttreatment CT scan at least 2 months after completion of treatment were evaluated for response to treatment using standard bidimensional objective response criteria. In patients with nonmeasurable cholangiocarcinomas, hepatic progression was defined as tumor progression as evidenced by cholangiography or CT scan. All patients who were accrued to the phase I trial of escalated focal liver RT and hepatic arterial FUdR, including those who did not complete their prescribed treatment, were included in the overall survival and progression-free survival analyses. Progression-free survival and overall survival were measured from the first day of treatment. For patients who were referred to hospice for whom the date of death was not available, this date was estimated to be the date of initiation of hospice care plus 1 month. Intrahepatic relapse was defined as the date of radiographic liver relapse, and extrahepatic relapse was defined as the date of radiographic or clinical extrahepatic relapse. Within RT volume, recurrences were defined as recurrences within the estimated 90% dose volume in the liver, as assessed by a comparison between the diagnostic and planning CT scans. RILD was defined as the development of anicteric elevation of alkaline phosphatase (at least two-fold) and nonmalignant ascites, in the absence of documented progressive disease.10
Statistics We evaluated possible relationships between RT dose and other potential prognostic factors, including hepatic tumor volume and diagnosis. In these analyses, hepatic tumor volume was measured by (1) the volume of the largest hepatic tumor, and (2) the volume of all hepatic disease, as assessed on the contrast-enhanced planning CT scan. Tumors with no measurable disease were included with a volume of zero.
Patients From April 1996 to January 1998, 43 patients with focal intrahepatic malignancies were consecutively treated with escalated focal liver RT and hepatic arterial FUdR (Table 1). Twenty-seven patients had primary hepatobiliary tumors (nine with hepatocellular carcinoma and 18 with intrahepatic cholangiocarcinoma). Sixteen patients had colorectal cancer with liver metastases. The majority of patients had very large tumors as measured on CT scan (median tumor size, 10 x 10 x 8 cm), and most of the patients with liver metastases had experienced treatment failure with previous systemic or hepatic arterial chemotherapy. As of November 1999, the median potential follow-up period for patients was 26.5 months (range, 19 to 33 months). One patient was lost to follow-up at 19 months. Six patients did not complete their prescribed course of treatment. Treatment was stopped early for three patients because of disease progression (these patients received 28.5 to 51 Gy of RT). One patient received 81 Gy of the prescribed 90 Gy and elected not to continue because of a brisk skin reaction. Two other patients had their hepatic arterial FUdR stopped early because of vascular complications, and the RT fractionation was changed to 2 Gy once daily for the remaining treatments.
Response The response rates to treatment were determined in patients with measurable disease. Thirteen patients had nonmeasurable disease, and seven patients (including two with nonmeasurable disease) died before the first follow-up CT, leaving 25 patients available for evaluation of response. Of these 25 assessable patients, 16 patients had partial responses and one patient had a complete response, for an overall response rate of 68%. The response rates in patients with metastatic colorectal cancer and primary hepatobiliary cancer were 86% (12 of 14 patients) and 45% (five of 11 patients), respectively. Figure 2 displays pretreatment and posttreatment CT scans of an unresectable hepatocellular carcinoma in a patient who was treated on this protocol.
Progression The median times to disease progression for all patients, patients with colorectal cancer liver metastases, and patients with primary hepatobiliary tumors were 6, 8, and 3 months, respectively. The actuarial progression-free survival curves are shown in Fig 3. The sites of first progression were extrahepatic in 13 patients, intrahepatic in 16 patients, and unknown in seven patients who died before their first CT scan (Table 2). Seven other patients had no sites of progressive disease (four alive and three dead). One of these patients died with no documented progression of disease 8 months after treatment, despite previous progression after systemic and hepatic arterial chemotherapy for colorectal liver metastases. The other six patients had primary hepatobiliary tumors (size, nonmeasurable to 13 x 10 x 9 cm). Of the intrahepatic recurrences, nine were within the RT volume and seven were outside of the irradiated volume. In patients with liver metastases, four of five intrahepatic recurrences occurred within the RT volume. The median time to in-RT field hepatic progression was 12 months. Patients treated with more than 70 Gy had improved in-field local control compared with those who received less than 70 Gy (median time to in-RT field progression, 22 v 9 months; P < .05).
Survival The 1- and 2-year actuarial survival rates of all 43 patients were 62% (95% confidence interval [CI], 47% to 76%) and 14% (95% CI, 5% to 36%), respectively (Fig 4). The median overall survival times of all patients, patients with colorectal cancer liver metastases, and patients with primary hepatobiliary tumors were 16, 18, and 11 months, respectively. Seventeen patients were alive at last follow-up, including four with no evidence of disease progression at 22, 23, 25, and 30 months.
Prognostic Factors We had hypothesized that dose would be a key determinant of tumor control. In agreement with our hypothesis, multivariate analyses for survival with the Cox proportional hazards model found that elevated RT dose was associated with significantly increased survival (P = .0001). Noncholangiocarcinoma pathology was also a significant prognostic factor. Nonsignificant factors included age, sex, and presence of extrahepatic disease at the time of treatment, a diagnosis of hepatocellular carcinoma, and, importantly, hepatic tumor volume. The importance of RT dose is emphasized by assessing progression-free survival and overall survival on the basis of dose quartiles (Figs 5 and 6). The median survival for the patients treated with the highest doses (70 to 90 Gy) has not yet been reached (16.4+ months), compared with 11 months (95% CI, 5.8 to 18.6 months) in patients treated with less than 70 Gy of RT (P = .0003). RT dose was a significant prognostic factor when evaluated as a continuous variable and when divided into quartiles. Higher RT doses were associated with improved survival for all tumor types. Progression-free survival was also improved in patients who were treated with higher doses of RT. The median progression-free survival was 24.5 months (95% CI, 8 to 33.5 months), compared with 5 months in patients who were treated with less than 70 Gy (log-rank, 9.2; P < .01). There were no significant differences in overall survival or progression-free survival between the three lowest dose quartiles. Characteristics of patients treated with more than 70 Gy are compared with those treated with lower doses of RT in Table 3.
Because one possible explanation for the observed improved survival in the high-RT dose group is that smaller tumors were treated in this dose group, we looked for an association between RT dose and tumor volume. No associations between RT dose and tumor volume were found, as demonstrated in a scatterplot in Fig 7. In addition, there was no obvious relationship between RT dose and diagnoses.
Toxicity A previous publication describes toxicity details of patients treated on this protocol.10 As of June 1999, the MTD of focal liver RT and hepatic arterial FUdR had not yet been reached, and RT dose escalation is ongoing. One case of RILD was seen among the patients described in the present study. This case of RILD was grade 3 and reversible. There were no treatment-related mortalities. Table 4 lists the nonhepatic acute and late toxicities. The most significant nonhepatic toxicity was upper gastrointestinal bleeding, which was seen in three patients.
The development of 3D conformal RT treatment planning tools has permitted us to deliver far greater doses of RT (with concurrent hepatic arterial FUdR) to the liver than was previously possible, both by minimizing the volume of liver irradiated and by allowing a better understanding of the relationships among dose, volume, and risk of complications.10 Because the impact of RT dose on the probability of tumor control is well established in other tumor sites,14 we wanted to begin to test the hypothesis that higher doses of RT could improve local control and possibly survival for patients with unresectable intrahepatic cancer who have little chance of cure with traditional treatments. In confirmation of this hypothesis, we found that dose was highly associated with hepatic control of disease and that the median survival of patients who received the highest doses of RT (> 70 Gy) approaches that seen in surgical series. Importantly, this improved outcome with increasing RT dose does not seem to depend entirely on the fact that smaller tumors received higher doses, because there was not a significant association between dose and tumor volume. To date, we have not yet reached the MTD of focal liver RT, and there has been little significant late treatment toxicity. Some patients, with few alternative therapeutic options at the initiation of the study, have had no progression of disease more than 1 year after treatment. We believe that these preliminary results suggest that high-dose focal RT in combination with other treatments may have an important role to play in patients with focal but unresectable intrahepatic cancer. As previously found with high-dose focal liver RT therapy, the median and overall survival obtained in the present report seem to be better than reported results using whole-liver RT alone for unresectable primary hepatobiliary cancer15,16 and colorectal liver metastases17-19 and are, overall, similar to our previous results.6,16 The presence of extrahepatic disease was associated with a decreased overall survival in previous patients treated with lower doses of focal liver RT and hepatic arterial FUdR.6,17 However, the presence of extrahepatic disease did not alter survival in the present series, which suggests that our selection of patients who would most likely benefit from liver RT was appropriate. Other investigators found that liver RT and concurrent intravenous or hepatic arterial fluorouracil-based chemotherapy was of benefit to patients with symptoms from colorectal cancer liver metastases. Increased rates and lengths of palliation as well as improved survival were seen in patients with liver metastases who were treated with a boost of RT to the tumor (33 to 60 Gy) as compared with those treated with whole-liver RT alone (20 to 30 Gy; median survival, 14 v 4 months; P = .03).20 Although North American published literature on RT for unresectable intrahepatic carcinomas is limited, several groups from Asia and Europe have reported excellent outcomes with RT.7,8,21-23 In Korea, transarterial chemoembolization and local RT (44.0 ± 9.3 Gy) for hepatocellular carcinoma resulted in a median survival of 17 months.21 Durable local control for unresectable hepatocellular carcinomas has also been achieved with focal photon22,23 and proton7,8 RT. Radioimmunotherapy has also been used as a single treatment and in combination with other therapies.24-27 Given the number of therapeutic options for patients with unresectable intrahepatic cancer,28 it would be desirable to know whether one therapy is superior to others. Unfortunately, it is difficult to compare treatments for unresectable intrahepatic malignancies, because few randomized studies have been performed and selection criteria vary widely. For unresectable hepatocellular carcinomas, hepatic arterial embolization was found to be no better then supportive therapy in one randomized trial,29 and radioimmunotherapy was found to be no better then hepatic arterial embolization in another randomized trial.27 Percutaneous ethanol injections (with and without chemoembolization),30,31 cryotherapy,32,33 microwave coagulation,34 and thermal ablation35 have also been used in select, well-defined intrahepatic tumors, although limitations of the above techniques relate to tumor size, number, and location relative to blood vessels. We note that the majority of patients in the present study had tumors that were refractory to other treatments, and the majority were ineligible for these potential alternative therapeutic options, primarily because of locally advanced disease that resulted in large tumor size in undesirable locations. Other treatments for patients with unresectable liver metastases from colorectal cancer include systemic chemotherapy,36,37 hepatic arterial chemotherapy,1,38,39 and protracted venous infusional chemotherapy.40,41 Some of the best survival rates have been observed in patients with liver metastases from colorectal cancer who were treated with protracted venous infusion.40 The use of this therapy should be viewed as complementary to our local therapy, because a combination of these therapies may result in improved local and distant disease control. Weaknesses of the present results include the patient heterogeneity and the nonrandomized nature of the study. Despite the fact that the results regarding the impact of RT dose on local control and survival are striking, it must be noted that dose was not allocated in a randomized fashion, and thus biases may be present. It is possible that the differences in survival seen with different RT doses could be due to the difference in patients or tumors treated with different doses, as opposed to a therapeutic effect from the RT. Dose was allocated on the basis of the amount of normal liver that could be spared from RT, which is dependent on the total tumor volume, tumor location, normal liver size, and RT techniques used. We looked for correlations between RT dose and other potential prognostic factors such as tumor volume and diagnosis, but none were found. Thus we feel that our results suggest that tumor control and survival can be increased with increased RT dose to intrahepatic cancers, but these results must be corroborated by other prospective and preferably randomized trials. The results from this study warrant continuation of the present dose-escalation study and further studies of high-dose focal liver RT for intrahepatic malignancies. In an effort to allow more patients with unresectable intrahepatic malignancies to receive safely more than 70 Gy of RT, we presently are studying the use of active breathing control42 during RT treatments. By treating patients with their respiration temporarily suspended using active breathing control, we should be able to decrease the amount of normal liver that must be treated to account for organ motion due to ventilation, producing less risk of RILD. Another potential method of increasing RT dose safely incorporates the use of radioprotective agents directed to the normal liver. These interventions may allow further dose escalation that may lead to improved in-field control of disease. Further improvements in local control may be possible by using hepatic artery embolization and/or surgery in lesions that become resectable after high-dose liver RT and hepatic arterial FUdR. The finding that disease progression was most often extrahepatic for patients with colorectal metastases suggests that new developments in systemic therapy,36,37 in combination with focal liver RT, may result in further improvements in local control and survival, particularly for patients with unresectable liver metastases from colorectal cancer.
Supported in part by grant nos. CA59827 and MO1RR00042 from the National Institutes of Health, Bethesda, MD. We thank Diane Brown for her superb care of the patients described in this article and Amy Pace for her assistance with figure preparation.
Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.
1. O’Connell MJ, Nagorney DM, Bernath AM, et al: Sequential intrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver. J Clin Oncol 16:2528-2533, 1998[Abstract] 2. Hughes KS, Simon R, Songhorabodi S, et al: Resection of the liver for colorectal carcinoma metastases: A multi-institutional study of patterns of recurrence. Surgery 100:278-284, 1986[Medline] 3. Ingold J, Reed G, Kaplan H: Radiation hepatitis. Am J Roentgenol 93:200-208, 1965 4. Wharton JT, Delclos L, Gallager S, et al: Radiation hepatitis induced by abdominal irradiation with the cobalt 60 moving strip technique. Am J Roentgenol Radium Ther Nucl Med 117:73-80, 1973[Medline] 5. Robertson JM, McGinn CJ, Walker S, et al: A phase I trial of hepatic arterial bromodeoxyuridine and conformal radiation therapy for patients with primary hepatobiliary cancers or colorectal liver metastases. Int J Radiat Oncol Biol Phys 39:1087-1092, 1997[Medline] 6. Robertson JM, Lawrence TS, Walker S, et al: The treatment of colorectal liver metastases with conformal radiation therapy and regional chemotherapy. Int J Radiat Oncol Biol Phys 32:445-450, 1995[Medline] 7. Ohara K, Okumura T, Tsuji H, et al: Clearance of parenchymal tumors following radiotherapy: Analysis of hepatocellular carcinomas treated by proton beams. Radiother Oncol 41:233-236, 1996[Medline] 8. Matsuzaki Y, Osuga T, Chiba T, et al: New, effective treatment using proton irradiation for unresectable hepatocellular carcinoma. Intern Med 34:302-304, 1995[Medline] 9. Lawrence TS, Ten Haken RK, Kessler ML, et al: The use of 3-D dose volume analysis to predict radiation hepatitis. Int J Radiat Oncol Biol Phys 23:781-788, 1992[Medline] 10. McGinn CJ, Ten Haken RK, Ensminger WD, et al: Treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model. J Clin Oncol 16:2246-2252, 1998[Abstract] 11. Balter JM, Lam KL, McGinn CJ, et al: Improvement of CT-based treatment-planning models of abdominal targets using static exhale imaging. Int J Radiat Oncol Biol Phys 41:939-943, 1998[Medline] 12. Ten Haken RK, Martel MK, Kessler ML, et al: Use of Veff and iso-NTCP in the implementation of dose escalation protocols. Int J Radiat Oncol Biol Phys 27:689-695, 1993[Medline] 13. Ensminger WD: Regional chemotherapy [review]. Semin Oncol 20:3-11, 1993[Medline] 14. Fletcher G: Clinical dose-response curves of human malignant epithelial tumours. Br J Radiol 46:1-12, 1973[Medline]
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Findlay M, Hill A, Cunningham D, et al: Protracted venous infusion 5-fluorouracil and interferon-alpha in advanced and refractory colorectal cancer. Ann Oncol 5:239-243, 1994 42. Wong JW, Sharpe MB, Jaffray DA, et al: The use of active breathing control (ABC) to reduce margin for breathing motion. Int J Radiat Oncol Biol Phys 44:911-919, 1999[Medline] Submitted December 9, 1999; accepted February 15, 2000. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
70 Gy) Compared With Lower-Dose Group (< 70 Gy)
