Phase II Study of Radiotherapy Employing Proton Beam for Hepatocellular Carcinoma
http://www.100md.com
▲還散笫雖悝◎
the Division of Radiation Oncology, Hepatobiliary, and Pancreatic Medical Oncology, and Hepatobiliary Surgery, National Cancer Center Hospital East, Chiba, Japan
ABSTRACT
PURPOSE: To evaluate the safety and efficacy of proton beam radiotherapy (PRT) for hepatocellular carcinoma.
PATIENTS AND METHODS: Eligibility criteria for this study were: solitary hepatocellular carcinoma (HCC); no indication for surgery or local ablation therapy; no ascites; age 20 years; Zubrod performance status of 0 to 2; no serious comorbidities other than liver cirrhosis; written informed consent. PRT was administered in doses of 76 cobalt gray equivalent in 20 fractions for 5 weeks. No patients received transarterial chemoembolization or local ablation in combination with PRT.
RESULTS: Thirty patients were enrolled between May 1999 and February 2003. There were 20 male and 10 female patients, with a median age of 70 years. Maximum tumor diameter ranged from 25 to 82 mm (median, 45 mm). All patients had liver cirrhosis, the degree of which was Child-Pugh class A in 20, and class B in 10 patients. Acute reactions of PRT were well tolerated, and PRT was completed as planned in all patients. Four patients died of hepatic insufficiency without tumor recurrence at 6 to 9 months. Three of these four patients had pretreatment indocyanine green retention rate at 15 minutes of more than 50%. After a median follow-up period of 31 months (16 to 54 months), only one patient experienced recurrence of the primary tumor, and 2-year actuarial local progression-free rate was 96% (95% CI, 88% to 100%). Actuarial overall survival rate at 2 years was 66% (48% to 84%).
CONCLUSION: PRT showed excellent control of the primary tumor, with minimal acute toxicity. Further study is warranted to scrutinize adequate patient selection in order to maximize survival benefit of this promising modality.
INTRODUCTION
Cirrhosis is found in more than 80% of patients with hepatocellular carcinoma (HCC). This precludes more than 70% of the patients from receiving potentially curative treatments, and also contributes eventually to fatal hepatic insufficiency and multifocal tumorigenesis.1,2 Approximately 50% to 70% and 30% to 50% of 5-year overall survival was achieved with surgery including liver transplantation3-6 and percutaneous local ablation,7-9 respectively, for an adequately selected population of patients. However, no standard strategy has been established for patients with unresectable HCC at present.
Partial liver irradiation for HCC using 50 to 70 Gy of megavoltage x-ray with or without transarterial chemoembolizaztion (TACE) for 5 to 7 weeks has been widely applied during the last two decades. This resulted in response rates of 33% to 67%, with a median survival period of 13 to 19 months and 10% to 25% overall survival at 3 years.10-12 Since 1985, proton radiotherapy (PRT) administered at a median dose of 72 cobalt gray equivalent (GyE) in16 fractions during 3 weeks with or without TACE, had been applied in more than 160 patients with HCC at the University of Tsukuba, resulting in a more than 80% local progression-free survival rate with 45% and 25% overall survival at 3 and 5 years, respectively.13,14 The excellent depth-dose profile of the proton beam enabled us to embark on an aggressive dose escalation while keeping a certain volume of the noncancerous portion of the liver free from receiving any dose of irradiation. This single-institutional, single-arm, prospective study was conducted to confirm encouraging retrospective results of PRT for HCC using our newly installed proton therapy equipment.
PATIENTS AND METHODS
Patient Population
Patients were required to have uni- or bidimensionally measurable solitary HCC of 10 cm in maximum diameter on computed tomography (CT) and/or magnetic resonance (MRI) imaging. In addition, the following eligibility criteria were required: no history of radiotherapy for the abdominal area; no previous treatment for HCC within 4 weeks of inclusion; no evidence of extrahepatic spread of HCC; age 20 years; Zubrod performance status (PS) of 0 to 2; WBC count 2,000/mm3; hemoglobin level 7.5 g/dL; platelet count 25,000/mm3; and adequate hepatic function (total bilirubin 3.0 mg/dL; AST and ALT < 5.0x upper limit of normal; no ascites). Patients who had multicentric HCCs were not considered as candidates for this study, except for those with the following two conditions: (1) multinodular aggregating HCC that could be encompassed by single clinical target volume; (2) lesions other than targeted tumor that were judged as controlled with prior surgery and/or local ablation therapy. Because a planned total dose would result in a significant likelihood of serious bowel complications, patients who had tumors abutting or invading the stomach or intestinal loop were excluded. The protocol was approved by our institutional ethics committee, and written informed consent was obtained from all patients.
Pretreatment Evaluation
All patients underwent indocyanine green clearance test, and the retention rate at 15 minutes (ICG R15) was measured for the purpose of quantitative assessment of hepatic functional reserve. CBC, biochemical profile including total protein, albumin, total cholesterol, electrolytes, kidney and liver function tests, and serological testing for hepatitis B surface antigen and antihepatitis C antibody were done. C-reactive protein and tumor markers including alpha feto-protein and carcinoembryonic antigen were also measured. Chest x-ray was required to exclude lung metastasis. All patients were judged as unresectable by expert hepatobiliary surgeons in our institution, based on their serum bilirubin level, ICG R15, and expected volume of resected liver.15 Gastrointestinal endoscopy was done to exclude active ulcer and/or inflammatory disease located at the stomach and the duodenum. All patients underwent abdominal ultrasonography, triphasic CT or MRI, CT during arteriography and arterial portography.16 Diagnosis of HCC was based on radiographic findings on triphasic CT/MRI. Radiologic criteria for HCC definition were as follows: tumor showing high attenuation during hepatic arterial and portal venous phase indicating hypervascular tumor; tumor showing low attenuation during delayed phase indicating rapid wash-out of contrast media. Confirmatory percutaneous fine-needle biopsies were required for all patients unless they had radiologically compatible, postsurgical recurrent HCC. Tumors that broadly abut on the vena cava, portal vein, or hepatic vein that were associated with caliber changes and/or filling defects of these vessels, were tentatively defined as positive for macroscopic vascular invasion. One patient had visible tumor on fluoroscopy because of residual iodized oil contrast medium used in previous TACE. For the other 29 patients, one or two metallic markers (inactive Au grain of which the diameter and length were 1.1 mm and 3.0 mm, respectively) were inserted percutaneously at the periphery of the target tumor.
Treatment Planning
PRT was performed with the Proton Therapy System (Sumitomo Heavy Industries Ltd, Tokyo, Japan), and treatment planning, with the PT-PLAN/NDOSE System (Sumitomo Heavy Industries Ltd). In this system, the proton beam was generated with Cyclotron C235 with an energy of 235 MV at the exit. Gross tumor volume (GTV) was defined using a treatment planning CT scan using X Vision Real CT scanner (Toshiba Co Ltd, Tokyo, Japan), and clinical target volume (CTV) and planning target volume (PTV) were defined as follows: CTV = GTV + 5 mm, and PTV = CTV + 3 mm of lateral, craniocaudal, and anteroposterior margins. Proton beam was delivered with two-beam arrangement to minimize irradiated volume of noncancerous liver using our rotating gantry system. The beam energy and spread-out Bragg peak13 were fine-tuned so that 90% isodose volume of prescribed dose encompassed PTV. To evaluate the risk of radiation-inducing hepatic insufficiency, dose-volume histogram (DVH) was calculated for all patients.17
Scanning of CT images for both treatment planning and irradiation of proton beam were done during the exhalation phase using a Respiration-Gated Irradiation System (ReGIS). Our ReGIS during this study period was composed in the following manner: strain gauge, which converts tension of the abdominal wall into electrical respiratory signal, was put on the abdominal skin of the patient; gating signal triggering CT scanning or proton beam was generated during the exhalation phase.
Treatment
The fractionation and dosage in this study were based on the results of a retrospective study at the University of Tsukuba. A total dose ranging from 50 GyE in 10 fractions to 87.5 GyE in 30 fractions (median, 72 GyE in16 fractions) was administered without serious acute and late adverse events. All patients received PRT to a total dose of 76 GyE for 5 weeks in 3.8-GyE once-daily fractions, four fractions in a week using 150 to 190 MV proton beam. Relative biologic effectiveness of our proton beam was defined as 1.1. No concomitant treatment (eg, TACE, local ablation, systemic chemotherapy) was allowed during and after the PRT, unless a treatment failure was detected. Verification of patient set-up was done in each fraction using a digital radiography subtraction system. In this system, fluoroscopic images obtained at daily set-up were subtracted by the original image that was taken at the time of treatment planning. Position of the patient couch was adjusted to overlap the diaphragm, inserted metallic markers, and bone landmarks on the original position at the end of the exhalation phase. PRT was administered 4 days a week, mainly Monday to Thursday, and Friday was reserved for maintenance of the PRT system. Predefined adverse reaction of PRT was dermatitis, pneumonitis, hepatic insufficiency, and gastrointestinal ulcer and/or bleeding. If one of these reactions of grade 3 or higher, or unexpected reactions of grade 4 or higher were observed in three patients, further accrual of patients was defined to be stopped. No further PRT was allowed when grade 4 hematologic toxicity or any of the toxicities of grade 3 or higher were observed at the digestive tract or lung. PRT was delayed up to 2 weeks until recovery when an acute nonhematologic toxicity of grade 3 or higher, other than that described above, was observed. However, when only an elevation of liver enzymes was observed without manifestation of clinically significant signs and symptoms, PRT was allowed to be continued according to the physician's judgment.
Outcomes
It has been reported that the tumor, although achieving a complete response, persisted over a long period, ranging from 3 weeks to 12+ months after the completion of PRT.18 Therefore, a local progression-free survival rate at 4 weeks after the end of PRT was adopted as the primary end point of this study, where an event was defined as progression of the primary tumor with size increase of more than 25%, in order to facilitate an interim analysis as described in the Statistical Design section below. Assessment of primary tumor response using CT and/or MRI was performed 4 weeks after the completion of PRT. Overall survival and disease-free survival rates were also evaluated as secondary end points. Death of any cause was defined as an event in calculation of overall survival, whereas tumor recurrences at any sites or patient deaths were defined as events for disease-free survival. Adverse events were reviewed weekly during the PRT by means of physical examination, CBC, liver function test, and the other biochemical profiles as indicated. The severity of adverse events was assessed using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. After completion of PRT, reviews monitoring disease status, including CT and/or MRI examinations and long-term toxicity were done at a minimum frequency of once every 3 months.
Statistical Design
The null hypothesis of a true local progression-free rate of 50% or lower was based on average results of photon radiotherapy reported from Japan, in which each study accumulated approximately 20 patients.11,12 This was tested against the alternative hypothesis of a true rate of 80% or higher with an level of 5% and a power of 80%, which required 30 patients according to the method by Makuch and Simon.19 If fewer than five patients experienced local progression-free status within 4 weeks postirradiation at the end of first nine enrollments, the trial would be stopped. Otherwise, if more than 24 patients remained locally progression-free among the total of 30 patients, this would be sufficient to reject the null hypothesis and conclude that PRT warrants further study. Time-to-event analyses were done using Kaplan-Meier estimates, and 95% CIs were calculated. The difference of time-to-event curve was evaluated with the log-rank test. Multivariate analyses were performed with Cox's proportional hazards model.
RESULTS
Patients
Thirty patients were enrolled between May 1999 and February 2003. Patient characteristics at the start of PRT are listed in Table 1. All patients had underlying liver cirrhosis with an initial ICG R15 value of 15%. Thirteen patients received PRT as a first treatment for their HCC. Six patients had postsurgical recurrences, and 11 received unsuccessful local ablation and/or TACE to the targeted tumor before PRT. Histologic confirmation was not obtained in one patient who had tumor with typical radiographic features compatible with HCC. Vascular invasion was diagnosed as positive in 12 patients. Three patients had HCC of 3 cm in diameter; however, they were not considered as candidates for local ablation therapy because of tumor locations that were in close proximity to the great vessels or the lung.
Adverse Events
All patients completed the treatment plan and received 76 GyE in 20 fractions of PRT with a median duration of 35 days (range, 30 to 64 days). Prolongation of overall treatment time of more than 1 week occurred in four patients: three were due to availability of the proton beam, and one because of fever associated with grade 3 elevation of total bilirubin that spontaneously resolved within 1 week. Adverse events within 90 days from commencement of PRT are listed in Table 2. Decrease of blood cell count was observed most frequently. A total of 10 patients experienced transient grade 3 leukopenia and/or thrombocytopenia without infection or bleeding necessitating treatment. Of note, eight of them already had leuko- and/or thrombocytopenia, which could be ascribable to portal hypertension, before commencement of PRT corresponding to grade 2 in terms of the NCI-CTC criteria. Because none of the five patients experiencing grade 3 elevation of transaminases showed clinical manifestation of hepatic insufficiency and maintained good performance status, PRT was not discontinued. Nevertheless, these events spontaneously resolved within 1 to 2 weeks.
Development of hepatic insufficiency within 6 months after completion of PRT was defined as proton-inducing hepatic insufficiency (PHI), and this was observed in eight patients. Causal relationship between PHI and several factors are described separately below. One patient developed transient skin erosion at 4 months that spontaneously resolved within 2 months. Another patient developed painful subcutaneous fibrosis at 6 months that required nonsteroidal analgesics for approximately 12 months thereafter. Both of these skin changes developed at the area receiving 90% of the prescribed dose because the targeted tumors were located at the surface of the liver adjacent to the skin. However, they remained free from refractory ulcer, bleeding, or rib fracture.
There were no observations made of gastrointestinal or pulmonary toxicity of grade 2 or greater in all patients. In addition, after percutaneous insertion of metallic markers, no serious adverse events, including bleeding or tumor seeding along the needle tracts, were observed.
Tumor Control and Survival
At the time of analysis on November 2003, 12 patients had already died because of intrahepatic recurrence of HCC in seven, distant metastasis in two, and hepatic insufficiency without recurrence in three. Eleven of these 12 patients had been free from local progression until death; the durations ranged from 6 to 41 months (median, 8 months). One patient who had a single nodular tumor of 4.2 cm in diameter experienced local recurrence at 5 months and subsequently died of multifocal intrahepatic HCC recurrence. Otherwise, 18 patients were alive at 16 to 54 months (median, 31 months) without local progression. A total of 24 patients achieved complete disappearance of the primary tumor at 5 to 20 months (median, 8 months) post-PRT. Five had residual tumor mass on CT and MRI images for 3 to 35 months (median, 12 months) until the time of death (n = 4) or until last follow-up at 16 months (n = 1). As a whole, 29 of 30 enrolled patients were free from local progression until death or last follow-up, and the local progression-free rate at 2 years was 96% (95% CI, 88% to 100%). Tumor regression was associated with gradual atrophy of the surrounding noncancerous portion of the liver that initially suffered from radiation hepatitis,20 as shown in Figure 1.
A total of 18 patients developed intrahepatic tumor recurrences that were outside of the PTV at 3 to 35 months (median, 18 months) post-PRT. Five of these occurred within the same segment of the primary tumor. Eight patients received TACE, and four received radiofrequency ablation for recurrent tumors; however, six did not receive any further treatment because of poor general condition in three and refusal in three. Five died without intrahepatic recurrence. Seven patients remained recurrence-free at 16 to 39 months (median, 35 months). Actuarial overall survival rates were 77% (95% CI, 61% to 92%), 66% (95% CI, 48% to 84%), and 62% (95% CI, 44% to 80%), and disease-free survival rates were 60% (95% CI, 42% to 78%), 38% (95% CI, 20% to 56%), and 16% (95% CI, 1% to 31%) at 1, 2, and 3 years, respectively (Fig 2).
Correlation of Survival With Prognostic Factors
Overall survival was evaluated according to 10 factors as listed in Table 3. Univariate analyses revealed that factors related to functional reserve of the liver and tumor size had significant influences on overall survival (P < .05). Liver function was the only independent and significant prognostic factor by multivariate analysis, as presented in Table 3. When clinical stage or Child-Pugh classification was substituted for ICG R15 as a covariate for liver function, the results of multivariate analyses were unchanged (data not shown). Overall survival according to pretreatment ICG R15 is shown in Figure 3.
Estimation of the Risk of Proton-Inducing Hepatic Insufficiency by Dose-Volume Histogram Analysis
Eight patients developed PHI and presented with ascites and/or asterixis at 1 to 4 months after completion of PRT, without elevation of serum bilirubin and transaminases in the range of more than 3x the upper limit of normal. Of these, four died without evidence of intrahepatic tumor recurrence at 6 to 9 months; three died with recurrences of HCC at 4, 8, and 22 months; and one was alive at 41 months without tumor recurrence. DVH for hepatic noncancerous portions (entire liver volume minus gross tumor volume) was drawn according to pretreatment ICG R15 values (Fig 4A to C). The results showed that all of the nine patients with ICG R15 less than 20% were free from PHI and alive at 14 to 54 months. Three of the four patients with pretreatment ICG R15 50% experienced fatal PHI without evidence of HCC recurrence, and another patient died of PHI with intrahepatic and systemic dissemination of HCC at 4 months. Among patients whose ICG R15 values ranged from 20% to 50%, all of the four patients whose percentage of hepatic noncancerous portions receiving 30 GyE (V30%) exceeded 25% developed PHI. On the other hand, none of the patients whose V30% was less than 25% experienced PHI, as shown in Figure 4B (P = .044, Mann-Whitney U test). Three-year overall survival for patients with either the V30% 25% or ICG R15 50% (n = 9) was 22% (95% CI, 0% to 50%), whereas it was 79% (95% CI, 60% to 98%) for the remaining 21 patients with favorable risk (P = .001).
DISCUSSION
The principal advantage of PRT lies in its possibility of aggressive dose escalation without prolongation of treatment duration in order to improve local control rate. The liver will be the most appropriate organ for this approach because it has a unique characteristic of developing compensatory hypertrophy when a part of this organ suffers from permanent damage. This study showed that the local control rate of PRT alone for patients with advanced HCC was consistent, as previously reported.14 Slow regression of tumor volumes associated with gradual atrophy of surrounding noncancerous liver tissue was also in agreement with a previous report.20 No serious gastrointestinal toxicity occurred, with careful patient selection performed in order to exclude these structures from PTV receiving high PRT dose. Eligibility criteria as to blood cell count in this study were eased up considerably in order to test the safety of PRT for patients with cirrhosis associated with portal hypertension. Nevertheless, no patients experienced serious sequelae relating to leukopenia or thrombocytopenia, which were the most frequently observed adverse events during PRT. All patients were able to complete their PRT basically in an outpatient clinic. Therefore we submit that the safety, accuracy, and efficacy of PRT administering 76 GyE/5 weeks using our newly installed Proton Therapy System and ReGIS for selected patients with advanced HCC has been confirmed.
Multivariate analysis suggested that the the functional reserve of the liver had significant influence on overall survival. Recent prospective series of untreated patients with advanced HCC and underlying cirrhosis showed that overall survival rate at 3 years ranged from 13% to 38%, and rarely exceeded 50% even for those with most favorable prognostic factors.1 In this study, actuarial overall survival rate at 3 years for all 30 patients including those who had HCC with vascular invasion and/or severe cirrhosis was 62%. Furthermore, 21 patients with initial ICG R15 of 50% and V30% of 25% achieved 79% of overall survival rate at 3 years. All of the eight patients with favorable liver functional reserve (ICG R15, 15% to 20%) were alive at 20 to 54 months as shown in Figure 3. This suggests that adequate local control with PRT provides survival benefit for selected patients with HCC and moderate cirrhosis. On the other hand, prognoses of aggressive PRT were disappointing for patients, with poor functional liver reserve showing an ICG R15 of 50% or worse, and, therefore, indication of PRT for such patients was thought to be extremely limited.
A part of noncancerous liver suffering from PRT-inducing hepatitis gradually developed dense fibrosis and resulted in almost complete atrophy,20 whereas the absorbed dose in a large proportion of the remaining liver was 0 GyE, as shown in Figures 1 and 4. This change is similar to that seen in partial liver resection, rather than after 3-dimensional conformal or intensity-modulated radiotherapy delivering a low-dose of x-ray to a large proportion of noncancerous liver. Therefore, estimation of the risk of PRT-inducing hepatic insufficiency should be done with similar guidelines to evaluate liver tolerance to surgery, rather than that with normal tissue complication probability model using a mean dose administered to the entire liver.21 Remnant liver volume and ICG R15 have been preferred indicators for that estimation, especially in Japan.15 DVH analyses (Figs 4A to C) suggested that V30% in combination with ICG R15 may be a useful indicator for estimation of liver tolerance to PRT, but no definite quantitative criteria emerged with the limited data obtained at present because of the small number of patients evaluated. The current staging system for HCC is based on survival data obtained in surgical series.22 There is no reliable system to stratify the prognosis of patients with solitary but unresectable HCC on the assumption that they achieve good local control after PRT. Because of the limited availability of PRT at present, the establishment of particular criteria for patient selection using quantitative parameters of hepatic function such as ICG R15, and volume parameter like V30%, is needed to maximize the cost-effectiveness of PRT.
Applicability of PRT instead of surgery for patients with early-stage disease should be considered with caution. Intraoperative ultrasonography (IOUS) has an important role in detecting small metastatic lesions, which could not be demonstrated in preoperative examinations. The high incidence of intrahepatic recurrences seen outside the PTV might be partly ascribable to the limit of pretreatment imaging studies. Infiltration of HCC to the portal vein and spread via portal blood flow is one of the mechanisms for the development of intrahepatic recurrence.15 Actually, five recurrences occurred within the same segment of the primary tumor in this study. Although anatomic resection according to the architecture of the portal vein using IOUS offered a better chance of cure only for patients with noncirrhotic livers,23 systematic segmental PRT based on multimodal imagings such as CT during arterial portography or MRI as well as image fusion technique24 has a theoretical advantage compared with nonanatomic PRT confined to GTV only. Because there were few potentially curative approaches other than surgery for patients with HCC showing vascular invasion, further study is warranted to scrutinize an efficacy of PRT for patients with HCC of 5 cm in diameter, of which a large majority will demonstrate vascular invasion around the periphery of the tumor,25 while giving attention to their V30% values.
The risk of this aggressive dose-fractionation for sites such as the gastrointestinal loop, hepatic hilum, skin, or subcutanous tissues must be carefully considered, and more conventional fractionation must be adopted when these structures are critically involved in the PTV.
In conclusion, PRT for localized HCC using an aggressive dose-fractionation scheme (76 GyE for 5 weeks) achieved excellent local control rate regardless of vascular invasion or tumor size, if 10 cm, without devastating acute toxicity. Further study is warranted to scrutinize adequate patient selection according to quantitative parameter of hepatic function, such as ICG R15, and irradiated noncancerous liver volume in order to maximize survival benefit of this promising modality.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
PURPOSE: To evaluate the safety and efficacy of proton beam radiotherapy (PRT) for hepatocellular carcinoma.
PATIENTS AND METHODS: Eligibility criteria for this study were: solitary hepatocellular carcinoma (HCC); no indication for surgery or local ablation therapy; no ascites; age 20 years; Zubrod performance status of 0 to 2; no serious comorbidities other than liver cirrhosis; written informed consent. PRT was administered in doses of 76 cobalt gray equivalent in 20 fractions for 5 weeks. No patients received transarterial chemoembolization or local ablation in combination with PRT.
RESULTS: Thirty patients were enrolled between May 1999 and February 2003. There were 20 male and 10 female patients, with a median age of 70 years. Maximum tumor diameter ranged from 25 to 82 mm (median, 45 mm). All patients had liver cirrhosis, the degree of which was Child-Pugh class A in 20, and class B in 10 patients. Acute reactions of PRT were well tolerated, and PRT was completed as planned in all patients. Four patients died of hepatic insufficiency without tumor recurrence at 6 to 9 months. Three of these four patients had pretreatment indocyanine green retention rate at 15 minutes of more than 50%. After a median follow-up period of 31 months (16 to 54 months), only one patient experienced recurrence of the primary tumor, and 2-year actuarial local progression-free rate was 96% (95% CI, 88% to 100%). Actuarial overall survival rate at 2 years was 66% (48% to 84%).
CONCLUSION: PRT showed excellent control of the primary tumor, with minimal acute toxicity. Further study is warranted to scrutinize adequate patient selection in order to maximize survival benefit of this promising modality.
INTRODUCTION
Cirrhosis is found in more than 80% of patients with hepatocellular carcinoma (HCC). This precludes more than 70% of the patients from receiving potentially curative treatments, and also contributes eventually to fatal hepatic insufficiency and multifocal tumorigenesis.1,2 Approximately 50% to 70% and 30% to 50% of 5-year overall survival was achieved with surgery including liver transplantation3-6 and percutaneous local ablation,7-9 respectively, for an adequately selected population of patients. However, no standard strategy has been established for patients with unresectable HCC at present.
Partial liver irradiation for HCC using 50 to 70 Gy of megavoltage x-ray with or without transarterial chemoembolizaztion (TACE) for 5 to 7 weeks has been widely applied during the last two decades. This resulted in response rates of 33% to 67%, with a median survival period of 13 to 19 months and 10% to 25% overall survival at 3 years.10-12 Since 1985, proton radiotherapy (PRT) administered at a median dose of 72 cobalt gray equivalent (GyE) in16 fractions during 3 weeks with or without TACE, had been applied in more than 160 patients with HCC at the University of Tsukuba, resulting in a more than 80% local progression-free survival rate with 45% and 25% overall survival at 3 and 5 years, respectively.13,14 The excellent depth-dose profile of the proton beam enabled us to embark on an aggressive dose escalation while keeping a certain volume of the noncancerous portion of the liver free from receiving any dose of irradiation. This single-institutional, single-arm, prospective study was conducted to confirm encouraging retrospective results of PRT for HCC using our newly installed proton therapy equipment.
PATIENTS AND METHODS
Patient Population
Patients were required to have uni- or bidimensionally measurable solitary HCC of 10 cm in maximum diameter on computed tomography (CT) and/or magnetic resonance (MRI) imaging. In addition, the following eligibility criteria were required: no history of radiotherapy for the abdominal area; no previous treatment for HCC within 4 weeks of inclusion; no evidence of extrahepatic spread of HCC; age 20 years; Zubrod performance status (PS) of 0 to 2; WBC count 2,000/mm3; hemoglobin level 7.5 g/dL; platelet count 25,000/mm3; and adequate hepatic function (total bilirubin 3.0 mg/dL; AST and ALT < 5.0x upper limit of normal; no ascites). Patients who had multicentric HCCs were not considered as candidates for this study, except for those with the following two conditions: (1) multinodular aggregating HCC that could be encompassed by single clinical target volume; (2) lesions other than targeted tumor that were judged as controlled with prior surgery and/or local ablation therapy. Because a planned total dose would result in a significant likelihood of serious bowel complications, patients who had tumors abutting or invading the stomach or intestinal loop were excluded. The protocol was approved by our institutional ethics committee, and written informed consent was obtained from all patients.
Pretreatment Evaluation
All patients underwent indocyanine green clearance test, and the retention rate at 15 minutes (ICG R15) was measured for the purpose of quantitative assessment of hepatic functional reserve. CBC, biochemical profile including total protein, albumin, total cholesterol, electrolytes, kidney and liver function tests, and serological testing for hepatitis B surface antigen and antihepatitis C antibody were done. C-reactive protein and tumor markers including alpha feto-protein and carcinoembryonic antigen were also measured. Chest x-ray was required to exclude lung metastasis. All patients were judged as unresectable by expert hepatobiliary surgeons in our institution, based on their serum bilirubin level, ICG R15, and expected volume of resected liver.15 Gastrointestinal endoscopy was done to exclude active ulcer and/or inflammatory disease located at the stomach and the duodenum. All patients underwent abdominal ultrasonography, triphasic CT or MRI, CT during arteriography and arterial portography.16 Diagnosis of HCC was based on radiographic findings on triphasic CT/MRI. Radiologic criteria for HCC definition were as follows: tumor showing high attenuation during hepatic arterial and portal venous phase indicating hypervascular tumor; tumor showing low attenuation during delayed phase indicating rapid wash-out of contrast media. Confirmatory percutaneous fine-needle biopsies were required for all patients unless they had radiologically compatible, postsurgical recurrent HCC. Tumors that broadly abut on the vena cava, portal vein, or hepatic vein that were associated with caliber changes and/or filling defects of these vessels, were tentatively defined as positive for macroscopic vascular invasion. One patient had visible tumor on fluoroscopy because of residual iodized oil contrast medium used in previous TACE. For the other 29 patients, one or two metallic markers (inactive Au grain of which the diameter and length were 1.1 mm and 3.0 mm, respectively) were inserted percutaneously at the periphery of the target tumor.
Treatment Planning
PRT was performed with the Proton Therapy System (Sumitomo Heavy Industries Ltd, Tokyo, Japan), and treatment planning, with the PT-PLAN/NDOSE System (Sumitomo Heavy Industries Ltd). In this system, the proton beam was generated with Cyclotron C235 with an energy of 235 MV at the exit. Gross tumor volume (GTV) was defined using a treatment planning CT scan using X Vision Real CT scanner (Toshiba Co Ltd, Tokyo, Japan), and clinical target volume (CTV) and planning target volume (PTV) were defined as follows: CTV = GTV + 5 mm, and PTV = CTV + 3 mm of lateral, craniocaudal, and anteroposterior margins. Proton beam was delivered with two-beam arrangement to minimize irradiated volume of noncancerous liver using our rotating gantry system. The beam energy and spread-out Bragg peak13 were fine-tuned so that 90% isodose volume of prescribed dose encompassed PTV. To evaluate the risk of radiation-inducing hepatic insufficiency, dose-volume histogram (DVH) was calculated for all patients.17
Scanning of CT images for both treatment planning and irradiation of proton beam were done during the exhalation phase using a Respiration-Gated Irradiation System (ReGIS). Our ReGIS during this study period was composed in the following manner: strain gauge, which converts tension of the abdominal wall into electrical respiratory signal, was put on the abdominal skin of the patient; gating signal triggering CT scanning or proton beam was generated during the exhalation phase.
Treatment
The fractionation and dosage in this study were based on the results of a retrospective study at the University of Tsukuba. A total dose ranging from 50 GyE in 10 fractions to 87.5 GyE in 30 fractions (median, 72 GyE in16 fractions) was administered without serious acute and late adverse events. All patients received PRT to a total dose of 76 GyE for 5 weeks in 3.8-GyE once-daily fractions, four fractions in a week using 150 to 190 MV proton beam. Relative biologic effectiveness of our proton beam was defined as 1.1. No concomitant treatment (eg, TACE, local ablation, systemic chemotherapy) was allowed during and after the PRT, unless a treatment failure was detected. Verification of patient set-up was done in each fraction using a digital radiography subtraction system. In this system, fluoroscopic images obtained at daily set-up were subtracted by the original image that was taken at the time of treatment planning. Position of the patient couch was adjusted to overlap the diaphragm, inserted metallic markers, and bone landmarks on the original position at the end of the exhalation phase. PRT was administered 4 days a week, mainly Monday to Thursday, and Friday was reserved for maintenance of the PRT system. Predefined adverse reaction of PRT was dermatitis, pneumonitis, hepatic insufficiency, and gastrointestinal ulcer and/or bleeding. If one of these reactions of grade 3 or higher, or unexpected reactions of grade 4 or higher were observed in three patients, further accrual of patients was defined to be stopped. No further PRT was allowed when grade 4 hematologic toxicity or any of the toxicities of grade 3 or higher were observed at the digestive tract or lung. PRT was delayed up to 2 weeks until recovery when an acute nonhematologic toxicity of grade 3 or higher, other than that described above, was observed. However, when only an elevation of liver enzymes was observed without manifestation of clinically significant signs and symptoms, PRT was allowed to be continued according to the physician's judgment.
Outcomes
It has been reported that the tumor, although achieving a complete response, persisted over a long period, ranging from 3 weeks to 12+ months after the completion of PRT.18 Therefore, a local progression-free survival rate at 4 weeks after the end of PRT was adopted as the primary end point of this study, where an event was defined as progression of the primary tumor with size increase of more than 25%, in order to facilitate an interim analysis as described in the Statistical Design section below. Assessment of primary tumor response using CT and/or MRI was performed 4 weeks after the completion of PRT. Overall survival and disease-free survival rates were also evaluated as secondary end points. Death of any cause was defined as an event in calculation of overall survival, whereas tumor recurrences at any sites or patient deaths were defined as events for disease-free survival. Adverse events were reviewed weekly during the PRT by means of physical examination, CBC, liver function test, and the other biochemical profiles as indicated. The severity of adverse events was assessed using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. After completion of PRT, reviews monitoring disease status, including CT and/or MRI examinations and long-term toxicity were done at a minimum frequency of once every 3 months.
Statistical Design
The null hypothesis of a true local progression-free rate of 50% or lower was based on average results of photon radiotherapy reported from Japan, in which each study accumulated approximately 20 patients.11,12 This was tested against the alternative hypothesis of a true rate of 80% or higher with an level of 5% and a power of 80%, which required 30 patients according to the method by Makuch and Simon.19 If fewer than five patients experienced local progression-free status within 4 weeks postirradiation at the end of first nine enrollments, the trial would be stopped. Otherwise, if more than 24 patients remained locally progression-free among the total of 30 patients, this would be sufficient to reject the null hypothesis and conclude that PRT warrants further study. Time-to-event analyses were done using Kaplan-Meier estimates, and 95% CIs were calculated. The difference of time-to-event curve was evaluated with the log-rank test. Multivariate analyses were performed with Cox's proportional hazards model.
RESULTS
Patients
Thirty patients were enrolled between May 1999 and February 2003. Patient characteristics at the start of PRT are listed in Table 1. All patients had underlying liver cirrhosis with an initial ICG R15 value of 15%. Thirteen patients received PRT as a first treatment for their HCC. Six patients had postsurgical recurrences, and 11 received unsuccessful local ablation and/or TACE to the targeted tumor before PRT. Histologic confirmation was not obtained in one patient who had tumor with typical radiographic features compatible with HCC. Vascular invasion was diagnosed as positive in 12 patients. Three patients had HCC of 3 cm in diameter; however, they were not considered as candidates for local ablation therapy because of tumor locations that were in close proximity to the great vessels or the lung.
Adverse Events
All patients completed the treatment plan and received 76 GyE in 20 fractions of PRT with a median duration of 35 days (range, 30 to 64 days). Prolongation of overall treatment time of more than 1 week occurred in four patients: three were due to availability of the proton beam, and one because of fever associated with grade 3 elevation of total bilirubin that spontaneously resolved within 1 week. Adverse events within 90 days from commencement of PRT are listed in Table 2. Decrease of blood cell count was observed most frequently. A total of 10 patients experienced transient grade 3 leukopenia and/or thrombocytopenia without infection or bleeding necessitating treatment. Of note, eight of them already had leuko- and/or thrombocytopenia, which could be ascribable to portal hypertension, before commencement of PRT corresponding to grade 2 in terms of the NCI-CTC criteria. Because none of the five patients experiencing grade 3 elevation of transaminases showed clinical manifestation of hepatic insufficiency and maintained good performance status, PRT was not discontinued. Nevertheless, these events spontaneously resolved within 1 to 2 weeks.
Development of hepatic insufficiency within 6 months after completion of PRT was defined as proton-inducing hepatic insufficiency (PHI), and this was observed in eight patients. Causal relationship between PHI and several factors are described separately below. One patient developed transient skin erosion at 4 months that spontaneously resolved within 2 months. Another patient developed painful subcutaneous fibrosis at 6 months that required nonsteroidal analgesics for approximately 12 months thereafter. Both of these skin changes developed at the area receiving 90% of the prescribed dose because the targeted tumors were located at the surface of the liver adjacent to the skin. However, they remained free from refractory ulcer, bleeding, or rib fracture.
There were no observations made of gastrointestinal or pulmonary toxicity of grade 2 or greater in all patients. In addition, after percutaneous insertion of metallic markers, no serious adverse events, including bleeding or tumor seeding along the needle tracts, were observed.
Tumor Control and Survival
At the time of analysis on November 2003, 12 patients had already died because of intrahepatic recurrence of HCC in seven, distant metastasis in two, and hepatic insufficiency without recurrence in three. Eleven of these 12 patients had been free from local progression until death; the durations ranged from 6 to 41 months (median, 8 months). One patient who had a single nodular tumor of 4.2 cm in diameter experienced local recurrence at 5 months and subsequently died of multifocal intrahepatic HCC recurrence. Otherwise, 18 patients were alive at 16 to 54 months (median, 31 months) without local progression. A total of 24 patients achieved complete disappearance of the primary tumor at 5 to 20 months (median, 8 months) post-PRT. Five had residual tumor mass on CT and MRI images for 3 to 35 months (median, 12 months) until the time of death (n = 4) or until last follow-up at 16 months (n = 1). As a whole, 29 of 30 enrolled patients were free from local progression until death or last follow-up, and the local progression-free rate at 2 years was 96% (95% CI, 88% to 100%). Tumor regression was associated with gradual atrophy of the surrounding noncancerous portion of the liver that initially suffered from radiation hepatitis,20 as shown in Figure 1.
A total of 18 patients developed intrahepatic tumor recurrences that were outside of the PTV at 3 to 35 months (median, 18 months) post-PRT. Five of these occurred within the same segment of the primary tumor. Eight patients received TACE, and four received radiofrequency ablation for recurrent tumors; however, six did not receive any further treatment because of poor general condition in three and refusal in three. Five died without intrahepatic recurrence. Seven patients remained recurrence-free at 16 to 39 months (median, 35 months). Actuarial overall survival rates were 77% (95% CI, 61% to 92%), 66% (95% CI, 48% to 84%), and 62% (95% CI, 44% to 80%), and disease-free survival rates were 60% (95% CI, 42% to 78%), 38% (95% CI, 20% to 56%), and 16% (95% CI, 1% to 31%) at 1, 2, and 3 years, respectively (Fig 2).
Correlation of Survival With Prognostic Factors
Overall survival was evaluated according to 10 factors as listed in Table 3. Univariate analyses revealed that factors related to functional reserve of the liver and tumor size had significant influences on overall survival (P < .05). Liver function was the only independent and significant prognostic factor by multivariate analysis, as presented in Table 3. When clinical stage or Child-Pugh classification was substituted for ICG R15 as a covariate for liver function, the results of multivariate analyses were unchanged (data not shown). Overall survival according to pretreatment ICG R15 is shown in Figure 3.
Estimation of the Risk of Proton-Inducing Hepatic Insufficiency by Dose-Volume Histogram Analysis
Eight patients developed PHI and presented with ascites and/or asterixis at 1 to 4 months after completion of PRT, without elevation of serum bilirubin and transaminases in the range of more than 3x the upper limit of normal. Of these, four died without evidence of intrahepatic tumor recurrence at 6 to 9 months; three died with recurrences of HCC at 4, 8, and 22 months; and one was alive at 41 months without tumor recurrence. DVH for hepatic noncancerous portions (entire liver volume minus gross tumor volume) was drawn according to pretreatment ICG R15 values (Fig 4A to C). The results showed that all of the nine patients with ICG R15 less than 20% were free from PHI and alive at 14 to 54 months. Three of the four patients with pretreatment ICG R15 50% experienced fatal PHI without evidence of HCC recurrence, and another patient died of PHI with intrahepatic and systemic dissemination of HCC at 4 months. Among patients whose ICG R15 values ranged from 20% to 50%, all of the four patients whose percentage of hepatic noncancerous portions receiving 30 GyE (V30%) exceeded 25% developed PHI. On the other hand, none of the patients whose V30% was less than 25% experienced PHI, as shown in Figure 4B (P = .044, Mann-Whitney U test). Three-year overall survival for patients with either the V30% 25% or ICG R15 50% (n = 9) was 22% (95% CI, 0% to 50%), whereas it was 79% (95% CI, 60% to 98%) for the remaining 21 patients with favorable risk (P = .001).
DISCUSSION
The principal advantage of PRT lies in its possibility of aggressive dose escalation without prolongation of treatment duration in order to improve local control rate. The liver will be the most appropriate organ for this approach because it has a unique characteristic of developing compensatory hypertrophy when a part of this organ suffers from permanent damage. This study showed that the local control rate of PRT alone for patients with advanced HCC was consistent, as previously reported.14 Slow regression of tumor volumes associated with gradual atrophy of surrounding noncancerous liver tissue was also in agreement with a previous report.20 No serious gastrointestinal toxicity occurred, with careful patient selection performed in order to exclude these structures from PTV receiving high PRT dose. Eligibility criteria as to blood cell count in this study were eased up considerably in order to test the safety of PRT for patients with cirrhosis associated with portal hypertension. Nevertheless, no patients experienced serious sequelae relating to leukopenia or thrombocytopenia, which were the most frequently observed adverse events during PRT. All patients were able to complete their PRT basically in an outpatient clinic. Therefore we submit that the safety, accuracy, and efficacy of PRT administering 76 GyE/5 weeks using our newly installed Proton Therapy System and ReGIS for selected patients with advanced HCC has been confirmed.
Multivariate analysis suggested that the the functional reserve of the liver had significant influence on overall survival. Recent prospective series of untreated patients with advanced HCC and underlying cirrhosis showed that overall survival rate at 3 years ranged from 13% to 38%, and rarely exceeded 50% even for those with most favorable prognostic factors.1 In this study, actuarial overall survival rate at 3 years for all 30 patients including those who had HCC with vascular invasion and/or severe cirrhosis was 62%. Furthermore, 21 patients with initial ICG R15 of 50% and V30% of 25% achieved 79% of overall survival rate at 3 years. All of the eight patients with favorable liver functional reserve (ICG R15, 15% to 20%) were alive at 20 to 54 months as shown in Figure 3. This suggests that adequate local control with PRT provides survival benefit for selected patients with HCC and moderate cirrhosis. On the other hand, prognoses of aggressive PRT were disappointing for patients, with poor functional liver reserve showing an ICG R15 of 50% or worse, and, therefore, indication of PRT for such patients was thought to be extremely limited.
A part of noncancerous liver suffering from PRT-inducing hepatitis gradually developed dense fibrosis and resulted in almost complete atrophy,20 whereas the absorbed dose in a large proportion of the remaining liver was 0 GyE, as shown in Figures 1 and 4. This change is similar to that seen in partial liver resection, rather than after 3-dimensional conformal or intensity-modulated radiotherapy delivering a low-dose of x-ray to a large proportion of noncancerous liver. Therefore, estimation of the risk of PRT-inducing hepatic insufficiency should be done with similar guidelines to evaluate liver tolerance to surgery, rather than that with normal tissue complication probability model using a mean dose administered to the entire liver.21 Remnant liver volume and ICG R15 have been preferred indicators for that estimation, especially in Japan.15 DVH analyses (Figs 4A to C) suggested that V30% in combination with ICG R15 may be a useful indicator for estimation of liver tolerance to PRT, but no definite quantitative criteria emerged with the limited data obtained at present because of the small number of patients evaluated. The current staging system for HCC is based on survival data obtained in surgical series.22 There is no reliable system to stratify the prognosis of patients with solitary but unresectable HCC on the assumption that they achieve good local control after PRT. Because of the limited availability of PRT at present, the establishment of particular criteria for patient selection using quantitative parameters of hepatic function such as ICG R15, and volume parameter like V30%, is needed to maximize the cost-effectiveness of PRT.
Applicability of PRT instead of surgery for patients with early-stage disease should be considered with caution. Intraoperative ultrasonography (IOUS) has an important role in detecting small metastatic lesions, which could not be demonstrated in preoperative examinations. The high incidence of intrahepatic recurrences seen outside the PTV might be partly ascribable to the limit of pretreatment imaging studies. Infiltration of HCC to the portal vein and spread via portal blood flow is one of the mechanisms for the development of intrahepatic recurrence.15 Actually, five recurrences occurred within the same segment of the primary tumor in this study. Although anatomic resection according to the architecture of the portal vein using IOUS offered a better chance of cure only for patients with noncirrhotic livers,23 systematic segmental PRT based on multimodal imagings such as CT during arterial portography or MRI as well as image fusion technique24 has a theoretical advantage compared with nonanatomic PRT confined to GTV only. Because there were few potentially curative approaches other than surgery for patients with HCC showing vascular invasion, further study is warranted to scrutinize an efficacy of PRT for patients with HCC of 5 cm in diameter, of which a large majority will demonstrate vascular invasion around the periphery of the tumor,25 while giving attention to their V30% values.
The risk of this aggressive dose-fractionation for sites such as the gastrointestinal loop, hepatic hilum, skin, or subcutanous tissues must be carefully considered, and more conventional fractionation must be adopted when these structures are critically involved in the PTV.
In conclusion, PRT for localized HCC using an aggressive dose-fractionation scheme (76 GyE for 5 weeks) achieved excellent local control rate regardless of vascular invasion or tumor size, if 10 cm, without devastating acute toxicity. Further study is warranted to scrutinize adequate patient selection according to quantitative parameter of hepatic function, such as ICG R15, and irradiated noncancerous liver volume in order to maximize survival benefit of this promising modality.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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