Radiation and the Treatment of Hepatomas

 

Actuarial survival of 158 patients treated with local RT. Survivals are shown from the diagnosis and from the commencement of radiotherapy.
Dose-response relationship in local radiotherapy for hepatocellular carcinoma. Park. IJROBP 2002;54:150
One hundred fifty-eight patients were enrolled in the present study between January 1992 and March 2000. The exclusion criteria included the presence of an extrahepatic metastasis, liver cirrhosis of Child class C, tumors occupying more than two-thirds of the entire liver, and a performance status on the Eastern Cooperative Oncology Group scale of more than 3. Radiotherapy was given to the field, including the tumor, with generous margin using 6- or 10-MV X-rays. The mean radiation dose was 48.2 ± 7.9 Gy in daily 1.8-Gy fractions. The tumor response was assessed based on diagnostic radiologic examinations, including a computed tomography scan, magnetic resonance imaging, and hepatic artery angiography 4–8 weeks after the completion of treatment. Liver toxicity and gastrointestinal complications were evaluated.

Results: An objective response was observed in 106 of 158 (67.1%) patients. Statistical analysis revealed that the total dose was the most significant factor associated with the tumor response. The response rates in patients treated with doses <40 Gy, 40–50 Gy, and >50 Gy were 29.2%, 68.6%, and 77.1%, respectively. Survivals at 1 and 2 years after radiotherapy were 41.8% and 19.9%, respectively, with a median survival time of 10 months. The rate of liver toxicity according to the doses <40 Gy, 40–50 Gy, and >50 Gy was 4.2%, 5.9%, and 8.4%, respectively, and the rate of gastrointestinal complications was 4.2%, 9.9%, and 13.2%, respectively.

Currently, a dose-response relationship has not been established, using a large number of patients, in local RT for HCC. However, indirect evidence suggests that the higher the radiation dose, the better the response. Phillips and Murikami showed that radiation doses <20 Gy were ineffective. Robertson et al. suggested that a dose-response relationship might exist for HCC, because hepatic control within the target volume was particularly encouraging in the high-dose focal radiation group. In contrast, their experience with whole liver RT determined that a substantial proportion of patients progressed within the field of radiation. The Radiation Therapy Oncology Group reported that 21 Gy whole liver RT plus an additional two courses of 131I-antiferritin infusion, which is comparable to 10–12 Gy, gave a better response (48%) than whole liver RT alone (23%). This implies that increasing the radiation dose is important for HCC; however, there is a paucity of appropriate published data for establishing a dose-response relationship in localized RT.

In the current study, a dose-response relationship was found with a total of 158 HCC patients treated with localized RT. The average radiation dose was 50.1 ± 6.6 Gy in the responders and 44.3 ± 9.0 Gy in the nonresponders. When the patients were divided into three groups according to radiation dose, the tumor response increased as the radiation dose increased. However, the average tumor size was smallest, and the rate of PVT was lowest, in the group of patients that received more than 50 Gy of radiation. It is thought that in prescribing the radiation dose, physicians might have been influenced partly by the larger tumor sizes of the patients with PVT and might have had a tendency to escalate the radiation dose for patients who had better tumor characteristics. Ohto et al. reported a close relation between the rate of tumor response and the size of the tumor . A PR was observed in 90% of patients with tumors smaller than 5 cm, but in only 60% of those with tumors greater than 5 cm. Nevertheless, in this study the rate of tumor response was influenced by neither tumor size nor the presence of a PVT. Therefore, an increased RT dose was concluded to be responsible for the improvement of the tumor response in the higher radiation dose group, although there was an imbalance in the tumor size and in the PVT proportion between each dose group.

Recently, a Michigan group published an article addressing a dose-response relationship for unresectable intrahepatic cancers. The group reported that higher radiation doses were associated with improved survival for patients treated with escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine, hypothesizing that the radiation dose would be a key determinant of tumor control. In our study, we provide evidence that escalating the radiation dose is the only significant factor for predicting an objective tumor response. We are now testing whether the improved tumor response by dose escalation could be correlated with improved survival. Further analysis of a possible influence of radiation dose on survival is ongoing.

The escalation of radiation dose is frequently accompanied by increased toxicity. In this study also, the rate of toxicity increased as radiation dose increased. Liver cirrhosis adds an extra disadvantage in the application of RT to HCC. In this study, 89.9% of patients had an associated LC. To prevent radiation-related complications, appropriate determination of the radiation field and radiation dose should be made; 3D-CRT seems to be helpful in this regard.

One of the shortcomings of this study was the failure to exclude the effects of concurrent treatments from the radiation effect. To be sure, most patients in our study were treated with another modality. The schedules of concurrent treatment were heterogeneous due to the retrospective nature of the study. The concurrent treatments consisted of systemic chemotherapy, transcatheter arterial chemo-infusion, and transcatheter arterial chemo-embolization. However, there was no difference between responders and nonresponders in the proportion of patients who received concurrent treatment.

In conclusion, the present study demonstrated a dose-response relationship in localized RT for primary HCC. The tumor response improved, but complications arising from increased RT doses were also observed. Dose escalation seems to be a very important issue, and 3D-CRT may play a key role in local RT for HCC.

Local radiotherapy for patients with unresectable hepatocellular carcinoma, 2 February 2005
Park W,
International Journal of Radiation Oncology*Biology*Physics
15 March 2005 (Vol. 61, Issue 4, Pages 1143-1150)

Between 1998 and 2002, 59 patients who were treated with localized RT were evaluated. RT was delivered with a curative intent, and the radiation dose was 30–55 Gy (biologic effective dose of 39.0–70.2 Gy10 using the α/β ratio of 10 Gy) with 2–3 Gy as a daily dose. The tumor response was evaluated by the change in maximum tumor size on serial CT scans, and the morbidity was evaluated by the Common Terminology Criteria for Adverse Events v3.0.

Results: An objective tumor response was achieved in 39 of 59 patients (66.1%) with complete response (CR) in 5 patients and partial response (PR) in 34 patients. More than 50 Gy10 had a significant response; CR or PR was 72.8% with >50 Gy10 and 46.7% with ≤50 Gy10 (p = 0.0299). The 2-year overall survival rate after RT was 27.4% (median survival time: 10 months), and this was affected by the tumor response (p = 0.0640); the 2-year overall survival rate after RT was 50.0% for CR and 21.8% for PR. There was no Grade 3 or 4 acute toxicity, and 3 patients (5.1%) developed gastric or duodenal ulcer.
Conclusions :Radiotherapy for unresectable HCC resulted in 66.1% of tumor response with acceptable toxicity, and the radiation dose seems to be a significant prognostic factor in RT response for HCC.