Dose-response relationship for lung cancer induction at radiotherapy dose

Cancer induction after radiation therapy is a severe side effect. It is therefore of interest to predict the probability of second cancer appearance for the treated patient. Currently there is large uncertainty about the shape of the dose-response relationship for carcinogenesis for most cancer types at high dose levels. In this work a dose-response relationship for lung cancer is derived based on (i) the analysis of lung cancer induction after Hodgkin's disease,(ii) a cancer risk model developed for high doses including fractionation based on the linear quadratic model, and(iii) the reconstruction of treatment plans for Hodgkin's patients treated with radiotherapy.The fitted model parameters for an α/β = 3 Gy were α = 0.061Gy^?1 and R = 0.84. The value for α is in agreement with analysis of normal tissue complications of the lung after radiation therapy. The repopulation/repair parameter R is large, but seems to be characteristic for lung tissue which is sensitive with regard to fractionation. Lung cancer risk is according to this model for small doses consistent with the finding of the A-bomb survivors, has a maximum at doses of around 15 Gy and drops off only slightly at larger doses. The predicted EAR for lung after radiotherapy of Hodgkin's disease is 18.4/10000PY which can be compared to the findings of several epidemiological studies were EAR for lung varies between 9.7 and 21.5/10000PY.     

肝细胞肝癌放射治疗研究进展

肝细胞肝癌（hepatocellular carcinoma,HCC）是世界范围内癌症死亡率较高的肿瘤之一。肝切除术（partial hepatectomy）是重要的治疗手段,然而,许多患者因肿瘤分期晚或潜在的慢性肝病和/或肝硬化不能接受肝切除术或肝移植术(liver transplantation)。此类患者,目前可选择肝动脉栓塞化疗（transarterial chemoembolization,TACE）、射频消融（radiofrequency ablation,RFA）、放射治疗、靶向治疗及免疫治疗等方法。肝癌诊断、治疗方式、对肝脏辐射耐受性的生物学理解和放疗技术的进步使得肝癌放射治疗的有效性和安全性都在不断提高,肝癌患者的生存和预后不断改善。     

Dose-response relationship for radiation-induced pneumonitis after pulmonary stereotactic body radiotherapy

Purpose

To evaluate dosimetric factors predictive for radiation-induced pneumonitis (RP) after pulmonary stereotactic body radiotherapy (SBRT).

Materials and methods

A retrospective analysis was performed based on 59 consecutive patients treated with cone-beam CT-based image-guided SBRT for primary NSCLC (n = 21) or pulmonary metastases (n = 54). The majority of patients were treated with radiosurgery of 26 Gy to 80% (n = 29) or three fractions of 12.5 Gy to 65% (n = 40). To correct for different single fraction doses, local doses were converted to 2 Gy equivalent normalized total doses (NTDs) using α/β ratio of 3 Gy for RP. Dose-volume parameters and incidences of RP ? grade II SWOG were fitted using NTCP models.

Results

Eleven patients developed RP grade II. With an average MLD of 10.3 ± 5.6 Gy to the ipsilateral lung, a significant dose-response relationship was observed: the MLD was 12.5 ± 4.3 Gy and 9.9 ± 5.8 Gy for patients with and without development of RP, respectively. Additionally, volumes of the lung exposed to minimum doses between 2.5 and 50 Gy (V_2.5-V₅₀) were correlated with incidences of RP with a continuous decrease of the goodness of fit for higher doses.

Conclusions

The MLD and V_2.5-V₅₀ of the ipsilateral lung were correlated with incidences of RP after pulmonary SBRT.     

Combined transcatheter arterial chemoembolization and local radiotherapy of unresectable hepatocellular carcinoma

PURPOSE: The best prognosis in hepatocellular carcinoma (HCC) can be achieved with surgical resection; however, the number of resected cases are limited due to advanced lesions or associated liver disease. The purpose of this study was to investigate the efficacy and toxicity of a prospective trial of combined transcatheter arterial chemoembolization (TACE) and local radiotherapy (RT) in unresectable HCC. METHODS AND MATERIALS: Patients with histologically proven unresectable HCC due to either advanced lesions or associated cirrhosis were eligible. From March 1992 to August 1994, 30 patients were entered into this study. TACE was performed with Lipiodol (5 ml) and doxorubicin (Adriamycin ; 50 mg), followed by gelatin sponge particle (Gelfoam) embolization. Local RT was started within 7-10 days following TACE. Mean tumor dose was 44.0+/-9.3 Gy in daily 1.8 Gy fractions. Response was assessed by computerized tomography (CT) scan 4-6 weeks following completion of the treatment and then at 1-3-month intervals. Survival was calculated from the start of TACE using the Kaplan-Meier method. RESULTS: An objective response was observed in 19 patients, giving a response rate of 63.3%. Distant metastasis occurred in 10 patients, with 8 in the lung only and 2 in both lung and bone. Survival rates at 1, 2, and 3 years were 67%, 33.3%, and 22.2%, respectively. Median survival was 17 months. There were 6 patients surviving more than 3 years. Toxicity included transient elevation of liver function tests in all patients, fever in 20, thrombocytopenia in 4, and nausea and vomiting in 1. There was no treatment-related death. CONCLUSION: Combined TACE and local RT is feasible and tolerable. It gives a 63.3% response rate with median survival of 17 months. We feel that this regimen would be a new promising modality in unresectable HCC. Further study is required to compare the therapeutic efficacy of this regimen to TACE alone.     

Dose-response relationship and dose optimization in radiotherapy of postoperative keloids

Background and purpose

The treatment dose and fractionation dose that are considered in postoperative keloids had been reported in the previous studies. We performed retrospective analysis to elucidate the factors influencing the treatment outcome.

Materials and methods

From 1979 to 1994, 194 lesions in 119 patients received postoperative radiotherapy after excision with the total dose ranging from 16 Gy/8 fr to 40 Gy/8 fr (mean: biologically effective dose (BED) 33.5 Gy). Kilo-voltage X-rays (55 or 100 kVp) or electron beams (4 or 6 MeV), including entire keloid scars, and any suture/puncture holes with a margin around the lesion were used. The median follow-up period was 36 months (range 12-164 months).

Results

Symptomatic pain and itching relief were achieved in 96% and 91%, respectively. The relapse rate was 11% at 20 Gy in five fractions or higher dose, while 43% at less than 20 Gy. On the other hand, the incidence of adverse effects was significantly higher for patients receiving more than 20 Gy in five fractions.

Conclusion

There was a significant correlation between the relapse rate and the total dose of irradiation, and between adverse effects and the total dose. To correlate local control and adverse effects, we proposed 20 Gy in five fractions as the optimal dose for the postoperative of keloids. A significant correlation between relapse rate and the interval time between excision and radiotherapy was not found in our current study.     

Pilot study of local radiotherapy for portal vein tumor thrombus in patients with unresectable hepatocellular carcinoma

BACKGROUND: Patients suffering from hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) generally have a poor prognosis. We therefore conducted a prospective pilot trial of combined transcatheter arterial chemoembolization (TACE) and local radiotherapy (RT) for PVTT in unresectable HCC. The aim of the study was to investigate the efficacy and toxicity of this preliminary trial regime and to explore RT guidelines for cirrhosis. METHODS: Eight patients with unresectable HCC accompanied by first branch PVTT were entered into the study from February 1998 to December 1999. TACE was performed using Lipiodol, epirubicin hydrochloride and mytomycin followed by gelatin sponge cubes. RT was started 10-14 days following TACE. A total delivered dose of 60 Gy was given as daily 2 Gy fractions, with the clinical target volume defined as PVTT only. We observed a relationship between deterioration of liver function and the percent volume of the total liver receiving a dose exceeding 30 Gy (V30). RESULTS: An objective response was observed in three of the eight patients. However, on follow-up angiograms the protrusion of PVTT into the main portal trunk was decreased in all cases. Deterioration of liver function was observed in all patients with V30 >40%. CONCLUSION: It is possible that this combined therapy prevents PVTT from spreading to the main trunk and that indicates a further benefit of TACE. Our results indicate that V30 constitutes a predictive test for the development of liver failure. More detailed evaluations of liver function and determination of the safe irradiation volume are necessary.     

肝细胞癌外照射放疗的研究进展

肝细胞癌（hepatocellular carcinoma,HCC）的根治性治疗方式主要为行手术切除、肝移植或消融术。然而,就诊时仅少数病例为可切除病变。随着放疗技术的发展,外照射放疗在HCC治疗中的应用越来越广泛。大量研究表明,放疗对肝功能良好的各期别肝癌均具有明显疗效。立体定向放射治疗（stereotactic body radiation therappy,SBRT）可替代射频消融治疗不可行手术切除的早期HCC,放疗联合其他局部或全身治疗, 如:经导管动脉化学栓塞（transcatheter arterial chemoembdization,TACE）、索拉非尼适用于局部晚期和远处转移晚期HCC的治疗。粒子束因Bragg峰而较X线具有更佳的剂量分布优势,临床应用前景广阔。本文重点阐述外照射放疗在各期别HCC治疗中的进展。      

Local radiotherapy for patients with unresectable hepatocellular carcinoma

PURPOSE: To evaluate the response to local radiotherapy (RT) for unresectable hepatocellular carcinoma (HCC) and to analyze the dose-response relationship and the treatment-related morbidities. METHODS AND MATERIALS: 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 Gy(10) using the alpha/beta 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 Gy(10) had a significant response; CR or PR was 72.8% with >50 Gy(10) and 46.7% with < or =50 Gy(10) (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.     

Technical considerations for fractionated stereotactic radiotherapy of hepatocellular carcinoma

Technical aspects of fractionated stereotactic radiotherapy for solitary hepatocellular carcinoma have been investigated. Precise positioning of the patient and substantial reduction of the liver movement due to respiration were achieved by placing the patient ventrally on the treatment couch without a body cast. Repeated CT examinations were required for verification of tumor targeting. Though there were geometrical limitations on gantry rotation when the linac couch was rotated from its standard position, dose distributions obtained were found to be excellent. A patient with a small solitary lesion in the posterior segment of the liver received 52 Gy in 13 fractions over 29 days. He tolerated the treatment well without experiencing any morbidities or deterioration of liver functions. Three months later his alpha-fetoprotein value returned to normal and CT examinations revealed tumor shrinkage as well as a reduction in the viability of the tumor cells. The results suggest that it is possible to overcome technical difficulties associated with fractionated stereotactic radiotherapy of intraabdominal tumors.      

放射治疗在原发性肝癌治疗中的应用进展

原发性肝癌为临床上常见的恶性肿瘤之一,手术及化疗等治疗疗效较为局限.作为非手术治疗方式之一的放射治疗近年来在肝癌的治疗方面取得了较大的进步与发展.本文就肝癌放射治疗的应用进展做一综述.     

原发性肝癌外放疗临床应用现状

目的总结外放疗对肝癌的临床应用。方法应用PubMed及CNKI期刊全文数据库检索系统,以"原发性肝癌、精确放疗"为中文关键词,检索1992-2014年的相关文献,共检索到英文文献222条,中文文献50条。纳入标准:1)原发性肝癌放疗与预后的关系;2)肝癌精确放疗定位技术的应用。根据纳入标准,符合分析文献37篇。结果精确放疗在肝癌综合治疗中发挥着重要作用,呼吸门控、图像引导放疗及四维放疗定位技术应用能够减小靶区的移位,降低正常组织的受照剂量,提高肿瘤靶区剂量。外放疗技术包括三维适形放疗(three-dimensional conformal radiotherapy,3DCRT)、调强适形放疗(intensity-modulated radiationtherapy,IMRT)、立体定向放疗和质子放疗等的发展,能够使局部肝脏肿瘤接受高剂量照射的同时显著减少正常肝组织受照剂量,不良反应较小,改善了中晚期肝癌患者的预后。结论精确外放疗对肝癌的治疗和预后有重要意义。     

Study of local three-dimensional conformal radiotherapy combined with transcatheter arterial chemoembolization for patients with stage III hepatocellular carcinoma

The purpose of this study was to evaluate treatment-related toxicity, outcome, patterns of failure, and prognostic factors for patients with stage III unresectable hepatocellular carcinoma (HCC) treated with a combination of local 3-dimensional conformal radiotherapy (3D-CRT) and transcatheter arterial chemoembolization (TACE) under the support of G-CSF. From October 1997 to August 2001, 45 patients with stage III unresectable hepatocellular carcinoma underwent transcatheter arterial chemoembolization with local 3D-CRT. Twenty-seven patients were classified as having stage IIIA disease according to the American Joint Committee on Cancer (AJCC) staging system and 18 were classified as stage IIIB. The mean diameter of the treated hepatic tumor was 8.5 cm. Before 3D-CRT, 2 cycles of transcatheter arterial chemoembolization were prescribed. Forty-eight hours later, the G-CSF was prescribed for 5 days after the completion of every TACE. With the interval of 10 to 14 days after the second cycle of TACE, 3D-CRT was prescribed to all patients with a total dose of 50.4 Gy at 1.8 Gy per fraction 5 days per week. After the completion of 3D-CRT, the additional 2 cycles of TACE were given. All patients were monitored for treatment-related toxicity, outcome, patterns of failure, causes of death, and prognostic factors. Forty-two of 45 patients were treated smoothly with the primary schedule. In a median follow-up period of 27 months, 22 patients were alive and 23 were dead. Progressive disease occurred in 28 patients, including local recurrence alone (4 patients), distant metastases with local recurrence (8 patients), and distant metastases alone (16 patients). Nine patients developed radiation-induced liver disease (RILD). Three patients had treatment-related gastrointestinal bleeding. There were 2 treatment-related deaths, including 1 from RILD and 1 from gastrointestinal bleeding. Complete regression (CR) was observed in 6 patients, partial regression (PR) in 35 patients, and stable disease (SD) in 4 patients. The median overall survival duration from treatment was 23.5 months with a 1-year overall survival rate of 68.5%, a 2-year survival rate of 48.3%, and a 3-year survival rate of 22.6%. The median freedom from progressive disease survival duration from treatment was 25 months with 1-year, 2-year, and 3-year progression-free survival rates of 76.2%, 56.8%, and 42.4%, respectively. The stage of HCC, regional lymph node status, portal vein thrombosis, pretreatment alpha-fetoprotein level (AFP), and tumor size affected the treatment outcomes significantly. Therefore, for patients with stage III unresectable hepatocellular carcinoma, combined local 3D conformal radiotherapy with transcatheter arterial chemoembolization under the support of G-CSF is an effective treatment protocol. Further research is required to decrease distant metastases and to determine the safe irradiation dose-volume.     

肝细胞癌放疗靶区勾画的研究进展

CT、MRI、PET-CT等现代影像学设备使肝细胞癌GTV的精确勾画成为可能,通过比较术后病理亚临床病灶、影像及临床指标等有助于CTV精确勾画,放疗辅助技术(如4DCT、腹部压迫、自主呼吸控制和呼吸门控等)可缩小ITV。真空袋和体膜固定可减小摆位误差,减小PTV和避免或减少照射误差。通过这些方法使肝细胞癌放射治疗的靶区缩小、剂量提升和并发症降低得以实现。本文就肝细胞癌外照射放射治疗靶区的研究进展作一综述。     

Evaluation of response after stereotactic body radiotherapy for hepatocellular carcinoma

BACKGROUND:

Hepatocellular carcinoma (HCC) is increasing in incidence due to hepatitis C. Stereotactic body radiotherapy (SBRT) is a noninvasive, effective therapy in the management of liver malignancies. The authors evaluated radiological response in 26 patients with HCC treated with SBRT at Indiana University.

METHODS:

Between March 2005 and June 2008, 26 patients with HCC who were not surgical candidates were enrolled in a phase 1 to 2 trial. Eligibility criteria included solitary tumors ≤ 6 cm or up to 3 lesions with sum diameters ≤ 6 cm, and well‐compensated cirrhosis. All patients had imaging before, at 1 to 3 months, and every 3 to 6 months after SBRT.

RESULTS:

Patients received 3 to 5 fractions of SBRT. Median SBRT dose was 42 Gray (Gy) (range: 24‐48 Gy). Median follow‐up was 13 months. Per Response Evaluation Criteria in Solid Tumors (RECIST), 4 patients had a complete response (CR), 15 had a partial response (PR), and 7 achieved stable disease (SD) at 12 months. One patient with SD experienced progression marginal to the treated area. The overall best response rate (CR + PR) was 73%. In comparison, by European Association for the Study of the Liver (EASL) criteria, 18 of 26 patients had ≥ 50% nonenhancement at 12 months. Thirteen of 18 demonstrated 100% nonenhancement, being > 50% in 5 patients. Kaplan‐Meier 1‐ and 2‐year survival estimates were 77% and 60%, respectively.

CONCLUSIONS:

SBRT is effective therapy for patients with HCC with an overall best response rate (CR + PR) of 73%. Nonenhancement on imaging, a surrogate for ablation, may be a more useful indicator than size reduction in evaluating HCC response to SBRT in the first 6 to 12 months, supporting EASL criteria. Cancer 2012;118: 3191–98. © 2011 American Cancer Society.     

Three-dimensional conformal radiotherapy for portal vein thrombosis of hepatocellular carcinoma

BACKGROUND: Portal vein thrombosis (PVT) is a common complication in patients with advanced-stage hepatocellular carcinoma (HCC). The authors evaluated the impact of radiotherapy (RT) for PVT of HCC and analyzed the dose-response relation between RT and PVT. METHODS: Between March 1995 and December 2003, 59 patients diagnosed as HCC with PVT were included. The inclusion criteria were unresectable tumor with thrombosis in the main or first branch of the portal vein, liver function of Child-Pugh Class A or B, and an Eastern Cooperative Oncology Group performance status score of 0-2. The median age of the patients was 57 years (range, 36-78 years). A daily dose ranging from 2 to 3 gray (Gy) was administered using 6 or 10-megavolt (MV) X-rays, at 5 fractions a week, to deliver a total dose range of 30-54 Gy, which was a biologic effective dose of 39-70.2 Gy(10) with an alpha/beta ratio of 10. RESULTS: Follow-up computed tomography scans showed a complete response (CR) in 4 of 59 patients (6.8%), a partial response (PR) in 23 patients (39.0%), no response (NR) in 28 patients (47.5%), and progressive disease (PD) in 4 patients (6.8%). The mean RT doses in the responders (CR and PR) and nonresponders (NR and PD) were 59.6 +/- 5.6 Gy(10) and 54.9 +/- 8.5 Gy(10), respectively (P = 0.036). The response rates in patients receiving < 58 Gy(10) and > or = 58 Gy(10) were 20% and 54.6%, respectively (P = 0.034). The median survival duration and the 1-year and 2-year survival rates in the responders were 10.7 months, 40.7%, and 20.7%, respectively, and were 5.3 months, 25.0%, and 4.7%, respectively, in the nonresponders (P = 0.050). CONCLUSIONS: RT induced a 45.8% objective response rate for PVT in patients with HCC. A dose-response relation was found to exist between the RT dose and PVT response. These results suggested that RT may be a treatment option for PVT in patients with HCC and that an RT dose > or = 58 Gy(10) should be recommended.