Clinical trial NCT02640924: Proton Radiotherapy Versus Radiofrequency Ablation for Patients With Medium or Large Hepatocellular Carcinoma
Official title: Proton Beam Radiotherapy Versus Switching Control Radiofrequency Ablation for Patients With Medium (>3, ≦5 cm) or Large (>5, ≦7cm) Treatment-naive Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Carcinoma, Hepatocellular
Keywords: Hepatocellular carcinoma
Proton therapy
Radiation therapy
Switching control radiofrequency ablation
Lead sponsor: Chang Gung Memorial Hospital
Sponsor class: OTHER
First posted: 2015-12-29
Enrollment: 166
Sex: ALL
Minimum age (years): 20
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Hepatocellular carcinoma (HCC) is one of the most common cancers in Taiwan, where chronic viral hepatitis is common. Patients with HCC typically have impaired liver function because of virus- or alcohol- induced cirrhosis and viral hepatitis, and only approximately 20% of them are appropriate candidates for surgery. The 5-year overall survival for patients treated by surgery is approximately 30%-70%. For those not treated with surgery, liver function affected by an underlying liver disease has a strong influence on clinical outcomes, and complicates treatment strategies further than for other tumors. Maximal preservation of normal liver volume and function is an important consideration in the choice of treatment.

Proton beam has been applied to HCC treatment in Japan for longer than a decade, and several retrospective results showed excellent 3-5 years local control rate ranging from 85-95% and nearly no major complications. The investigators also retrospectively reviewed 75 index tumors sized 3.1-7.0cm in 70 patients receiving multiple-electrode radiofrequency ablation with switching controller (ME-SWC RFA) treatments in the period between 1 January 2009 and 31 December 2011 (Oral report in Taiwan Digestive Disease Week, October, 2012). Estimated 1-, 2-, and 3-year cumulative overall survival rates and local control rates were 94%, 85%, 81% and 89%, 83%, 67%, respectively.

Since ME-SWC RFA is the present one of standard modalities for non-surgery, moderate to larger (3-7 cm) HCC, and based on retrospective studies the local control rate of proton therapy was better than radiofrequency ablation, this prospective trial is aimed to compare the effects of these two modalities in 3-7 cm HCC patients who are not candidates for surgery or refuse surgery. This prospective study has high possibility to confirm the role of proton beam in HCC.

Along with the clinical trial, the investigators will also use next generation sequencing (NGS) to exam gene expression profile of tumor samples and find out candidate genes related to local control, intrahepatic control (treatment out-field control in liver), regional lymph node relapse, distant metastasis, and treatment response in HCC.


Eligibility criteria: Inclusion Criteria:

* Pathologically confirmed hepatocellular carcinoma or lesion with typical triphasic CT or MRI imaging features for HCC
* Single tumor and tumor size \> 3cm, ≦7cm in diameter
* Patients are unsuitable for resection or unwilling to accept surgery.
* Age ≥20 years old
* Eastern Cooperative Oncology Group performance status score of 0 or 1
* Child-Pugh score ≦ 8
* Willing to sign informed consent regarding participation in this study

Exclusion Criteria:

* Patients have received any treatment for HCC before this study
* Pregnancy/breast feeding women
* Tumor adjacent to bowel \<1cm
* Extrahepatic metastasis
* Extrahepatic invasion
* Portal or hepatic vein tumor invasion/thrombosis
* Uncontrolled ascites
* Glomerular filtration rate (GFR) \< 30 ml/min\*
* Platelet count \< 50,000/L\*
* Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 5 years
* Ongoing medically significant active infection.
* MRI incompatible devices
* \* Baseline laboratories results must be within the protocol range prior to sign informed consent. Repeat lab tests are permitted to evaluate eligibility during the Screening Period.

Primary outcomes:
measure: Local control rate (treatment in-field control rate)
timeFrame: 3-year
Secondary outcomes:
measure: Overall survival rate
timeFrame: 3-year
measure: Intrahepatic control rate
timeFrame: 3-year
measure: Distant metastasis free survival rate
timeFrame: 3-year
measure: Local control rate (treatment in-field control rate)
timeFrame: 5-year
measure: Overall survival rate
timeFrame: 5-year
measure: Intrahepatic control rate
timeFrame: 5-year
measure: Distant metastasis free survival rate
timeFrame: 5-year
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 3-year
measure: Patient report outcome - quality of life as assessed by the functional assessment of cancer therapy - hepatobiliary (FACT-Hep)
timeFrame: 3-year
measure: Patient report outcome - fatigue as assessed by the functional assessment of cancer therapy (FACT-F)
timeFrame: 3-year
measure: Patient report outcome - pain as assessed by the brief pain inventory-short form (BPI-SF)
timeFrame: 3-year
measure: Patient report outcome - symptom distress as assessed by the Memorial symptom assessment scale-short form (MSAS-SF)
timeFrame: 3-year
measure: Patient report outcome - treatment satisfaction as assessed by the functional assessment of chronic illness therapy-treatment satisfaction-general (FACIT-TS-G)
timeFrame: 3-year
measure: Patient report outcome - quality of life as assessed by the EQ-5D-3L
timeFrame: 3-year
Other outcomes:
Locations:
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital, Linkou
Study officials:
affiliation: Chang Gung Memorial Hospital
name: Shi-Ming Lin, MD
role: STUDY_CHAIR
References:
citation: Kan Z, Zheng H, Liu X, Li S, Barber TD, Gong Z, Gao H, Hao K, Willard MD, Xu J, Hauptschein R, Rejto PA, Fernandez J, Wang G, Zhang Q, Wang B, Chen R, Wang J, Lee NP, Zhou W, Lin Z, Peng Z, Yi K, Chen S, Li L, Fan X, Yang J, Ye R, Ju J, Wang K, Estrella H, Deng S, Wei P, Qiu M, Wulur IH, Liu J, Ehsani ME, Zhang C, Loboda A, Sung WK, Aggarwal A, Poon RT, Fan ST, Wang J, Hardwick J, Reinhard C, Dai H, Li Y, Luk JM, Mao M. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 2013 Sep;23(9):1422-33. doi: 10.1101/gr.154492.113. Epub 2013 Jun 20.
citation: Mizumoto M, Okumura T, Hashimoto T, Fukuda K, Oshiro Y, Fukumitsu N, Abei M, Kawaguchi A, Hayashi Y, Ookawa A, Hashii H, Kanemoto A, Moritake T, Tohno E, Tsuboi K, Sakae T, Sakurai H. Proton beam therapy for hepatocellular carcinoma: a comparison of three treatment protocols. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):1039-45. doi: 10.1016/j.ijrobp.2010.07.015. Epub 2010 Oct 1.
citation: Seror O, N'Kontchou G, Ibraheem M, Ajavon Y, Barrucand C, Ganne N, Coderc E, Trinchet JC, Beaugrand M, Sellier N. Large (>or=5.0-cm) HCCs: multipolar RF ablation with three internally cooled bipolar electrodes--initial experience in 26 patients. Radiology. 2008 Jul;248(1):288-96. doi: 10.1148/radiol.2481071101. Epub 2008 May 15.
citation: Lee J, Lee JM, Yoon JH, Lee JY, Kim SH, Lee JE, Han JK, Choi BI. Percutaneous radiofrequency ablation with multiple electrodes for medium-sized hepatocellular carcinomas. Korean J Radiol. 2012 Jan-Feb;13(1):34-43. doi: 10.3348/kjr.2012.13.1.34. Epub 2011 Dec 23.
citation: Lee JM, Han JK, Kim HC, Kim SH, Kim KW, Joo SM, Choi BI. Multiple-electrode radiofrequency ablation of in vivo porcine liver: comparative studies of consecutive monopolar, switching monopolar versus multipolar modes. Invest Radiol. 2007 Oct;42(10):676-83. doi: 10.1097/RLI.0b013e3180661aad.