The treatment of colorectal liver metastases with conformal radiation therapy and regional chemotherapy

Inc. J. Radiarion

Oncology

Pergamon

Biol.

Phys., Vol. 32. No. 2, pp. 44-450, 1995 Copyright 0 1995 Elsevier Science Ltd Printed in the USA. All rights reserved 036@3016/95 $9.50 + DO

0360-3016(94)00591-5

l

Phase I/II Clinical

Trials

THE TREATMENT OF COLORECTAL LIVER METASTASES WITH CONFORMAL RADIATION THERAPY AND REGIONAL CHEMOTHERAPY JOHN M. ROBERTSON, M.D.,* THEODORE S. LAWRENCE, M.D., PH.D.,* R.N., O.C.N.,’ MARC L. KESSLER, PH.D.,* JAMES C. ANDREWS, M.D.’ AND WILLIAM D. ENSMINGER, M.D., PH.D.’

SUZETTE WALKER,

*Departmentsof RadiationOncology, ‘Radiology, tPharmacologyand Internal Medicine, and the Clinical ResearchCenter, The University of Michigan Medical Center, Ann Arbor, MI Purpose: Whole-liver radiation, with or without chemotherapy, has been of modest benefit in the treatment of unresectable hepatic metastases from colorectal cancer. A Phase I/II study combining escalating doses of conformally planned radiation therapy (RT) with intraarterial hepatic (IAH) fluorodeoxyuridine (FdUrd) was performed. Methods and Materials: Twenty-two patients with unresectable hepatic metastases from colorectal cancer, 14 of whom had progressed after previous chemotherapy (2 with prior IAH FdUrd), were treated with concurrent IAH FdUrd (0.2 mgikg/day) and conformal bepatic radiation therapy (1.5-1.65 Gy/fraction twice a day). The total dose of radiation given to the tumor (48-72.6 Gy) depended on the fraction of normal liver excluded from the high-dose volume. All patients were assessed for response, toxicity, hepatohiliary relapse, and survival. Median potential follow-up was 42 months. Results: Eleven of 22 patients demonstrated an objective response, with the remainder showing stable disease. Actuarial freedom from hepatic progression was 25% at 1 year. The most common acute toxicity was mild to moderate nausea and transient liver function test abnormalities. There were three patients with gastrointestinal bleeding (none requiring surgical intervention) after the completion of treatment. Overall median survival was 20 months. The presence of extrahepatic disease was associated with decreased survival (p < 0.01). Conclusions: Combined conformal radiation therapy and IAH FdUrd can produce an objective response in 50% of patients with hepatic metastases from colorectal cancer. However, response was not durable, and hepatic progression was frequent. Improvements in hepatic tumor control for patients with metastatic colorectal cancer may require higher doses of conformal radiation and/or improved radiosensitization. In an effort to increase radiosensitization, we have recently initiated a clinical trial combining IAH bromodeoxyuridine, a tbymidine analog radiosensitizer, with conformal high dose radiation therapy. Colorectal

cancer,

Liver

metastases,

Conformal

radiation

INTRODUCTION

therapy,

Intraarterial

chemotherapy.

planning techniques to help minimize the amount of normal liver irradiated, a higher dose of radiation can be given to patients with localized intrahepatic tumors with an acceptable incidence of complications (17- 19, 24). Another modality for the treatment of hepatic malignancies is intraarterial hepatic chemotherapy (IAH), which can have pharmacological advantages over systemic therapy (7). Randomized studies of IAH chemotherapy for metastatic colorectal cancer have typically used fluorodeoxyuridine (FdUrd) (6, 12, 15, 25). Intraarterial hepatic

The whole organ tolerance of the liver to radiation therapy has limited the dose for conventional treatment of metastatic cancer to 30 Gy or less, at standard fractionation. As would be expected, this dose is of modest palliative benefit, but does not result in control of the intrahepatic disease (20). Until recently, there was little experience giving a dose of radiation that might be in the tumoricidal range. By using three-dimensional radiation treatment

Presentedin part at the Thirty-Sixth Annual Meeting of the

Acknowledgements-The authors wish to thank Allen S. Lichter, M.D., for a critical review of the manuscript. These investigations are supported in part by NIH Grants #MO1 RR

American Society for Therapeutic Radiology and Oncology, San Francisco, CA, October 3-7, 1994. Reprint requests to: John M. Robertson, M.D., University of Michigan Medical Center, Department of Radiation Oncology, 1500 E. Medical Center Dr., UH B2-C490, Box 0010, Ann Arbor. Ml 48109.

00042, CA 42671,and an American Society of Clinical Oncology Clinical Research Career Development Award Accepted for publication 4 November 1994. 445

(J.M.R.).

446 IA

I. J. Radiation Oncology 0 Biology l Physics First treatment

(18 Gy)

!Seoond

tmetment

(30 Gy)

Firet treatment

(30 Gy)

Second

trwtment

(30 Gy)

I

Fig. 1. Treatment schema used for this study. After conformal treatment planning and calculation of the DVH of the normal liver, patients were eligible to receive either a total dose of radiation of 48852.8 Gy (A) or 66-72.6 Gy (B) given b.i.d. at 1S- 1.65 Gy per fraction. IAH FdUrd was given at 0.2 mg/kg/ day for the first 8 (A) or 15 days (B) followed by a second 14day infusion.

FdUrd may also provide radiosensitization, as preclinical studies have shown that FdUrd is a potent radiosensitizer in vitro (3, 10). Therefore, because three-dimensional treatment planning can allow a higher dose of radiation to be given and IAH FdUrd can provide radiosensitization, we designed a trial combining these two nonsurgical therapies for patients with unresectable intrahepatic malignancies. In the initial experience with 33 patients who had primary or metastatic liver disease(17), 14 out of 29 evaluable patients had an objective response. Treatment was well tolerated, with only two patients developing a mild radiation hepatitis. However, when the dose of radiation given to the focal abnormalities was increased in combination with whole-liver radiation, the incidence and severity of radiation hepatitis increased (18). Based on these results, whole-liver radiation as a portion of treatment was discontinued. With this change, the dose of radiation was escalated without clinically evident hepatic toxicity and with encouraging results for treatment of primary hepatobiliary cancer (24). We now describe the results of treatment of 22 patients with unresectable localized colorectal cancer metastatic to the liver.

METHODS

AND MATERIALS

Patient Selection Patients with unresectable liver metastasesfrom colorectal cancer were eligible for this study. Evaluation included physical examination, blood hematological and chemical studies, chest x-ray, computed tomography (CT) scan of the abdomen, and biopsy of the intrahepatic tumor. Patients were determined to be unresectable based on the pretreatment evaluation, including hepatic angiography (if necessary) using accepted surgical criteria (8, 9). The criteria for unresectability included: the presence of extrahepatic disease, proximity of the tumor to the vasculature preventing an anatomic resection or the ability to obtain adequate margins, and the presence of four or

Volume 32, Number 2, 1995

more metastases.A performance status of 2 60% (Karnofsky), life expectancy of at least 12 weeks, adequate bone marrow function (total granulocytes 2 1500 mm’; platelets 2 100,000 mm’), and adequate renal function (blood urea nitrogen 5 40 mg%; creatinine < 2.0 mg%) were required. Previous treatment with chemotherapy, including IAH FdUrd, was allowed, although prior upper abdominal radiation therapy rendered patients ineligible. Patients with extrahepatic disease were eligible if it appeared that progression of intrahepatic disease was the greatest short-term threat to the life of the patient. Informed consent was obtained from all patients in accordance with the procedures of the Institutional Review Board of the University of Michigan Medical Center. Radiation Treatment Planning and Dose Determination The radiation therapy treatment planning and dose prescription methods have been previously described (1719, 27). All patients were immobilized using a low-density body cradle. At the time of cradle construction, a simulation was performed to measurethe ventilatory motion of the diaphragm, as seen flouroscopically, and to define both the superior and inferior limits of scanning for the treatment planning CT. These limits extended from above the diaphragm to below the iliac crests. Including the entire abdomen as well as the inferior thorax in the treatment planning CT allowed both better verification of the patient position and improved planning for nonaxial fields. The treatment planning CT scan was then obtained on a flat couch insert in the radiation treatment position, using both oral and intravenous contrast. Contours of the liver, tumor(s), kidneys, spinal cord, and vertebral bodies were defined for each patient. The tumor volume(s) were defined as radiographically abnormal area(s) within the liver. The tumor volume(s) plus a 1.5 cm margin (to account for both daily variation in patient positioning and for subclinical biologic tumor extension) was defined as the target volume. The ventilatory motion of the liver observed flouroscopically was added to the cranial and caudad portions of the target volume. Contours of the structures of interest were then combined to form a threedimensional representation that was used for treatment planning. The goal of treatment planning was to maximally sparenormal liver while maintaining a 2 5% homo-

Table 1. Patient characteristics Characteristic

Number of patients

Total number Median age (years) Previous chemotherapy Extrahepatic disease Number of lesions 1 2-3 >3

22 (15 male: 7 female) 61 (range, 34-81) 14 (including 2 IAH) 6 8 6 8

IAH = Intraarterial

hepatic chemotherapy.

Conformal

radiation

for liver

metastases

geneity in the target volume. Each patient had at least one individualized treatment plan in which the high dose region encompassed the target volume and maximally spared normal liver outside of the target volume. A cumulative dose-volume histogram (DVH) of the normal liver was calculated for each treatment plan, which summarized the fraction of the liver receiving greater than or equal to a particular dose. The volume of normal liver used for the DVH was defined as the total liver volume minus the tumor volume(s). The total radiation dose prescribed was determined by the percent volume of liver treated to more than 50% of the dose to the isocenter. If the fraction of normal liver treated to > 50% of the isocenter dose was c= 33%, then the target volume received 66 Gy. If the percent of normal liver treated to > 50% of the isocenter dose was 33-66%, then the target volume received 48 Gy. The first three patients received 30 Gy of whole-liver radiation as the first portion of their treatment; however, this was later discontinued, basedon our analysis of patterns of failure and toxicity (17, 18). Treatment (Fig. I) Patients were admitted to the Clinical Research Center of the University of Michigan Medical Center for treatment. Continuous infusional IAH FdUrd (0.2 mg/kg/day) delivered via either an implanted pump or a percutaneous catheter introduced through the brachial artery was initiated 2 days prior to radiation. Radiation therapy was administered twice a day using lo- 15 MV photons at 1.5 Gy per fraction, with each fraction separated by at least 4 h. The dose of radiation was escalated by 10% after at least three patients had completed treatment and been observed for at least 2 months, for each total dose of 48 Gy and 66 Gy. To maintain the same overall treatment time, the 10% escalation was achieved by increasing the fraction size 1.65 Gy. All patients received a 2-week break between IAH infusions. Correct catheter placement was verified by nuclide infusion scanning using Tc99mmacroaggregated albumin prior to each course of therapy. Evaluation Acute toxicity was evaluated weekly during treatment and 1 month following treatment using World Health Or-

MONTHS

Fig. 2. Actuarial Meier analysis).

freedom

from hepatic progression

(Kaplan-

0 J.

M. ROBERTSON et al. Table 2. Radiation Dose

447

dose prescribed Number

48 Gy 52.8 Gy 66 Gy 72.6 Gy

of patients 6 5 6 5

ganization criteria (21). Subacute or long-term toxicity was defined as occurring after 1 month. Radiation hepatitis was defined as the development of anicteric elevation of alkaline phosphataseof at least twofold, with cytologyproven nonmalignant ascites in the absence of documented progressive disease. Six to 8 weeks after completion of treatment, patients were assessedby physical exam, chemistries, and a CT scan. Standard bidimensional objective response criteria were used.Thereafter, routine exam and laboratory testing were performed at 1-2-month intervals or as clinically indicated. Routine abdominal CT scanning was performed at 2-3 month intervals. Hepatic progression was determined to be either within the volume irradiated to the full dose or outside of the full dose volume. The median potential follow-up was 42 months. Statistics Survival and progression-free survival were assessed from the start of treatment using the Kaplan-Meier method (13). Survival curves were compared using the log-rank test, and statistical significance was assessedat the level of p < 0.05 (two tailed). RESULTS A total of 22 patients were treated (Table l), most of whom had received previous chemotherapy. Eleven patients received 48-52.8 Gy and 11 received 66-72.6 Gy (Table 2). Eleven of 22 patients demonstrated an objective response (two complete responses, nine partial responses),while the remainder of patients showed stable disease.The liver was the first site of progression in 13 patients. Five patients progressedwithin the volume that received the full dose of radiation, six patients progressed elsewhere in the liver, and two patients progressedin both sites. Of the 11 responders,5 patients ultimately had some component of tumor progression in the liver (2 in the volume of full radiation dose and 3 in another portion of the liver). The actuarial freedom from hepatic progression was 25% at 1 year (Fig. 2). There was no grade 4 or 5 toxicity (Table 3). Four grade 3 toxicities were observed, predominantly mild to moderate nauseaand transient elevations in the liver function tests without clinical evidence of radiation hepatitis. One patient had a cerebrovascular accident (right homonymous hemianopsia) during removal of the brachial artery catheter. Long-term toxicity consisted of three patients

448

I. J. Radiation Oncology 0 Biology 0 Physics

MONTHS

Fig. 3. Actuarial survival of patients treated with combined conformal radiation therapy and intraarterial hepatic fluorodeoxyuridine (Kaplan-Meier analysis)shown for all patients. The actuarialsurvival of patientswith extrahepaticdisease,as well asdiseaselimited to the liver only, is provided.

who developed upper gastrointestinal bleeding requiring transfusion but not surgical intervention. Endoscopic examination of the three patients revealed diffuse hemorrhagic gastritis, multiple arteriovenous malformations, and no abnormalities in one patient each. Two of the three patients who had received whole-liver radiation to a total dose of 30 Gy as a portion of their treatment developed radiation hepatitis, which probably was the causeof death in one patient. Radiation hepatitis was not observed in the 19 patients treated without whole-liver radiation. The overall median survival was 20 months (Fig. 3). The effect of three variables on survival was assessed using a log rank analysis: (a) the presenceof extrahepatic disease;(b) the number of lesions treated; and (c) a history of previous chemotherapy. Only the presence of extrahepatic disease was found to have a significant impact on survival. The survival of patients with extrahepatic disease was significantly less than that of patients who presented without extrahepatic diseaseat the time of treatment (median survival 22 months vs. 14 months, p < 0.01) (Fig. 3).

DISCUSSION Three-dimensional treatment planning for patients with focal intrahepatic tumors can allow substantial portions of normal liver to be spared from the area of high dose during a course of radiation therapy (17- 19, 24). When compared to the dose typically given for palliation, a higher dose could be expected to improve the response to therapy and, potentially, hepatic control. Becausemost patients die due to progressive hepatic disease,improved control could lead to an increase in survival. Indeed, our preliminary experience with primary hepatobiliary tumors supports this concept (24). The study reported here also supports the hypothesis, with an objective response rate of 50% and a median survival of 20 months. However, response was not durable, and actuarial freedom from hepatic progression was 25% at 1 year. As with all small pilot trials, differences in selection

Volume 32, Number 2. 1995

factors make comparing studiesdifficult. The most widely used therapies for patients with unresectable hepatic metastasesfrom colorectal cancer are systemic chemotherapy, palliative whole-liver radiation therapy, and chronic IAH FdUrd. Systemic chemotherapy has been recommended only for symptomatic patients, as responsesare obtained in about 20% of patients, and median survival is about 6-8 months (7). Whole-liver radiation alone has been reported to provide palliation; however, objective response rates were less than 10% (20), and median survival was 2-4 months (2, 20). Trials combining wholeliver radiation with IAH FdUrd have been reported, but were small and, with one exception, have not reported objective responsecriteria (1, 5, 11, 28). Although there is little data from the literature, the results of this trial are favorable when compared to systemic chemotherapy or whole-liver radiation alone, as well aswhole-liver radiation combined with chronic IAH FdUrd. Trials of chronic IAH FdUrd alone provide better responsedata, but are difficult to compare and only include patients without extrahepatic disease. Unlike our study, a permanent pump has been used to deliver a 1Cday continuous infusion once every 4 weeks until toxicity or progression developed. The reported trials do not provide the total number of infusions given, and there are no response data for only two infusions. Nonetheless, an objective responsehas been observed in 40-60% of patients, with a median survival of 12- 17 months (6, 12, 15, 25). Toxicity is substantial with chronic IAH FdUrd and is usually the reason for discontinuence (6, 25), although the most life-threatening toxicity, sclerosing cholangitis, appears to have been avoided with a lower daily dose (12). Therefore, a comparison of this trial to those of chronic IAH FdUrd reveals similar results, although the treatment given in this study was administered in a much shorter period of time, and without the placement of a permanent hepatic artery catheter. In fact, focal radiation therapy and chronic IAH FdUrd could be viewed as complementary treatments, and it may be possible to combine them, as has been reported after surgical resection (14). Despite the encouraging responserate and median survival, hepatic control was not maintained. This finding is similar to that reported with other modalities for metastatic colorectal cancer, including resection (4, 12, 22, Table 3. Acute toxicity System Bone marrow

0

Hemoglobin

15

WBC

15

Platelets

19

Nausea/vomiting Gastritis Liver Pain

10

22 8 21

I

2

3

4 2 2 5

3 4 6

1 1

11 -

2

-

WBC = White blood cell count.

1

4 -

1 1

-

Conformal

radiation

for liver

metastases

26). This contrasts with our experience using identical treatment for primary hepatobiliary tumors, which found responsesin 11 of 11 patients and an actuarial hepatic control rate of 70% 2 years after treatment (24). This difference is probably not a chemotherapeutic effect, as IAH FdUrd alone for primary hepatobiliary tumors is of little value (23). These findings suggest, however, that differences in sensitivity to combined radiation and FdUrd between primary hepatobiliary cancer and colorectal cancer may exist. Based on this evidence, we have begun laboratory studies of radiation and FdUrd in hepatocellular carcinoma cells to assessthis possibility. In an effort to improve the results with metastatic colorectal cancer we have performed preclinical evaluations

0

J. M. ROBERTSON et ul.

449

of bromodeoxyuridine (BrdUrd), a thymidine analog that radiosensitizes colon cancer cells in proportion to the incorporation in deoxyribonucleic acid (16). These and other data have led to a clinical trial that is now underway using IAH BrdUrd combined with high-dose radiation therapy. Also of interest is a parallel study for patients with potentially resectable disease that infuses IAH BrdUrd for 4 days immediately prior to an attempted resection of the hepatic disease.At the time of surgery, the intrahepatic tumor is either resected or, if unresectable, biopsied. Initial results show that levels of BrdUrd incorporation are obtained that would be anticipated to produce radiosensitization (J. Knol, oral communication, May 1994).

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Volume 32, Number 2, 1995 Gallot, D.; Gouzi, J. L.; Pailler, J. L.; Elisa, D.; Lacaine, F.; Roos, S.; Rotman, N.; Luboinski, M.; Lasser, P. Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: Long-term results of a prospective randomized trial. J. Clin. Oncol. 10:11121118; 1992. 26. Steele, G., Jr.; Bleday, R.; Mayer, R. J.; et al. A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group Protocol 6584. J. Clin. Oncol. 9:1105-1112; 1991. 27. Ten Haken, R. K.; Lawrence, T. S.; McShan, D. L.; Tesser, R. J.; Fraass, B. A.; Lichter, A. S. Technical considerations in the use of 3-D beam arrangements in the abdomen. Radiother. Oncol. 22: 19-28; 1991. 28. Webber, B. M.; Soderberg, C. H.; Leone, L. A.; Rege, V. B.; Glicksman, A. S. A combined treatment approach to management of hepatic metastases. Cancer 42:10871095; 1978.