Worldwide, liver cancer in men is the fifth most frequently diagnosed cancer but the second most frequent cause of cancer-related death. In women, it is the seventh most commonly diagnosed cancer and the sixth leading cause of cancer-related death [
In our study, we compared the oncologic effects of IG-IMRT to 3D-CRT to assess the efficacy and safety of hypofractioned IG-IMRT by helical tomotherapy for unresectable but confined intrahepatic hepatocellular carcinoma.
This study retrospectively reviewed 90 patients with unresectable but confined intrahepatic hepatocellular carcinoma without lymph node metastasis, vascular invasion, and distant metastasis who received EBRT at our institution between April 2009 and December 2014. The diagnosis of hepatocellular carcinoma was based on the diagnosis criteria of the American Association for the Study of Liver Diseases (AASLD) [
This retrospective single-institution study was approved by local ethics review board (ID: 2011235).
The patients who received RT in our research were the cases with incomplete TACE. None of the cases underwent radiotherapy for the newly developed lesions. 3D-CRT or IG-IMRT was performed based on the patient’s choice and the status of the disease. IG-IMRT has a dose distribution advantage over multiple lesions or adjacent gastrointestinal tumors and is recommended for such patients. Patients that received radiotherapy were in the supine position with arms raised and vacuum pad fixed posture, and we used abdominal compression (AC) techniques as part of a fixed position to minimize the movement of liver. The AC was applied to the subxiphoid area under patient’s maximum tolerability [
There were 45 patients who received IG-IMRT by helical tomotherapy, and 45 received 3D-CRT. The median fraction dose of IG-IMRT was 3.2 Gy (2.2–5.5 Gy/fx), and the median total hypofractionated dose was 54 Gy (range, 35–68 Gy). The 3D-CRT was designed to deliver a median total dose of 54 Gy (range, 46–70 Gy) with a conventional fraction (2.0 Gy/fx). Radiotherapy was delivered once per day, 5 times a week. Both 3D-CRT and IG-IMRT were performed with 95% of the goal dose to cover 95% of the PTV. The prescription dose of radiotherapy was determined mainly according to the mean dose to the liver, which was limited to 23 Gy and was also limited by the tolerance dose of the gastrointestinal tract. Organs at risk (OARs) were under the tolerance dose, including the liver, kidneys, stomach, small intestine, and spinal cord.
The treatment applied after radiotherapy was variable. In the IG-IMRT group, 19 patients (42.2%) underwent TACE, 6 patients (13.3%) underwent liver cancer resection, 1 patient (2.2%) underwent liver transplantation, and 1 patient (2.2%) underwent radiofrequency ablation. In the 3D-CRT group, 28 patients (62.2%) underwent TACE, 3 patients (6.67%) underwent liver cancer resection, 1 patient (2.2%) underwent liver transplantation, and 2 patients (4.4%) underwent radiofrequency ablation.
The patients were evaluated weekly during treatment, and this included physical examination, complete blood counts, and liver function tests. After treatment, the evaluation was performed monthly. The responses to therapy were confirmed by CT scan or MRI during follow-up, 1.5–2 months after the completion of EBRT. Clinical and radiological follow-up was performed every 3 months during the first 24 months following treatment and every 6 months thereafter. All images were reviewed by an independent radiologist who classified responses according to the revised Response Evaluation Criteria in Solid Tumors (version 1.1) [
Overall survival (OS) was calculated from the day of first treatment of the primary tumor. Progression-free survival (PFS) was defined as the time from radiotherapy start date to the date of target lesions progression, relapse, patient death, or the last contact. The chi-square test and an independent samples
The baseline demographic, clinical, and laboratory characteristics are shown in Table
Patient characteristics.
Characteristic | IG-IMRT |
3D-CRT |
|
---|---|---|---|
Gender | |||
Male | 36 | 35 | 0.796 |
Female | 9 | 10 | |
Age (years) | |||
<60 | 20 | 25 | 0.292 |
≥60 | 25 | 20 | |
KPS | |||
<90 | 13 | 5 | 0.035 |
≥90 | 32 | 40 | |
HBsAg | |||
Negative | 10 | 7 | 0.419 |
Positive | 35 | 38 | |
Total bilirubin ( |
|||
≤34 | 39 | 41 | 0.502 |
>34 | 6 | 4 | |
Albumin (g/L) | |||
≤35 | 37 | 38 | 0.777 |
>35 | 8 | 7 | |
Child-Pugh classification | |||
A | 40 | 42 | 0.459 |
B | 5 | 3 | |
AFP (ng/mL) | |||
≤20 | 26 | 20 | 0.356 |
20–400 | 8 | 8 | |
≥400 | 11 | 17 | |
Tumor size (cm) | |||
≤8 | 35 | 33 | 0.624 |
>8 | 10 | 12 | |
Number of tumors | |||
Single | 30 | 25 | 0.280 |
Multiple | 15 | 20 | |
TACE (before RT) | |||
No | 10 | 11 | 0.803 |
Yes | 35 | 34 | |
TACE frequency | |||
0 | 10 | 11 | 0.537 |
1-2 | 24 | 19 | |
>2 | 11 | 15 |
Most of the patients received TACE before radiotherapy. Chemotherapeutic agents and embolization agents were selected according to the tumor location and size. The percentages of patients that received TACE were similar between the IG-IMRT group and the 3D-CRT group, and the average TACE frequency was 2.4 and 2.9, respectively. However, neither the percentage nor frequency of TACE administration before RT was significantly different between the groups.
Because of the performance status of patients, size and location of the tumor, and the limits of the OARs, the prescription dose and fraction of radiotherapy were different. Correlation analysis showed that the prescription dose was negatively correlated with GTV, which was determined by tumor size. The correlation coefficient was
Correlation between GTV and BED. Correlation analysis showed that the prescription dose was negatively correlated with GTV. The correlation coefficient was
To make the radiation doses comparable, the total dose was converted to the biologically effective dose (BED) using an L-Q model with an HCC
Dose distribution.
Variables | IG-IMRT |
3D-CRT |
|
---|---|---|---|
RT dose (Gy) | |||
Average |
|
|
0.427 |
BED average |
|
|
0.004 |
RT fraction (Fx) |
|
|
0.001 |
Dose to liver | |||
V5 (%) |
|
|
0.001 |
V10 (%) |
|
|
0.116 |
V20 (%) |
|
|
0.595 |
V30 (%) |
|
|
0.079 |
|
|
|
0.768 |
In comparing the response to IG-IMRT with that to 3D-CRT, the CR rate was 8.9% (4/45) versus 4.4% (2/45), the PR rate was 48.9% (22/45) versus 28.9% (13/45), the percentage of those with SD was 37.8% (17/45) versus 55.6% (25/45), and the percentage of those with PD was 4.4% (2/45) versus 11.1% (5/45), respectively. The ORR (CR+PR) was significantly higher in the IG-IMRT group (
After radiotherapy, there were 11 patients having Child-Pugh scores decreased in IG-IMRT group and 12 patients in 3DCRT group, 4 patients, and 3 patients improved from Child-Pugh B to Child-Pugh A in IG-IMRT and 3-DCRT group, respectively. The tumors in 7 patients shrunk to less than 5 cm in both groups, which might convert patients to resectable cases.
As to survival analysis, the median follow-up of all patients was 44.8 months, that for patients in HT group was 51.9 months (4.5–75.4 months), and that for patients in 3D-CRT group was 34.6 months (2.1–56.2 months), respectively. Target lesions in the radiation field were followed to evaluate progression-free survival in the two groups. 21 patients in the IG-IMRT group and 28 patients in the 3D-CRT group had target lesion progression or relapse. The median progression-free survival in the IG-IMRT group and the 3D-CRT group was
PFS rates of target lesions according to the modality of radiotherapy. The IG-IMRT group had a significantly longer median progression-free survival time of target lesions (
Patients that received IG-IMRT showed significantly higher 1-year survival (93.3 versus 77.8%,
OS rates according to the modality of radiotherapy. Patients who received IG-IMRT showed longer median survival (44.7 versus 24.0 months,
On univariate analysis, Child-Pugh classification (A versus B,
Univariate and multivariate analysis of OS.
Variables | Median OS |
|
|
---|---|---|---|
Univariate | Multivariate | ||
Gender | |||
Male |
|
0.347 | |
Female |
|
||
Age (years) | |||
<60 |
|
0.454 | |
≥60 |
|
||
KPS | |||
<90 |
|
0.606 | |
≥90 |
|
||
HBsAg | |||
Negative |
|
0.476 | |
Positive |
|
||
Total bilirubin ( |
|||
≤34 |
|
0.209 | |
>34 |
|
||
Albumin (g/L) | |||
≤35 |
|
0.317 | |
>35 |
|
||
Child-Pugh classification | |||
A |
|
0.044 | 0.144 |
B |
|
||
AFP (ng/mL) | |||
≤20 |
|
0.247 | |
20–400 |
|
||
≥400 |
|
||
Tumor size (cm) | |||
≤8 |
|
0.014 | 0.000 |
>8 |
|
||
Number of tumors | |||
Single |
|
0.216 | |
Multiple |
|
||
TACE (before RT) | |||
No |
|
0.000 | 0.000 |
Yes |
|
||
TACE (after RT) | |||
No |
|
0.269 | |
Yes |
|
||
RT modality | |||
IG-IMRT |
|
0.046 | 0.012 |
3D-CRT |
|
No grade IV toxicity was observed in either group, and the common toxicity of radiotherapy was acute upper gastrointestinal (GI) toxicity, liver dysfunction, and hematological toxicity. GI toxicity includes anorexia, nausea, vomiting, and abdominal discomfort. The increase of Child-Pugh score was also evaluated as a toxicity index. There was no significant difference in the toxicity between the two groups (Table
Radiation toxicities.
Variables | Grade | IG-IMRT |
3D-CRT |
|
---|---|---|---|---|
GI toxicity | None | 37 | 29 | 0.114 |
I | 6 | 9 | ||
II | 2 | 7 | ||
III/IV | 0 | 0 | ||
Increase of alanine aminotransferase | None | 39 | 37 | 0.496 |
I | 5 | 7 | ||
II | 1 | 0 | ||
III | 0 | 1 | ||
IV | 0 | 0 | ||
Increase of Aspartate aminotransferase | None | 32 | 34 | 0.425 |
I | 13 | 9 | ||
II | 0 | 1 | ||
III | 0 | 1 | ||
IV | 0 | 0 | ||
Thrombocytopenia | None | 28 | 23 | 0.434 |
I | 8 | 14 | ||
II | 5 | 3 | ||
III | 4 | 5 | ||
IV | 0 | 0 | ||
Decrease in hemoglobin | None | 32 | 25 | 0.303 |
I | 10 | 16 | ||
II | 3 | 4 | ||
III/IV | 0 | 0 | ||
Increase of Child-Pugh score | None | 28 | 23 | 0.503 |
1 | 8 | 14 | ||
2 | 5 | 3 | ||
3 | 4 | 5 | ||
Above 3 | 0 | 0 |
At the end of this study, 25 patients had died in the IG-IMRT group. 18 patients died of hepatic decompensation or tumor progression (or both), 3 patients died of multiple organ failure, 2 patients died of gastrointestinal hemorrhage, 1 patient died of lung metastasis, and 1 patient died of biliary tract infection. In the 3D-CRT group, 36 patients died. 22 patients died of hepatic decompensation or tumor progression (or both), 4 patients died of lung metastases, 4 patients died of multiple organ metastases, 2 patients died of gastrointestinal hemorrhage, 1 patient died of a ruptured liver cancer with hemorrhage, and the cause of death of 3 patients was undefined.
As an advanced technique integrating IMRT and IGRT, helical tomotherapy is inherently capable of acquiring CT images of the patient in the treatment position and using this information for image guidance to offer an efficient, accurate, and safe treatment [
In our study, the IG-IMRT group received a significantly higher dose (BED) and less fractions of RT than the 3D-CRT group. Regarding the whole liver, V5 was higher in IG-IMRT plans than 3D-CRT plans, while V10, V20, V30, and MDTNL showed no significant differences, which is consistent with previous reports [
The dose difference of IG-IMRT and 3DCRT was just less than 10% in BED (69.4 Gy versus 63.9 Gy). However, the treatment outcomes have bigger differences. ORRs were 57.3% versus 33.3%, DCRs were 95.6% versus 88.9%, 1- and 2-year overall survival rates were 93.3%/73.3% versus 77.8%/51.1%, and median overall survival was 44.7 months versus 24.0 months in the IG-IMRT and 3DCRT, respectively. There are some similar studies reporting that the higher therapeutic dose applied by IG-IMRT leads to excellent local control within the radiation field and a potential survival benefit [
After radiotherapy, some patients underwent curative therapies including tumor resection, liver transplantation, and radiofrequency ablation. As a conversion therapy or bridge therapy, whether IG-IMRT is superior to conventional radiotherapy requires studies with large sample.
Our results show that the IG-IMRT group had a significantly longer median survival than the 3D-CRT group, and the tumor size was also significantly associated with OS. We noticed that tumor size was the main factor limiting the prescription dose; tumor size determined the GTV, and the GTV determined the radiation volume. Higher prescription doses could not be applied due to the potential toxicity to OARs, resulting in reduced treatment efficacy. As an advanced radiotherapy technology, IG-IMRT eased this limitation to some extent. Furthermore, a role for the combination of TACE and RT in the treatment of HCC has been reported [
The safety and feasibility of IG-IMRT in liver cancer have been widely demonstrated [
With the continuous development of radiotherapy equipment, medical imaging, and computer technology, radiotherapy has become more important in the treatment of HCC. Although our study had several limitations, such as limited sample volume and a lack of random sampling, hypofractioned IG-IMRT provided a potential survival benefit and had satisfactory safety profile. However, the appropriate prescription dose and fraction of radiotherapy were not identified in this study, which will require additional randomized studies.
Compared with 3D-CRT, hypofractioned IG-IMRT provided a higher therapeutic dose in a shorter treatment period with similar and well-tolerated toxicity, which conferred a potential survival benefit.
The authors declare that no potential conflicts of interest exist.