Clinical Applied Study Of Proton Beam Therapy For Hepatocellular Carcinoma

BackgroundThe prevalence rates of hepatocellular carcinoma (HCC) is rising worldwide, it is one of the most frequent cause of death in China. Although surgical resection remains the most standard and reliable curative modality for the treatment of HCC, a retrospective study demonstrated only 18% of the patients were surgically resectable, more than 80% of HCC patients are inoperable at the time of diagnosis owing to advanced tumors, ascites or coexisting cirrhosis. The management of technically unresectable and medically inoperable HCC remains challenging. HCC is highly resistant to currently available chemotherapeutic drugs. Liver transplantation might be better than resection for some of the unresectable patients. However, recurrence of malignant tumor within 6 to 24 months has been the usual outcome and immunosuppressive medication seems contradicting with respect to tumor control; this option is also dependent on the availability of vital organs, which are in short supply. Several treatment modalities are currently available for patients with HCC such as PEIT(percutaneous ethanol injection therapy), TACE(transarterial chemoembolization), RFA (radiofrequency ablation) and MCT (microwave coagulation therapy), although limitations of the above techniques relate to tumor size, number and location relative to blood vessels. A less-invasive and effective treatment modality is required for patients with HCC.Conventional radiotherapy has usually been considered to be of limited value for patients with HCC because the tolerance dose is 30Gy in 3 weeks when the entire organ is irradiated, which is considered lower than that necessary for tumor control Proton beams allow a rapidly increasing dose at the end of the beam range (Bragg peak) with which excellent dose localization to the target is obtained. Theoretically this should minimize the current limitation of normal liver tissue tolerance as the dose-limiting factor in radiation therapy in the treatment of HCC. That is, the absorption and distribution characteristics of proton beam therapy should allow much higher doses to be given to a tumor volume than conventional radiotherapy, while at the same time keeping doses to adjacent normal structures below tolerance levels. Advances in diagnosing imaging have allowed the boundaries of a tumor and areas of potential regions spread to be more precisely defined. Proton beam therapy enables the radiation oncologist to utilize this precision by being able to design and deliver treatments to define 3-dimensional volumes. A preliminary trial with proton beam therapy has been conducted with promising results at Wanjie Proton Therapy Center.Objectives1 A comparative dose distribution study has been undertaken between proton beam therapy(PBT),3-dimensional conformal radiation therapy(3D-CRT) and intensity-modulated radiation therapy(IMRT) in the treatment of hepatocellular carcinoma, so as to assess the dose distribution differences of normal liver tissues, V10Gy V20Gy and V30Gy (percentage volume of normal liver with radiation dose more than 10Gy,20Gy,30Gy) and organs at risk among PBT,3D-CRT and IMRT.2 To evaluate the feasibility, security, toxicity, effectiveness and prognostic factors of hepatocellular carcinoma treated by proton beam therapy.Materials and Methods1 Twenty two patients who refused being treated with surgery or unresectable patients with stage I-IIA HCC treated at Wanjie Proton Therapy Center during April 2005 to May 2008 were studied. Seventeen patients were diagnosed based on cytology. Five patients who refused accepting biopsy were based clinically upon CT/MRI imaging and elevated AFP value of 400μg/L or higher. The treatment planning system were Eclipse Proton, Eclipse Photon and inverse IMRT from Varian Medical System, Inc.,Palo Alto, CA, USA. Immobilization and simulation:the patient was in supine position and immobilized with a custom-made vacuum frame. Routine CT scan was done with and without enhancement with a 8-slice helical CT from GE Medical Systems Inc., Milwaukee, WI, USA. A CT slice thickness of 5 mm was used. Pre-contrast CT images were used for stopping power correction instead of enhancement CT images in case of affection of the contrast agent. The criteria for HCC diagnosing and staging made by Chinese Society of Liver Cancer at Guangzhou in 2001 was used. Dose-volume histograms(DVHs) were compared between PBT and 3D-CRT or IMRT planning at a total dose of 66Gy and 86Gy in stage I patients (n=10, diameter≤5cm),60Gy and 72Gy in stage IIA patients (n=12, diameter=5.1-10cm). The same target contouring method was use for comparison of the dose distribution of the three treatment techniques. GTV was defined from the fused images (precontrast and contrast CT images), CTV was defined as GTV plus a 0.5cm margin. PTV was defined as CTV plus a 1.5 to 2.5cm margin (head-foot direction) and a 1.0 to 1.5cm margin (left-right direction) account for ventilatory motion, determined using flouroscopy. Normal liver tissues and organs at risks (spinal cord, right kidney and stomach) were also defined.2 to 3 beams and 3 to 5 beams were used for PBT and 3D-CRT respectively. For patients in stage IIA, IMRT planning were performed with step and shoot technique,5 coplanar beams were used. An aperture block was designed to project outside of the target by a distance determined from the user input parameter aperture margin for each proton beam. To make better lateral conforming and minimize the lateral scattering, a compensator was designed to shape the distal edge upon different shape of the tumor and body surface and different density of the tissues for each proton beam. Proton beam was generated with a 230MeV fixed energy cyclotron (IBA Inc., Belgium) and 70 to 230MeV proton beam could be produced through a degrader. The maximum energy of the proton beam used for the treatment and the SOPB (spread out Bragg peak) could be given through the treatment planning system(TPS). A range modulator was used to get the SOBP to have a better coverage of the PTV. Double scattering mode was used in this study. Our goal was to have 90%-95% PTV coverage and±3% homogeneity in the final DVHs analysis. The same criterion was used for the three techniques upon report ICRU 62(the international commission on radiation units and measurements). A relative biologic effectiveness (RBE) factor for protons of 1.1 (relative to 60Cobalt) was employed, and proton dose was expressed in terms of cobalt Gray equivalent (CGE,1 proton Gray=1.1CGE). DVHs were used for comparison. Evaluation parameters included(1) mean dose, V10Gy,V20Gy and V30Gy dose to the normal liver tissues;(2) dose to the OARs—maximum dose to the spinal cord and mean dose to right kidney and stomach. Paired t test was used for comparisons (SPSS software; SPSS Inc., Chicago, IL, USA). A two-tailed p<0.05 was accepted as statistically significance.2 Between April 2004 and May 2010, seventy five patients with HCC received PBT at Wanjie Proton Therapy Center. The patients were grouped based on the criterion made by Chinese Society of Liver Cancer (CSLC) in Sep.,1999 at Guangzhou, there were 26 patients with I-IIA HCC and 49 patients with IIB-IIIA.43 patients had Child-Pugh Grade A cirrhosis and 32 patients had Child-Pugh Grade B cirrhosis. All patients received a total dose of 50-78Gy,2-6Gy per fraction and 3-6 fractions per week.Results1 For patients with stage I, the mean liver dose(Dmean), V10Gy,V20Gy and V30Gy were 13.01Gy,51.89%,36.13% and 21.24% for 3D-CRT, whereas they were 6.34Gy, 30.23%,17.86% and 10.66%, respectively, for PBT(p<0.002). With dose escalation to 86Gy, the Dmean,V10Gy,V20Gy and V30Gy were 16.91Gy,67.51%,46.84% and 27.61% for 3D-CRT, whereas they were 8.26Gy,39.31%,23.22% and 13.86%, respectively, for PBT(p<0.002). Compared with 3D-CRT with dose of 66Gy, PBT reduced the Dmean, V10Gy,V20Gy and V30Gy even with dose escalation to 86Gy(p< 0.042). For patients with stage IIA, the Dmean,,V10Gy,V2oGy and V30Gy were 29.18Gy, 72.25%,58.17%,44.01% and 24.92Gy,73.32%,56.15%,37.75% for 3D-CRT and IMRT, respectively, with dose of 60Gy, whereas they were 16.28Gy,43.93%,33.54% and 22.78%, respectively, for PBT(p<0.002). With dose escalation to 72Gy, the Dmean, V10Gy,V20Gy,V30Gy were 35.02Gy,86.70%,69.80%,52.81% and 29.90Gy, 87.98%,67.74% and 45.30% for 3D-CRT and IMRT, respectively, whereas they were 19.54Gy,52.72%,40.25% and 27.34%, respectively, for PBT (p<0.002). Compared with 3D-CRT and IMRT with total dose of 60Gy, PBT reduced the Dmean, V10Gy,V20Gy and V30Gy even with dose escalation to 72Gy(p<0.05). In all of the 22 cases, compared with 3D-CRT, PBT reduced the doses to the organs at risks (OARs) including spinal cord, right kidney and stomach(p<0.002). Compared with IMRT, PBT also reduced the dose to the right kidney and stomach significantly(p<0.05), while no significant difference was found with respect to the dose to spinal cord (p> 0.05).2 The complete response (CR) and partial response (PR) was 26.7% and 58.7% respectively. The total response rate was 85.3%. The overall 1 year and 3 years survival rates were 72.2% and 36.4% respectively. The clinical staging, Child-Pugh class, portal vein thrombosis, size and number of the tumors and BED were significantly correlated with the prognosis by individual analysis. A multivariate analysis showed that clinical staging, portal vein thrombosis and number of the tumors were associated with prognosis.Conclusions1 Compared with 3D-CRT, PBT reduced the dose to the normal liver tissues and OARs significantly, even with 20%-30.3% of dose escalation. Compared with IMRT, PBT reduced the dose to the normal liver tissues significantly; PBT reduced the dose to the right kidney and stomach significantly; no significant difference was observed with respect to the dose to spinal cord.2 PBT is a non-invasive technique highly suitable for HCC with tolerable side-effect. Clinical staging, portal vein thrombosis and number of the tumors are individual prognostic factors.