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Chun-Shu Lin, Yee-Min Jen, Su-Yun Chiu, Jing-Min Hwang, Hsing-Lung Chao, Hon-Yi Lin, Weng-Yoon Shum, Treatment of Portal Vein Tumor Thrombosis of Hepatoma Patients with Either Stereotactic Radiotherapy or Three-Dimensional Conformal Radiotherapy, Japanese Journal of Clinical Oncology, Volume 36, Issue 4, April 2006, Pages 212–217, https://doi.org/10.1093/jjco/hyl006
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Abstract
Background: Patients with hepatocellular carcinoma (HCC) often have unresectable tumors. Transcatheter arterial chemoembolization (TACE) is one of the limited alternative treatments that can prolong these patients' survival. However, the presence of portal vein tumor thrombosis (PVTT) is a contraindication for TACE and, therefore, HCC patients with PVTT would be depleted of the advantage of TACE. The purpose of this study was to analyze the recanalization rate of thrombosed portal vein and treatment toxicities after stereotactic radiotherapy (SRT) or three-dimensional conformal radiotherapy (3DCRT).
Methods: From March 2002 to November 2004, 43 patients were enrolled in this prospective study. Twenty-two patients were in the SRT group and 21 in the 3DCRT group. For SRT, 3 Gy per fraction, 3 fractions per week, was given to a total dose of 45 Gy. For 3DCRT, a daily dose of 1.8 Gy, 5 fractions per week, was given to a total dose of 45 Gy.
Results: Of the 43 patients, 16 completed the planned radiotherapy. Eventually, 14 patients received evaluation for portal vein recanalization, 8 in the SRT and 6 in the 3DCRT group, respectively. For all patients, the crude response rate was 26%. For 14 evaluable patients, the crude response rate was 79%. It was 75% in the SRT group and 83% in the 3DCRT group (P = 0.71). The median survival time was 6.0 and 6.7 months for the SRT and 3DCRT group, respectively (P = 0.911).
Conclusions: Image-based radiotherapy, either SRT or 3DCRT, can recanalize the PVTT in unresectable HCC patients. Responders also had better 1 year and 2 year survivals. A more strict patient selection criterion may maximize the potential benefits of radiotherapy for hepatoma patients with PVTT.
INTRODUCTION
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers in Taiwan and several regions in East Asia. A significant proportion of HCC patients have unresectable tumors and for these patients transcatheter arterial chemoembolization (TACE) has been the alternative option that could prolong patient survival(1–7). Although TACE gives a meager 1 year survival rate of 40–80%, it is one of the limited available treatments that has a beneficial effect on this group of patients(6–10). However, the presence of tumor thrombosis of the portal trunk or bilateral major portal vein branches has been considered a contraindication for TACE owing to the risk of hepatic failure(4,7–8). HCC patients with portal vein tumor thrombosis (PVTT), therefore, have a very dismal prognosis with a survival time of only about 2–4 months(2,12–13).
Radiotherapy (RT) has been shown to be a potentially effective treatment for PVTT since 1994 (14–20). Starting from 2002, we have treated our HCC patients with PVTT using image-based radiotherapy, including stereotactic radiotherapy (SRT) and three-dimensional conformal radiotherapy (3DCRT). The purpose of RT is to recanalize the PVTT and make it possible for our patients to receive subsequent TACE. In this report, we analyze the recanalization rate of the thrombosed portal vein and toxicities after SRT or 3DCRT.
PATIENTS AND METHODS
From March 2002 to November 2004, 43 patients (34 men and 9 women) with unresectable HCC accompanied by tumor thrombosis in the portal trunk and/or bilateral main portal vein branches were enrolled in this study. The diagnosis of HCC was either histologically based or made by radiographic findings plus a serum alpha-fetoprotein (AFP) value exceeding 400 IU/ml. Seven patients had received surgery and 18 patients had had TACE before the diagnosis of PVTT. Six patients had distant metastases. The median age at the diagnosis of PVTT was 57 years (range 21–81 years). For all these patients, TACE was considered contraindicated by the diagnostic radiologists responsible for TACE. The presence of PVTT was confirmed using sonogram, contrast-enhanced CT scan and hepatic angiogram, with or without MRI. Thirty-one patients were hepatitis B and 14 hepatitis C carriers. Ten patients took thalidomide as an angiogenesis inhibitor during radiotherapy.
Twenty-two patients were in the SRT group, and 21 in the 3DCRT group. Patients' characteristics are shown in Table 1. Owing to the palliative intent, most patients in this study had poor performance status. Of the 43 patients, full RT dose was delivered to 16 (37%) of whom 14 received evaluation for PVTT response. Response rate was analyzed for these 14 patients as well as for the entire group.
. | SRT group (n = 22) . | 3DCRT group (n = 21) . | P-value . |
---|---|---|---|
Sex | M = 17 | M = 17 | P = 0.77 |
F = 5 | F = 4 | ||
Age (years, mean ± SD*) | 59.5 ± 13.1 | 54.0 ± 18.0 | |
Child-Pugh classification | |||
A | 7 | 5 | P = 0.21 |
B | 11 | 7 | |
C | 4 | 9 | |
CLIP score | |||
1–2 | 3 | 3 | P = 0.72 |
3–4 | 13 | 10 | |
5–6 | 6 | 8 | |
Completion of RT | 9 (41%) | 7 (33%) | P = 0.61 |
Evaluable patients | 8 (36%) | 6 (29%) | P = 0.59 |
Median HCC size (cm) | 6.5 | 13.8 | |
Median CTV volume (ml) | 72 | 102.4 | |
Median liver volume (ml) | 1806.3 | 2011.6 | |
Median V30 (%) | 24.8 | 16.2 | |
Median margin (cm) | 0.9 | 0.6 | |
Prescribed dose (Gy) | 45 | 45 | |
Median RT dose (Gy) | 45 | 45 | |
Response of all patients | |||
Complete response | 0 (0%) | 1 (5%) | |
Partial response | 6 (27%) | 4 (19%) | |
Stable disease | 2 (9%) | 1 (5%) | |
Died before evaluation | 14 (64%) | 15 (71%) | |
Response of evaluable patients | |||
Complete response | 0 (0%) | 1 (17%) | P = 0.75 |
Partial response | 6 (75%) | 4 (67%) | |
Stable disease | 2 (25%) | 1 (17%) |
. | SRT group (n = 22) . | 3DCRT group (n = 21) . | P-value . |
---|---|---|---|
Sex | M = 17 | M = 17 | P = 0.77 |
F = 5 | F = 4 | ||
Age (years, mean ± SD*) | 59.5 ± 13.1 | 54.0 ± 18.0 | |
Child-Pugh classification | |||
A | 7 | 5 | P = 0.21 |
B | 11 | 7 | |
C | 4 | 9 | |
CLIP score | |||
1–2 | 3 | 3 | P = 0.72 |
3–4 | 13 | 10 | |
5–6 | 6 | 8 | |
Completion of RT | 9 (41%) | 7 (33%) | P = 0.61 |
Evaluable patients | 8 (36%) | 6 (29%) | P = 0.59 |
Median HCC size (cm) | 6.5 | 13.8 | |
Median CTV volume (ml) | 72 | 102.4 | |
Median liver volume (ml) | 1806.3 | 2011.6 | |
Median V30 (%) | 24.8 | 16.2 | |
Median margin (cm) | 0.9 | 0.6 | |
Prescribed dose (Gy) | 45 | 45 | |
Median RT dose (Gy) | 45 | 45 | |
Response of all patients | |||
Complete response | 0 (0%) | 1 (5%) | |
Partial response | 6 (27%) | 4 (19%) | |
Stable disease | 2 (9%) | 1 (5%) | |
Died before evaluation | 14 (64%) | 15 (71%) | |
Response of evaluable patients | |||
Complete response | 0 (0%) | 1 (17%) | P = 0.75 |
Partial response | 6 (75%) | 4 (67%) | |
Stable disease | 2 (25%) | 1 (17%) |
*SD: standard deviation; SRT: stereotactic radiotherapy; 3DCRT: 3-dimensional conformal radiotherapy; M: male; F: female; CTV: clinical target volume; RT: radiotherapy; HCC: hepatocellular carcinoma; V30: percentage volume of the total liver receiving a dose exceeding 30 Gy.
. | SRT group (n = 22) . | 3DCRT group (n = 21) . | P-value . |
---|---|---|---|
Sex | M = 17 | M = 17 | P = 0.77 |
F = 5 | F = 4 | ||
Age (years, mean ± SD*) | 59.5 ± 13.1 | 54.0 ± 18.0 | |
Child-Pugh classification | |||
A | 7 | 5 | P = 0.21 |
B | 11 | 7 | |
C | 4 | 9 | |
CLIP score | |||
1–2 | 3 | 3 | P = 0.72 |
3–4 | 13 | 10 | |
5–6 | 6 | 8 | |
Completion of RT | 9 (41%) | 7 (33%) | P = 0.61 |
Evaluable patients | 8 (36%) | 6 (29%) | P = 0.59 |
Median HCC size (cm) | 6.5 | 13.8 | |
Median CTV volume (ml) | 72 | 102.4 | |
Median liver volume (ml) | 1806.3 | 2011.6 | |
Median V30 (%) | 24.8 | 16.2 | |
Median margin (cm) | 0.9 | 0.6 | |
Prescribed dose (Gy) | 45 | 45 | |
Median RT dose (Gy) | 45 | 45 | |
Response of all patients | |||
Complete response | 0 (0%) | 1 (5%) | |
Partial response | 6 (27%) | 4 (19%) | |
Stable disease | 2 (9%) | 1 (5%) | |
Died before evaluation | 14 (64%) | 15 (71%) | |
Response of evaluable patients | |||
Complete response | 0 (0%) | 1 (17%) | P = 0.75 |
Partial response | 6 (75%) | 4 (67%) | |
Stable disease | 2 (25%) | 1 (17%) |
. | SRT group (n = 22) . | 3DCRT group (n = 21) . | P-value . |
---|---|---|---|
Sex | M = 17 | M = 17 | P = 0.77 |
F = 5 | F = 4 | ||
Age (years, mean ± SD*) | 59.5 ± 13.1 | 54.0 ± 18.0 | |
Child-Pugh classification | |||
A | 7 | 5 | P = 0.21 |
B | 11 | 7 | |
C | 4 | 9 | |
CLIP score | |||
1–2 | 3 | 3 | P = 0.72 |
3–4 | 13 | 10 | |
5–6 | 6 | 8 | |
Completion of RT | 9 (41%) | 7 (33%) | P = 0.61 |
Evaluable patients | 8 (36%) | 6 (29%) | P = 0.59 |
Median HCC size (cm) | 6.5 | 13.8 | |
Median CTV volume (ml) | 72 | 102.4 | |
Median liver volume (ml) | 1806.3 | 2011.6 | |
Median V30 (%) | 24.8 | 16.2 | |
Median margin (cm) | 0.9 | 0.6 | |
Prescribed dose (Gy) | 45 | 45 | |
Median RT dose (Gy) | 45 | 45 | |
Response of all patients | |||
Complete response | 0 (0%) | 1 (5%) | |
Partial response | 6 (27%) | 4 (19%) | |
Stable disease | 2 (9%) | 1 (5%) | |
Died before evaluation | 14 (64%) | 15 (71%) | |
Response of evaluable patients | |||
Complete response | 0 (0%) | 1 (17%) | P = 0.75 |
Partial response | 6 (75%) | 4 (67%) | |
Stable disease | 2 (25%) | 1 (17%) |
*SD: standard deviation; SRT: stereotactic radiotherapy; 3DCRT: 3-dimensional conformal radiotherapy; M: male; F: female; CTV: clinical target volume; RT: radiotherapy; HCC: hepatocellular carcinoma; V30: percentage volume of the total liver receiving a dose exceeding 30 Gy.
We have routinely used Child-Pugh scoring system to grade the severity of impaired liver function for our HCC patients, and the Cancer of the Liver Italian Program (CLIP) scoring system for disease staging(21).
Radiotherapy
Patients were assigned to receive either SRT or 3DCRT arbitrarily. A diagnostic contrast-enhanced CT scan was used for the simulation in both SRT and 3DCRT groups. Patient treatment position was the same for these two techniques. Patients were placed in a supine position with both arms raised above the head. After immobilization, slices of 5 mm were taken for the range of interest. Some patients had oral contrast medium immediately before simulation to delineate the upper gastrointestinal tract.
For SRT, the Stereotactic Body Frame system (Elekta) was used for localization and stereotactic targeting. The system was composed of a body frame, a vacuum cushion, a chest marker laser, a stereotactic arc, a Z-scale, a level control and a diaphragm control. It features a highly reproducible, accurate and safe fixation of the patient compared with conventional RT. The patient was secured in the frame in a non-invasive way and a body mould was made with a vacuum cushion. With a diaphragm control, the diaphragm movement can be considerably reduced during SRT. Three Gy per fraction on Monday, Wednesday and Friday per week (tiw) was given to a total prescribed dose of 45 Gy. A median of 5 portals (range 4–7 portals) was used.
For 3DCRT, a daily dose of 1.8 Gy was given, 5 fractions per week, to a total prescribed dose of 45 Gy. A median of 5 portals (range 3–6 portals) was used. We used vacuum cushion to immobilize the patient.
We used Plato planning system (Nucletron) for treatment planning. Instead of defining a gross target volume (GTV), we contoured clinical target volume (CTV) directly. The CTV was defined as the detectable PVTT (GTV) plus a small margin of 3–5 mm. Part of the hepatic tumor was included in CTV only if the tumor directly invaded the portal vein. The definition of CTV is the same for SRT and 3DCRT. The planning target volume (PTV) included the CTV plus a 0.8 cm margin for set-up variation. A single PTV was used throughout the treatment course without a reduction. Forty-five Gy was prescribed mostly to the 90% isodose curve covering 100% PTV in both groups. Figure 1 is an example of dose volume histograms of SRT and 3DCRT. The percentage volume of the total liver receiving a dose exceeding 30 Gy was presented as V30.
RT was given using 15 MV photon from an Elekta Precise or Siemens Primus linear accelerator. Fields were shaped using a multileaf collimator or custom-made blocks.
Response Evaluation
The primary end points are response rate of PVTT and toxicities, and the secondary end point is survival time. The response of PVTT after RT was evaluated with contrast-enhanced CT scan within 3 months after the completion of RT. Complete disappearance of the portal vein thrombus was defined as a complete response (CR), >50% decrease of thrombus size as a partial response (PR), <50% decrease of thrombus size or no change defined as stable disease (SD) and tumor growth as progressive disease (PD). Response rate includes both CR and PR. If a response was noted, the patient continued to receive TACE. A mixed solution of adriamycin 40 mg and lipiodol 10 c.c. was injected through an arterial catheter, and the feeding artery was subsequently embolized with 10 c.c. of lipiodol and gelfoam.
We checked pre-RT and post-RT GOT, GPT and total bilirubin to monitor liver function change. Gastrointestinal and hematological side effects were documented with the RTOG score.
Statistical Analysis
Survival and follow-up times were calculated from the date of diagnosis of PVTT to the last follow-up. All the analyses were performed with SPSS 11.0 software. The Pearson Chi-square test was used to compare the patients' characteristics between the SRT and 3DCRT groups. Survival curves were computed using the Kaplan–Meier method and the log-rank test was used to compare the effect of each factor on survival. Paired-Samples t test was used to evaluate the difference of liver function before and after RT, and the Pearson Correlation was used to evaluate the correlation of V30 and liver functions. An α error of 0.05 was chosen for statistical significance.
RESULTS
The median follow-up time for the entire group and evaluable group was 2.5 and 7.4 months, respectively. For all the patients, the median V30 was 21.6% (range 7.6–81.0%), and the median doses covering 90 and 95% PTV were 45.73 Gy (range 39.79–52.03 Gy) and 44.94 Gy (range 37.38–51.54 Gy), respectively.
Of all the 43 patients, 29 received incomplete RT or did not have follow-up evaluation and they all died of the disease before the first follow-up. Treatment interruptions were caused by cancer death or poor performance status. The crude response rate of the whole group was 26%. In the 14 evaluable patients, 1 (7%) had CR, 10 (71%) had PR and 3 (21%) had SD. No PD was noted. The crude response rate was 79% for the evaluable patients. Subsequent TACE was conducted in five patients. Out of the three patients with SD, two died before re-evaluation and one had persistent SD. The median survival time for the evaluable patients was 6.7 months.
In the SRT group, nine (41%) patients completed RT, of whom eight received follow-up evaluation (Table 1). Six (75%) patients had PR, 2 (25%) had SD and none had PD. The crude response rate was 75% for evaluable patients. In the 3DCRT group, 7 (33%) patients completed RT, of whom six received follow-up evaluation. One (17%) patient had CR, 4 (67%) had PR, 1 (17%) had SD and none had PD. The crude response rate was 83% for evaluable patients. The crude response rates between the SRT and 3DCRT groups did not show significant difference (P = 0.75). The median survival time was 6.0 and 6.7 months for the SRT and 3DCRT groups (P = 0.911), respectively. The response status significantly influenced the overall survival (P = 0.003, Figure 2). The 1 year overall survival was 100, 56 and 0% for patients with CR, PR and SD, respectively. The 2 year overall survival was 100, 37 and 0% for patients with CR, PR and SD, respectively.
The GOT before and after RT was significantly different (P = 0.032), and so was total bilirubin (P = 0.045). The difference in GPT before and after RT was not significant (P = 0.444), neither was AFP (P = 0.584). V30 did not show correlation with the difference in liver functions, including GOP (P = 0.362), GPT (P = 0.376) and total bilirubin (P = 0.343).
Of all the 43 patients, grade 2 acute gastrointestinal complication occurred in 13 patients, including vomiting requiring antiemetics or weight loss between 5 and 15%. Grade 1 toxicity, namely, nausea not requiring antiemetics or weight loss less than 5%, occurred in 11 patients. No patient had grade 3 or grade 4 toxicities. One patient had grade 2 leukocytopenia with white blood count (WBC) between 2000 and 3000 per μl, and seven had grade 1 with WBC between 3000 and 4000 per μl. No grade 3 or 4 leukocytopenia occurred. We evaluated late toxicities 3 months after completion of RT. Among the 14 evaluable patients, five patients died of the disease before evaluation, and the other eight patients did not have radiation-induced late toxicities.
DISCUSSION
There have been few studies reporting on the treatment of portal trunk/branch thrombosis in HCC patients with conventional RT (Table 2). The first reported trial to evaluate RT effect on PVTT recanalization was conducted by Chen from Taiwan in 1994 (14). He treated 10 unresectable HCC patients with unilateral PVTT by conventional RT technique. The radiation dose was 30–50 Gy. Five patients had CR, and the other five had PR. The response rate was 100%. Huang also reported 41 unresectable HCC patients with PVTT who were contraindicated to TACE (16). The patients were treated with conventional RT to the PVTT site followed by TACE to the primary tumor. The radiation dose ranged from 36 to 66 Gy. CR rate is 39% and PR is 41%. The cumulative survival is correlated with RT response of PVTT. Recently, Zeng reviewed 158 HCC patients with portal vein and/or inferior vena cava thrombi(20). Forty-four patients had conventional RT to the PVTT, including nine with RT and surgery, 25 with RT and TACE and 10 with RT alone. Of these, 15 (34.1%) patients had CR and 5 (11.4%) had PR of the tumor thrombi. The median survival rates are 8 and 4 months for the RT patients and the other 114 patients without RT, respectively. He also found that the median survival is 15 and 5 months for patients with CR or PR versus patients with SD or PD. In stepwise multivariate analysis, RT is an independent factor for survival rate.
Series . | Patient no. . | RT technique . | Radiation dose (range) (Gy) . | Response rate of PVTT (%) . | Median survival (months) . |
---|---|---|---|---|---|
Chen et al. (14) | 10 | Conventional RT | 30–50 | CR: 50 PR: 50 | |
Huang et al. (16) | 41 | Conventional RT | 51.4 (36–66) | CR: 39 PR: 41 | CR: 17 PR: 8 SD: 4 |
Yamada et al. (17) | 8 | Conventional RT | 60 | CR+PR: 37.5 | 5.7 |
Ishikura et al. (18) | 20 | Conventional RT | 50 | CR+PR: 50 | 5.3 |
Zeng et al. (20) | 44 | Conventional RT | 50 (36–60) | CR: 34.1 PR: 11.4 | 8 (CR+PR: 15, SD+PD: 5) |
Leung et al. (15) | 1 | 3DCRT | 55 | CR: 100 | |
Yamada et al. (19) | 19 | 3DCRT | 60 (46–60) | CR+PR: 57.9 | 7 |
Our study | 14* | 3DCRT or SRT | 45 | CR: 7.1 PR: 71.4 | 6.7 |
Series . | Patient no. . | RT technique . | Radiation dose (range) (Gy) . | Response rate of PVTT (%) . | Median survival (months) . |
---|---|---|---|---|---|
Chen et al. (14) | 10 | Conventional RT | 30–50 | CR: 50 PR: 50 | |
Huang et al. (16) | 41 | Conventional RT | 51.4 (36–66) | CR: 39 PR: 41 | CR: 17 PR: 8 SD: 4 |
Yamada et al. (17) | 8 | Conventional RT | 60 | CR+PR: 37.5 | 5.7 |
Ishikura et al. (18) | 20 | Conventional RT | 50 | CR+PR: 50 | 5.3 |
Zeng et al. (20) | 44 | Conventional RT | 50 (36–60) | CR: 34.1 PR: 11.4 | 8 (CR+PR: 15, SD+PD: 5) |
Leung et al. (15) | 1 | 3DCRT | 55 | CR: 100 | |
Yamada et al. (19) | 19 | 3DCRT | 60 (46–60) | CR+PR: 57.9 | 7 |
Our study | 14* | 3DCRT or SRT | 45 | CR: 7.1 PR: 71.4 | 6.7 |
*Fourteen out of forty-three patients completed radiotherapy and had evaluation for recanalization of the treated PVTT in our study. HCC: hepatocellular carcinoma; PVTT: portal vein tumor thrombosis; RT: radiotherapy; TACE: transcatheter arterial chemoembolization; CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; 3DCRT: 3-dimensional conformal radiotherapy; SRT: stereotactic radiotherapy.
Series . | Patient no. . | RT technique . | Radiation dose (range) (Gy) . | Response rate of PVTT (%) . | Median survival (months) . |
---|---|---|---|---|---|
Chen et al. (14) | 10 | Conventional RT | 30–50 | CR: 50 PR: 50 | |
Huang et al. (16) | 41 | Conventional RT | 51.4 (36–66) | CR: 39 PR: 41 | CR: 17 PR: 8 SD: 4 |
Yamada et al. (17) | 8 | Conventional RT | 60 | CR+PR: 37.5 | 5.7 |
Ishikura et al. (18) | 20 | Conventional RT | 50 | CR+PR: 50 | 5.3 |
Zeng et al. (20) | 44 | Conventional RT | 50 (36–60) | CR: 34.1 PR: 11.4 | 8 (CR+PR: 15, SD+PD: 5) |
Leung et al. (15) | 1 | 3DCRT | 55 | CR: 100 | |
Yamada et al. (19) | 19 | 3DCRT | 60 (46–60) | CR+PR: 57.9 | 7 |
Our study | 14* | 3DCRT or SRT | 45 | CR: 7.1 PR: 71.4 | 6.7 |
Series . | Patient no. . | RT technique . | Radiation dose (range) (Gy) . | Response rate of PVTT (%) . | Median survival (months) . |
---|---|---|---|---|---|
Chen et al. (14) | 10 | Conventional RT | 30–50 | CR: 50 PR: 50 | |
Huang et al. (16) | 41 | Conventional RT | 51.4 (36–66) | CR: 39 PR: 41 | CR: 17 PR: 8 SD: 4 |
Yamada et al. (17) | 8 | Conventional RT | 60 | CR+PR: 37.5 | 5.7 |
Ishikura et al. (18) | 20 | Conventional RT | 50 | CR+PR: 50 | 5.3 |
Zeng et al. (20) | 44 | Conventional RT | 50 (36–60) | CR: 34.1 PR: 11.4 | 8 (CR+PR: 15, SD+PD: 5) |
Leung et al. (15) | 1 | 3DCRT | 55 | CR: 100 | |
Yamada et al. (19) | 19 | 3DCRT | 60 (46–60) | CR+PR: 57.9 | 7 |
Our study | 14* | 3DCRT or SRT | 45 | CR: 7.1 PR: 71.4 | 6.7 |
*Fourteen out of forty-three patients completed radiotherapy and had evaluation for recanalization of the treated PVTT in our study. HCC: hepatocellular carcinoma; PVTT: portal vein tumor thrombosis; RT: radiotherapy; TACE: transcatheter arterial chemoembolization; CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; 3DCRT: 3-dimensional conformal radiotherapy; SRT: stereotactic radiotherapy.
However, for conventional RT, it is difficult to localize precisely the small area of PVTT. Leung noticed this problem and reported the first case of HCC patients with PVTT treated with 3DCRT(15). The radiation dose was 55 Gy. Shrinkage of the tumor and thrombus and restoration of the hepatopedal flow of the portal vein were noted 3 months after the treatment. He concluded that 3DCRT is technically feasible and effective for the treatment of a small volume of liver tissue with a high dose of radiation for hepatoma patients with PVTT. Yamada first treated eight patients with TACE and conventional RT in his pilot study of RT for PVTT (17). The response rate of the PVTT was 37.5%. In his second study, he used 3DCRT instead of conventional RT while the other treatment modality was the same as in the pilot study (19). Nineteen patients were entered into this study and the response rate was 57.9%. The mean tumor dose was 57 Gy in these two trials.
As for SRT, there have been no data in the literature reporting its efficacy for PVTT. In our analysis, both SRT and 3DCRT have encouraging and comparable results, and both could be used to recanalize PVTT effectively. The crude response rate was significantly correlated with the cumulative survival rates(16,20).
It is difficult to compare our results with other reports owing to difference in patient selection. Many patients in this analysis had poor performance status. Compared with the results listed in Table 2, most patients in the other studies had good performance status and had a life expectancy greater than their RT course. Therefore we also analyzed the subgroup patients who completed the whole RT course and compared the results with those from the other reports. For this group, our result conforms to Zeng's finding that RT is beneficial for HCC patients with tumor thrombi and prolongs survival in treated patients (20). Although we used a relatively low dose of 45 Gy for both SRT and 3DCRT, the response rate was better than Yamada's where 60 Gy was used (17,19). It appears that to recanalize PVTT with SRT or 3DCRT, 45 Gy may be sufficient. However we now intend to escalate the dose to 45 Gy in the hep that the recanalization rate may be increased.
We added a margin of 0.8 cm to the CTV for set-up error and internal organ movement. This margin should be adequate for ventro-dorsal and lateral directions; however, it may be insufficient for cranio-caudal direction(22). A larger margin will increase the V30 significantly, causing treatment intolerance in these patients who mostly had a poor performance status. With the advent of image-guided radiotherapy (IGRT), this problem will be solved in the future. Furthermore, a dose escalation may be possible without an increase in toxicity with IGRT.
In our study, acute gastrointestinal and hematological toxicities were acceptable. Although GOT, GPT and total bilirubin were elevated after RT in 9 (64%), 7 (50%) and 9 (64%) patients, respectively, only GOT had a significant elevation after RT. The cause of impaired liver function was difficult to determine. The primary liver mass was not treated during RT and it could continue to grow and induce liver function impairment. Nevertheless, the liver function impairment could be treatment related. In Yamada's studies, deterioration of liver function was observed in all patients with V30 > 40%(17,19). However, only two patients had a V30 > 40% in our evaluable patients, and both of them did not have deterioration of liver function. The others had a V30 < 30%. No late toxicity was noted in our study. The low incidence of toxicity may be owing to the lower dose we used and a precise targeting and small volume of liver treated to a high dose, reflected by the small V30.
Palliative RT can effectively recanalize PVTT with a response rate of approximately 75% in patients who completed the treatment. Both SRT and 3DCRT can target the PVTT more precisely and increase the response rate compared with conventional RT. However, owing to the aggressive disease nature, only 33% of patients completed RT and could be evaluated in our study. A selection criterion is needed to select patients who will benefit from this treatment. Patients with a performance status of ECOG 0–2 may be a reasonable criterion. According to the linear-quadratic model, assuming an α/β of 10 Gy for the PVTT, the biologically effective doses (BED) for 3DCRT and SRT were 53.1 Gy and 58.5 Gy, respectively. SRT was approximately 10% higher in terms of BED. Compared with 3DCRT, the benefit of SRT is the reduction of the patient's treatment course from 25 to 15 fractions. For the SRT group, the tiw treatment strategy seems to offer no theoretical advantage and has been changed back to the conventional 5-day-per-week scheme. Randomized trials with larger sample size are needed to test the efficacy of 3DCRT or SRT on the resolution of PVTT in hepatoma patients.
This study is partly supported by the CY Foundation for Advancement of Education, Sciences, and Medicine.
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