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© 2001 American Society for Clinical Oncology Stereotactic Single-Dose Radiation Therapy of Liver Tumors: Results of a Phase I/II TrialFrom the Divisions of Radiation Oncology, Radiological Diagnostics and Therapy, and Medical Physics, German Cancer Research Center; and Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany. Address reprint requests to K.K. Herfarth, MD, Division of Radiation Oncology, E0500, German Cancer Research Center (dkfz), INF 280, 69120 Heidelberg, Germany; email k.herfarth{at}dkfz.de
PURPOSE: To investigate the feasibility and the clinical response of a stereotactic single-dose radiation treatment for liver tumors. PATIENTS AND METHODS: Between April 1997 and September 1999, a stereotactic single-dose radiation treatment of 60 liver tumors (four primary tumors, 56 metastases) in 37 patients was performed. Patients were positioned in an individually shaped vacuum pillow. The applied dose was escalated from 14 to 26 Gy (reference point), with the 80% isodose surrounding the planning target volume. Median tumor size was 10 cm3 (range, 1 to 132 cm3). The morbidity, clinical outcome, laboratory findings, and response as seen on computed tomography (CT) scan were evaluated. RESULTS: Follow-up data could be obtained from 55 treated tumors (35 patients). The median follow-up period was 5.7 months (range, 1.0 to 26.1 months; mean, 9.5 months). The treatment was well tolerated by all patients. There were no major side effects. Fifty-four (98%) of 55 tumors were locally controlled after 6 weeks at the initial follow-up based on the CT findings (22 cases of stable disease, 28 partial responses, and four complete responses). After a dose-escalating and learning phase, the actuarial local tumor control rate was 81% at 18 months after therapy. A total of 12 local failures were observed during follow-up. So far, the longest local tumor control is 26.1 months. CONCLUSION: Stereotactic single-dose radiation therapy is a feasible method for the treatment of singular inoperable liver metastases with the potential of a high local tumor control rate and low morbidity.
SO FAR, RADIATION therapy has played a minor role in the potentially curative treatment of patients with liver metastases because of the limited radiotolerance of the liver. It may be used as palliative treatment in patients with liver metastases.1 The tolerance dose of the whole liver to fractionated radiation is limited to 30 Gy. However, whole-liver irradiation does not result in longer survival.2 Higher doses can safely be applied to a liver tumor if functional liver tissue can be spared from high radiation doses.3 Stereotactic and conformal radiotherapy allows precisely locating and delivering dose. Those techniques made high-dose radiation therapy possible in the brain, achieving palliation and high local tumor control in the case of brain metastases.4 Blomgren et al5,6 published the first results of stereotactic high-dose radiation therapy using a hypofractionated schedule. Others also reported a stereotactically guided hypofractionated radiation therapy approach in the treatment of liver malignancies.7,8 In analogy to the stereotactic radiation treatment of brain metastases, we investigated the feasibility and the clinical outcome of stereotactic single-dose radiation therapy of liver metastases in a prospective phase I/II trial.
Between April 1997 and September 1999, 60 liver tumors of 37 patients (25 male, 12 female) were treated in a total of 40 treatments. The median age of the patients was 61 years (range, 37 to 84 years). All patients had a Karnofsky performance index  80%. Inclusion criteria for the study were unresectable tumors in the liver. The number of liver lesions could not exceed three tumors (four if two tumors of less than 3 cm were close together). The size of a single lesion could not exceed 6 cm, and none of the tumors could be immediately adjacent to parts of the gastrointestinal tract (distance > 6 mm). Exclusion criteria were insufficient liver function (eg, cholinesterase < 3,000 U/L), specific histologic tumor types (eg, germ cell tumors, hematologic tumors), and adjacent gastrointestinal organs. The targets included four primary hepatic tumors (three cholangiocellular carcinomas, one hepatocellular carcinoma) and 56 metastases from other primary neoplasms (colorectal cancer, 30; breast cancer, 14; soft tissue sarcoma, four; lung cancer, four; pancreatic cancer, two; hypernephroma, one; or malignant melanoma, one). The median target size was 10 cm3 (range, 1 to 132 cm3). All tumors were either histologically confirmed or showed a volume increase before treatment. A surgical intervention was not possible (intrahepatic central location, seven patients; bilateral tumor location, three patients; previous hepatic surgery, six patients; advanced age or medical risk factors, five patients) or not indicated (other extrahepatic systemic metastases, 11 patients; or patients with breast carcinoma and previous systemic tumor spread, five patients) in any of the patients. All patients with breast carcinoma had experienced treatment failure with standard chemotherapy. Other systemic metastases (eg, lung, bone) were present in 11 patients (18 targets) at the time of treatment. In these patients, the treatment had a purely palliative intention to prevent hepatic symptoms. Additional single-dose treatment sessions were performed in two patients for new singular metastases, which appeared during follow-up. The study was in accordance with the Declaration of Helsinki (1996). The ethics committee of the University of Heidelberg approved the study (no. 192/97), and all patients gave their written consent.
Treatment Planning and Treatment The purpose of the treatment planning was a homogenous dose distribution in the PTV with the 80% isodose encompassing the PTV. This aim was achieved using different techniques. For circular targets, we used a coplanar rotational field (14 targets). For irregularly shaped targets, we used a median of six coplanar conformal fields (range, five to 10 fields). If more than one target had to be treated in one patient, we used one common target point whenever possible and concentrated the beam on the individual targets using a multileaf collimator (Fig 1A and 1B). In each treatment, the radiation beams were shaped using a multileaf collimator with 5-mm leaf width (n = 15) or 10-mm leaf width (n = 45) at the isocenter. An example of a dose distribution is shown in Fig 1C. The dose had been escalated from 14 to 26 Gy at a reference point (< 20 Gy, five targets; 20 to 22 Gy, 32 targets; 23 to 26 Gy, 23 targets). The reference point was the isocenter if only one lesion was treated. If more than one target had to be treated, the reference point was the location with the maximum dose. The dose varied between 14 and 20 Gy at the reference point for the first six targets. Further escalation was performed in 2-Gy steps up to a maximum dose of 26 Gy (reference point) based on the dose-volume histogram: the dose to 30% of the liver was increased from 6 to 12 Gy while the maximum dose to 50% of the liver was escalated from 4 to 7 Gy. However, dose was reduced during the dose escalation if normal tissue constraints of nearby gastrointestinal organs (esophagus, 14 Gy; stomach, 12 Gy; small bowel, 12 Gy) did not allow higher doses.
The patients were treated using a Siemens linear accelerator with 15 MeV energy (n = 56) or 6 MeV energy (n = 4) (Siemens Corporation, Concord, CA). In every patient, a control CT for positioning verification was performed directly before treatment and the position corrected if necessary.9 As part of the quality assurance program, metal markers were sewn on the skin. The stereotactic coordinates of these markers were determined in treatment planning and targeted in the treatment room. In addition, portal imaging was performed and compared with digitally reconstructed radiographs of the treatment planning. All patients received 12 or 20 mg of intravenous dexamethasone directly before treatment and 6 hours after therapy. The patients were hospitalized for one night after treatment.
Follow-Up
Additional Systemic Therapy
Statistics
Clinical Data All patients tolerated the treatment well and no major side effects were observed. Eleven patients experienced an intermittent loss of appetite or mild nausea for 1 to 3 weeks after therapy. Two patients with tumors close to the diaphragm experienced a moderate singultus for 2 to 3 days after therapy. One patient developed fever in the 2 days after therapy. CT and magnetic resonance imaging scans showed signs of complete tumor necrosis of the radiated lesion in this patient. None of the treated patients developed clinically detectable radiation-induced liver disease (weight gain, ascites, newly developed increase of alkaline phosphatase concentrations). Thirteen patients died during follow-up as a result of progressive systemic disease. The actuarial overall 1-year survival rate was 72%.
CT Data At the 6-month follow-up appointment, further response or stable disease was achieved in 34 of 43 tumors examined (79%). This included stable disease in seven, partial response in 20, and complete response in seven treated tumors. Local failure was observed in nine treated tumors. A 1-year follow-up examination could be obtained for 21 treated liver lesions. Two additional local failures were documented at this time. Nineteen tumors still showed stable disease (two), partial (11), or complete response (six). Eight of 55 liver tumors disappeared during follow-up. Examples of such tumors after radiation are shown in Figs 2 and 3.
Local failure was observed in 12 (22%) of the 55 tumors with follow-up data available. Among these failures, there were three tumors treated with doses of 14 and 16 Gy (reference point) at the beginning of the study. The radiation therapy was performed with smaller safety margins, resulting in doses of less than 16 Gy close to the CTV in four targets. An example of a patient treated with smaller safety margins is shown in Fig 4. In one patient, the PTV surrounding dose was limited because of nearby duodenum, resulting also in a dose less than 16 Gy in parts of the PTV. New multiple satellite metastases occurred near the radiated tumor in two cases.
Tumors with local failure were larger than locally controlled tumors (mean, 31.0 cm3 [range, 2 to 102 cm3] v 19.4 cm3 [range, 1 to 132 cm3]). However, this difference was not statistically significant.
Statistical Analysis
Stratification by size did not reveal a significant difference in the local control rate in the treatment of larger targets ( 15 cm3) compared with smaller targets (< 15 cm3) in the later-treated patients.
Laboratory Findings
Surgical resection of singular liver metastases might result in a longer survival in colorectal cancer patients.12 In the recent years, a number of alternative local therapies have been published. These included laser-induced thermo-therapy, cryosurgery, ethanol injection, intra-arterial chemotherapy, and radiofrequency ablation therapy.13-17 Robertson et al18,19 published a trial with the combination of conformal radiation therapy and locoregional chemotherapy in patients with primary liver tumors or liver metastases. However, all of these methods include invasive approaches. If liver tumors are treated with radiation therapy alone, it requires normal liver tissue–sparing radiation techniques, because the tolerance dose of the liver declines with the volume irradiated.3 Improvements in the positioning of patients and in three-dimensional planning software made a stereotactic approach in the treatment of liver tumors possible. Blomgren et al5,6 published the first experiences of a stereotactic radiation therapy of liver tumors. They suggested a hypofractionated radiation approach with an inhomogeneous dose distribution in the target. Also, Tokuuya et al7 and Sato et al8 used a fractionated stereotactic approach in the treatment of intrahepatic malignancies. Based on our experience in the single-dose radiation treatment of brain metastases,4 we designed a phase I/II study to explore the feasibility and the clinical outcome of stereotactic single-dose radiation therapy in patients with inoperable liver tumors. We could not find any major side effects after single-dose radiation therapies of 60 neoplastic liver lesions. All but one tumor showed stable disease or partial or complete response at first follow-up. Parts of the volume decrease might be influenced by the method of CT imaging. The initial volume is based on the segmentation in the planning CT studies. These studies were performed under shallow breathing, whereas follow-up CT scans were performed in breath-hold techniques. In the planning CT, this might result in slightly larger or smaller calculated volumes than in reality, because the liver movement might influence the tumor size as seen on the images. However, later follow-up CT studies were also performed in breath-hold technique and showed a further decrease of the tumor volume or confirmed the previous findings: of the 17 patients with stable disease at the first follow-up and a minimum of 6 months of follow-up, seven showed a partial response and one a complete response after 6 months, whereas six tumors showed stable disease and three demonstrated local failure. Thirteen patients received chemotherapy during the follow-up period because of progressive systemic disease or synchronous chemotherapy with fluorouracil/leucovorin for advanced rectal cancer. This might have an additional effect on the local control of the radiated tumors. However, eight patients showed further tumor progression in nonirradiated areas during chemotherapy or after completion of chemotherapy, whereas the irradiated tumor remained unchanged or showed a further volume reduction (data not shown). Exclusion of all patients with chemotherapy from the follow-up at the time of the beginning of the systemic therapy does not significantly change the control rate of the later-treated tumors on the basis of the Kaplan-Meier calculation, with an actuarial control rate of 77% after 18 months (data not shown). We observed 12 local failures. Low dose as a possible explanation for the failures was assumed in eight of these failures. The recurrent tumors were also larger at the time of treatment compared with the locally controlled tumor. However, the overall control rate for larger tumors did not significantly differ from the control rates for smaller tumors in the later-treated patients. We did not perform a multivariate analysis to examine other factors that might influence the local failure, because the numbers are too low. Therefore, other factors (eg, histology) might play a role in the failure of the therapy. The first six targets showed worse results than later-treated targets. Again, one possible explanation is a low-dose delivery to the target or to the periphery of the target. In the beginning of our study, the safety margins around the CTV were smaller, especially in cranio-caudal direction. This resulted in lower doses closer to the CTV than in later patients, which might increase the risk of marginal failures, as is shown in Fig 4. However, other factors might also have influenced the outcome, because the first targets were significantly larger than later targets (data not shown). Stable disease at initial follow-up was not associated with local recurrence. Of the 12 tumors with local failure, only three showed stable disease at the first follow-up. Eight recurrent tumors had a partial response at the first follow-up and one showed no response at all to the therapy. Also, 17 of the 22 tumors with stable disease at the first follow-up also underwent a later follow-up examination. Eight of these showed partial or complete response at this time. Reasons for a delayed volume reduction after single-dose radiation therapy might be a sublethal cell damage of the majority of the cells, vital tumor cells with a radiation-induced mitotic block, or a delayed absorption of necrotic tumor cells. We could not obtain any histopathologic specimen from irradiated tumors in any of our patients. Fine-needle aspiration of irradiated tumors showed either necrotic or viable cells months after therapy in the Stockholm experience.6 Further studies are needed to investigate this issue of histopathologic changes in the radiated tumor. Other local techniques showed overall local control rates of 56% after ethanol injection15 or a 6-month local control rate of 66% after radiofrequency ablation.17 Better results were achieved by Vogl et al20 using laser-induced thermo-therapy who published 6-month local control rates of 29% for the first 100 patients, 67% for the second 70 patients and, finally, 97% for the last 150 patients. However, all of these techniques include invasive procedures. In addition, several injections have to be performed for larger tumors, and normal liver tissue sparing is difficult to achieve in complex-shaped tumors. Robertson et al18,19 studied the combination of conformal radiation therapy with local chemotherapy in a phase I/II study. However, there was a local response in only 50% of the cases. Blomgren et al6 were the first to publish a stereotactic radiation approach in the treatment of liver malignancies. They suggested a fractionated radiation schedule. They published only one local failure after the treatment of 41 liver malignancies after the exclusion of the first five patients. A reduced normal tissue reaction is an advantage of fractionated radiotherapy. Fractionation can reduce the normal tissue complication probability, especially for late-reacting normal tissue. Blomgren et al6 reported a hemorrhagic gastritis in a patient after exposing the stomach wall with 7 Gy in each of two fractions. We have not seen any clinically significant complication after single-dose radiation therapy in our patients. We found only a focal tissue reaction with a change in contrast enhancement in the liver (Fig 3). However, similar observations were made also after fractionated radiotherapy.21,22 The intention of radiation planning was to create a steep dose gradient to nearby serial organs like bowel parts or the myelon without compromising the dose in the PTV. We found that beam arrangements could be found in most cases, limiting the dose applied to the gastrointestinal structures if they were not directly adjacent to the target. In case of critical structures in longitudinal axis, other techniques of liver movement reduction like jet-ventilation can be used, as performed in two of our patients. This technique can substantially reduce the diaphragm mobility and is used in the stereotactic treatment of lung tumors (Debus et al, manuscript submitted for publication). Stereotactic radiation therapy for targets in the head is usually based on planning CT scans with a maximum of 3-mm slice thickness. However, we used 5 mm for the stereotactic treatment planning of liver targets. The target in the liver moves also in craniocaudal direction, with a median of 7 mm.9 Therefore, we do not see an advantage of thinner CT slices for treatment planning. Liver tumors usually are larger without critical structures within the organ like it is the optical nerves, the chiasm and the brainstem for cerebral targets. However, thinner CT slices might improve the treatment planning in the case of critical nearby organs in craniocaudal direction, which requires more restricted target movement reduction, as described earlier. In nine of 10 patients with metastatic breast carcinoma, the treated liver metastases were the only tumor manifestation at the time of treatment. All of these patients had experienced treatment failure with standard chemotherapy. Seven of these patients (78%) developed further systemic disease during follow-up. Additional adjuvant chemotherapy after radiation treatment might be beneficial in these patients to reduce the risk of further systemic spread. However, five patients (45%) also developed further systemic disease of 11 patients with metastatic colorectal cancer in whom the treated lesions were the only systemic manifestation at the time of therapy. Adjuvant chemotherapy significantly improved disease-free survival after hepatic resection for colorectal metastases in a retrospective study23 and it is currently investigated in an ongoing prospective randomized phase III trial (European Organization for Research and Treatment of Cancer [EORTC] 40923). We see indications for stereotactic radiation therapy in patients with unresectable tumors of the liver or as a second-line therapy in patients with recurrence after liver surgery. We performed the therapy only in targets with a size of less than 6 cm in diameter, because the potential of liver tissue–sparing radiation decreases with the size of the target. We did not reach the maximum-tolerated dose; therefore, we cannot give any statement regarding the single-dose radiation therapy for larger tumors. We also performed the therapy only if a maximum of four tumors were in the liver. It might be safe to treat even more tumors in one radiation session. However, if more than four tumors have to be treated, normal tissue sparing becomes more and more difficult and compromises the safety margin and, therefore, the applied marginal doses are likely. In conclusion, our data show that stereotactic radiation may have a role in the treatment of singular inoperable liver tumors. The therapy shows a low morbidity with the potential of a high local control rate. However, a prospective randomized trial is necessary to compare the single-dose method with a hypofractionated schedule. In addition, it should be clarified whether patients benefit from additional chemotherapy also treating potential microscopic intrahepatic and extrahepatic metastatic lesions.
Supported in part by a grant of the Tumorzentrum Heidelberg/Mannheim (K.K.H.).
1. Eble MJ, Gademann G, Wannenmacher M: The value of radiotherapy for liver metastases. Strahlenther Onkol 169: 459-468, 1993[Medline] 2. Russell AH, Clyde C, Wasserman TH, et al: Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: Results of the RTOG dose escalating protocol. Int J Radiat Oncol Biol Phys 27: 117-123, 1993[Medline] 3. 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] 4. Pirzkall A, Debus J, Lohr F, et al: Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. J Clin Oncol 16: 3563-3569, 1998[Abstract] 5. Blomgren H, Lax I, Näslund I, et al: Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Acta Oncol 34: 861-870, 1995[Medline] 6. Blomgren H, Lax I, Göranson H, et al: Radiosurgery for tumors in the body: Clinical experience using a new method. J Radiosurgery 1: 63-74, 1998
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Tokuuye K, Sumi M, Ikeda H, et al: Technical considerations for fractionated stereotactic radiotherapy of hepatocellular carcinoma. Jpn J Clin Oncol 27: 170-173, 1997 8. Sato M, Uematsu M, Yamamoto F, et al: Feasibility of frameless stereotactic high-dose radiation therapy for primary or metastatic liver cancer. J Radiosurgery 1: 233-238, 1998 9. Herfarth KK, Debus J, Lohr F, et al: Extracranial stereotactic radiation therapy: Set-up accuracy of patients treated for liver metastases. Int J Radial Oncol Biol Phys 46: 329-335, 2000 10. Höss A, Debus J, Bendl R, et al: Computerverfahren in der drei-dimensionalen Strahlentherapieplanung. Radiologe 35: 583-586, 1995[Medline] 11. Schlegel W, Pastyr O, Bortfeld T, et al: Stereotactically guided fractionated radiotherapy: Technical aspects. Radiother Oncol 29: 197-204, 1993[Medline] 12. Wagner JS, Adson MA, van Heerden JA, et al: The natural history of hepatic metastases from colorectal cancer. Ann Surg 199: 502-508, 1984[Medline]
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Solbiati L, Goldberg SM, Ierace T, et al: Hepatic metastases: Percutaneous radio-frequency ablation with cooled-tip electrodes. Radiology 205: 367-373, 1997 18. 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] 19. 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] 20. Vogl TJ, Mack MG, Straub R, et al: Interventionelle MR-gesteuerte laserinduzierte Thermotherapie bei onkologischen Fragestellungen. Radiologe 39: 764-771, 1999[Medline] 21. Unger EC, Lee JKT, Weyman PJ: CT and MR imaging of radiation hepatitis. J Comp Assist Tom 11: 264-268, 1987
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Yamasaki SA, Mam CS, Francis IR, et al: High-dose localized radiation therapy for treatment of hepatic malignant tumors: CT findings and their relation to radiation hepatitis. Am J Radiol 165: 79-84, 1995 23. Kokudo N, Seki M, Ohta H, et al: Effects of systemic and regional chemotherapy after hepatic resection for colorectal metastases. Ann Surg Oncol 5: 706-712, 1998[Abstract] Submitted January 31, 2000; accepted July 27, 2000. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
