A pilot study of three-dimensional conformal radiotherapy in unresectable hepatocellular carcinoma

A pilot study of three-dimensional conformal radiotherapy in unresectable hepatocellular carcinoma
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   Journal of Gastroenterology and Hepatology (1999) 14 ,1025–1033 choice.However,approximately only one of fivepatients is amenable to surgery at the time of diagno-sis. 2,3 Ethanol injection treatment has become an effec-tive alternative treatment for small tumours in recentyears. 4 For patients with unresectable HCC,treatmentcombining intra-arterial embolization with lipiodol,an iodized oily contrast agent,and intra-arterialchemotherapy is believed to be most effective on the See editorial on page 941. INTRODUCTION Hepatocellular carcinoma (HCC) is the leading causeof cancer death in Taiwan and several other countriesin Asia. 1,2 Surgical resection remains the treatment of  HEPATOBILIARY AND PERITONEAL DISEASES A pilot study of three-dimensional conformal radiotherapy inunresectable hepatocellular carcinoma SKYE HONGIUN CHENG,* YU-MONG LIN, † VINCENT P CHUANG, ‡ PO-SHENG YANG, §  JASON CHIA-HSIEN CHENG,* ANDREW T HUANG †¶ AND JUEI-LOW SUNG † Departments of * Radiation Oncology, † Internal Medicine, ‡ Radiology and § Surgical Oncology, Koo Foundation,Sun Yat-Sen Cancer Center,Taipei,Taiwan and  ¶ Department of Medicine,Duke University Medical Center,Durham,North Carolina,USA Abstract  Background  :The purpose of this study was to determine the potential role of three-dimensional (3-D) conformal radiotherapy (RT) in treatment of unresectable hepatocellular carcinoma (HCC).  Methods :Thirteen patients were included in this study,which was conducted between 1993 and 1996.Nine patients (group A) were treated with 3-D conformal RT alone because of main portal vein throm-bosis,inferior vena cava thrombosis,obstructive jaundice and failure of previous transcatheter arterialchemoembolization (TACE) to control the disease.The remaining four patients (group B) were treatedwith a combination of TACE and 3-D conformal RT.  Results :The greatest dimension of the main tumour in the whole group of patients ranged from 6 to25cm (median 15cm).The radiation dose ranged from 40 to 60Gy.The tumour response was evalu-ated by computed tomography scans of the liver 6–8 weeks after completion of radiotherapy.Partialresponse was observed in 58% of the patients (seven of 12) and minimal response in another 25% of patients (three of 12).One patient could not be evaluated because of the development of hepatic failure1 month after completion of RT.All patients in group B lived for more than 1 year (range 16–40months).In group A,one patient who had a large tumour (11 ¥ 10 ¥ 21cm) with portal vein thrombo-sis was converted to become resectable after 45Gy of radiation.The resection specimen revealed noresidual cancer cells.This patient is alive longer than 15 months after treatment without the evidenceof disease. Conclusions :Our experience indicates that HCC is more radiosensitive than it was traditionallyexpected.Three-dimensional reconstruction of tumour and surrounding organs helps to avoid exces-sive exposure of the liver and adjacent organs to RT and makes it a safer treatment modality for unre-sectable HCC.Our preliminary data show promise and are worthy of further study to explore thepotential role of radiotherapy in the treatment strategy for HCC at various stages of involvement.© 1999 Blackwell Science Asia Pty Ltd Key words :conformal radiotherapy,hepatocellular carcinoma,transcatheter arterial chemoemboliza-tion. Correspondence:Dr SH Cheng,Department of Radiation Oncology,Koo Foundation Sun Yat-Sen Cancer Center,no.125,Lih-Der Road,Pei-Tou District,Taipei,Taiwan.Email:<>Accepted for publication 14 January 1999.  basis that it significantly decreased tumour volume 5–8 and was more effective than systemic chemotherapy. 9 However,prospective randomized studies failed to showsignificant survival benefit with transcatheter arterialchemoembolization (TACE) over conservative manage-ment in a group of patients with unresectable HCC. 10,11 Thus,there is room for development of more effectivetreatment modalities for HCC.Radiotherapy (RT) is infrequently used in the treat-ment of HCC.The major drawbacks with RT are thepoor radiation tolerance of normal liver and the difficultyin tumour localization.The radiation treatment volumebefore the advent of computed tomography (CT)-assisted radiation treatment planning usually includedthe whole liver.It,thus,limited the dose of radiation tobe below 30–35Gy.With this low dose of radiation theresponse of the unresectable HCC is unsurprisinglydismal. 12–14 Several methods have been designed todeliver higher radiation dosage to hepatic tumours.TheRadiation Therapy Oncology Group reported that 105patients who had unresectable HCC had whole-livertreatment with external beam radiation and chemo-therapy,followed by [ 131 I]-antiferritin infusion.Thepartial response rate after external beam irradiation of 21Gy was 23% and,after an additional two courses of [ 131 I]-antiferritin infusion of 10–12Gy per course,was48%.This study offered the clue that the response rateof HCC to RT was likely to be dose-related. 15 Although the Japanese literature has demonstratedthat partial hepatic irradiation using conventional ra-diation techniques is feasible and effective in selectivepatients with small HCC located in the upper and lateralportion of right lobe of liver, 16 conventional RT is almostuseless for HCC because of the severe adverse effects of radiation to the accompanying liver cirrhosis. 17 Protontherapy,which combines the specific,characteristic,proton beam distribution and the ability of three-dimensional (3-D) calculation by using a treatment-planning computer,has been proved to be a safe andeffective therapeutic option for patients with unre-sectable tumour or those with serious cirrhosis of theliver. 17 However,proton therapy is very expensive and isnot readily available in most areas of the world.Pub-lished reports on 3-D conformal RT with photon energysuggest that part of the liver can be treated to muchhigher doses with acceptable complications.Lawrenceand his associates have demonstrated that the tolerableRT dose for the whole liver is approximately 35Gy,for70% liver approximately 42Gy,for 50% liver approxi-mately 52Gy,and for 30% liver approximately 70 Gy. 18 Hence,3-D conformal RT to a portion of the liver canbe potentially increased to the tumoricidal level withoutdamaging the remaining liver.In this pilot study,13patients with unresectable HCC were treated with ra-diation limited to the involved area in order to determinethe potential role of this new treatment modality. METHODS Patient selection The entry requirements included:(i) histopathologi-cally or cytopathologically proven HCC;(ii) disease1026 SH Cheng et al . confined to the liver but surgically unresectable due tomain portal vein thrombosis,inferior vena cava inva-sion,main hepatic vein invasion,obstructive jaundice or tumour involving one or both lobes of liver with inadequate hepatic functional reserve for surgery; 19 (iii)Eastern Cooperative Oncology Group performancestatus £ 2;(iv) greatest dimension of the primarytumour more than 5cm;(v) indocyanine green (ICG)retention rate £ 30% at 15min;(vi) absence of uncon-trollable ascites;(vii) no prior RT;and (viii) writteninformed consent. Patient characteristics Thirteen patients (10 men,three women) with unre-sectable HCC were treated with 3-D conformal RTbetween 1993 and 1996.The median age was 62 years(range 46–83 years).All patients had a history of eitherhepatitis B and/or C virus infection.Patients weredivided into two groups:In group A,nine patients weretreated with 3-D conformal RT alone because they were not suitable for TACE due to main portal veinthrombosis (six patients),obstructive jaundice (onepatient),both main portal vein thrombosis and obstruc-tive jaundice (one patient) and inferior vena cava inva-sion (one patient;Table1).In group B,four patientswere treated with combination of TACE and 3-D con-formal RT.The number of tumours per patient in thisgroup was £ 4.The radiotherapy was usually delivered4–8weeks after TACE (Table2). Radiation treatment planning Radiation treatment was given to patients placed in asupine position with both arms raised above the headand with the head in natural position.The patient wasimmobilized in this position in a custom-made alphacradle for both simulation and treatment-planning CT.All patients were scanned for treatment planning on aflat couch inserted to simulate the radiation treatmentposition.Radiopaque catheters were also used to markthe reference points along the body contour of thepatient.The CT data were stored on a magnetic tapeand then transferred to the treatment-planning com-puter system for treatment planning and calculation of dose distribution.The hepatic tumour,liver,kidneys,spinal cord and vertebral bodies of each patient werecontoured and reconstructed to form a 3-D represen-tation.The radiation treatment volumes and treatmentangles were designed according to the beam eye’s viewtechnique to avoid as much critical organ injury as possible (Fig.1). Radiation dose The determination of radiation dose was based on thepurpose of preserving liver function and on protectingthe uninvolved liver from radiation volumes.The radi-ation targeted volume was defined according to the sizeand shape of the hepatic tumour plus a 1–1.5cm   3 -D c  o n f   or  m a l  r  a d  i   o t  h  e r  a p  y i   n u nr  e  s  e  c  t  a b  l   e H C C 1   0  2  7   Table1 Characteristics of group A (computed tomography-assisted RT alone for unresectable hepatocellular carcinoma) Tumour*Child–RTPre-RT Post-RTPre-RT Post-RTViralno./PughVesselPreviousdosetumourtumour AFPAFP MajorSymptomsFirst site of PtAg/Ab + locationcriteriainvasionTACE(Gy)(cm)size(ng/mL)(ng/mL)symptomsrelievedfailureStatus1HBsAg  > 4 in bothB Æ AMain portalNo5118 ¥ 9 ¥ 1210 ¥ 8 ¥ 12188300350000AbdominalYesIntrahepaticDOD,3mlobesvein51% Ø 86% ≠ distension,metastasespain4HBsAg1 in rightB Æ CIVCYes5615 ¥ 14 ¥ 10NA5NAAbdominalYesNADied of hepaticlobefullness,failure,3mpain7HBsAg  > 4 in bothA Æ AMain portalNo4025 ¥ 12 ¥ 2021 ¥ 10 ¥ 1887200067314Post-YesIntrahepaticDied of stroke,lobesvein37% Ø 92% Ø prandialmetastasesnature?,7mvomiting8Anti-HBs1 in rightB Æ CMain portalYes4612 ¥ 14 ¥ 1612 ¥ 15 ¥ 165.6NAAbdominalNoPrimaryDOD,2mlobevein7% ≠ fullness,tumour rupturepain9HBsAg1 in leftB Æ CMain portalYes5013 ¥ 7 ¥ 89 ¥ 4 ¥ 540728  > 100000AbdominalYesIntrahepaticDOD,5mlobevein75% Ø Progressiondiscomfortmetastases12Anti-HBc1 in rightB Æ AMain portalNo4511 ¥ 10 ¥ 213 ¥ 3 ¥ 68017005AbdominalYesNoneNED,15 + mlobevein98% Ø 100% Ø fullness,pain,vomiting13Anti-HCV1 in rightB Æ BMain portalYes4014 ¥ 13 ¥ 219 ¥ 10 ¥ 104194525AbdominalYesIntrahepaticDOD,5mlobevein77% Ø 88% Ø distention,metastasesascites,legoedema6HBsAg1 in rightB Æ ACommonNo506 ¥ 7 ¥ 86 ¥ 6 ¥ 5  < 3NAObstructiveJaundiceNoneDied of hepaticlobebile duct46% Ø jaundicerelievedfailure,19m10Anti-HBc1 in leftB Æ ACommonNo465 ¥ 5 ¥ 135 ¥ 3 ¥ 51237404ObstructiveJaundiceIntrahepaticDOD,7mlobebile duct,77% Ø ≠≠≠ jaundicerelievedmetastasesmain portalveinPt,patient;TACE,transcatheter arterial chemoembolization;RT,radiotherapy;AFP,alpha-fetoprotein;IVC,inferior vena cava;NA,not assessable;DOD,died of disease NED,no evidence of disease.Ag,antigen;Ab,antibody;m,months;HBsAg,hepatitis B virus surface antigen;Anti-HBs,antibody to HBsAg;anti-HBc,antibody to hepatitis B core antigen;Anti-HCV,antibody to hepatitis C virus.*Child–Pugh criteria before and after radiotherapy.  1028 SH Cheng et al . margin.All treatment was delivered by a linear acceler-ator with 6 or 18MV photons.Radiotherapy was givenfive times a week at 1.8–2Gy per day.Radiation doseto the target volume ranged from 40 to 60 Gy depend-ing on the tolerance and the functional reserve of theliver.The detailed radiation treatment guidelines areshown in Table3. Evaluation of response All patients had CT scans before initiation and 6–8weeks after the completion of RT.The tumour volumewas measured in 3-D axes.Alpha-fetoprotein (AFP)was also measured before and after treatment forpatients with elevated levels.Complete response wasdefined as complete disappearance of the entire tumourby imaging studies.Partial response was defined asregression of tumour volume equal to or greater than50%.Minimal response was defined as regression of thetumour volume by 25–49%. Statistical methods Overall survival duration was calculated from the firstday of radiotherapy until the day of death or last contact      T    a     b     l    e     2    C   h  a  r  a  c  t  e  r   i  s  t   i  c  s  o   f  g  r  o  u  p   B   (  c  o  m  p  u  t  e   d  t  o  m  o  g  r  a  p   h  y -  a  s  s   i  s  t  e   d   R   T  a  n   d   T   A   C   E   f  o  r  u  n  r  e  s  e  c  t  a   b   l  e   h  e  p  a  t  o  c  e   l   l  u   l  a  r  c  a  r  c   i  n  o  m  a   )   T  u  m  o  u  r   *   C   h   i   l   d –   I  n  t  e  r  v  a   l  o   f   R   T   P  r  e -   R   T   P  o  s  t -   R   T   P  r  e -   R   T   P  o  s  t -   R   T   V   i  r  a   l  n  o .   /   P  u  g   h   V  e  s  s  e   l   T   A   C   E   b  e   f  o  r  e   d  o  s  e  t  u  m  o  u  r  t  u  m  o  u  r   A   F   P   A   F   P   M  a   j  o  r   S  y  m  p  t  o  m  s   F   i  r  s  t  s   i  t  e   P  t   A  g   /   A   b    +    l  o  c  a  t   i  o  n  c  r   i  t  e  r   i  a   i  n  v  a  s   i  o  n   R   T   (  w  e  e   k  s   )   (   G  y   )   (  c  m   )   (  c  m   )   (  n  g   /  m   L   )   (  n  g   /  m   L   )  s  y  m  p  t  o  m  s  r  e   l   i  e  v  e   d  o   f   f  a   i   l  u  r  e   S  t  a  t  u  s   2   A  n  t   i -   H   B  c   4   i  n   l  e   f  t   A    Æ    B   S  t  a  t  u  s  p  o  s  t   8   5   0   6    ¥    5    ¥    5   3    ¥    2    ¥    2    <    3   N   A   A   b   d  o  m   i  n  a   l   Y  e  s   L  u  n  g   M  e  t  a  s  t  a  s   i  s   l  o   b  e  r   i  g   h  t   9   2   %      Ø    f  u   l   l  n  e  s  s ,  a  t   3   8  m ,   l  o   b  e  c  t  o  m  y  p  a   i  n  a   l   i  v  e   4   0    +   m   3   A  n  t   i -   H   C   V   2   i  n  r   i  g   h  t   A    Æ    A   R   i  g   h  t  p  o  r  t  a   l   4   6   0   1   1    ¥    1   5    ¥    1   4   8    ¥    1   3    ¥    1   0   6   8   5   4   4   P  a   i  n   Y  e  s   S  c  a   l  p   D   O   D ,   2   3  m   A  n  t   i -   H   B  c   l  o   b  e  v  e   i  n   5   5   %      Ø    9   4   %      Ø    5   H   B  s   A  g   2   i  n  r   i  g   h  t   A    Æ    A   R   i  g   h  t  p  o  r  t  a   l   8   4   6   9    ¥    1   0    ¥    1   3   8    ¥    9    ¥    1   1   3   N   A   A   b   d  o  m   i  n  a   l   Y  e  s   L  u  n  g   D   O   D ,   1   6  m   l  o   b  e  v  e   i  n   3   2   %      Ø    d   i  s  c  o  m   f  o  r  t   1   1   H   B  s   A  g   2   i  n   l  e   f  t   A    Æ    A   N  o  n  e   8   4   5   1   1    ¥    5    ¥    8   1   4    ¥    5    ¥    8   3   3   2   7   A   b   d  o  m   i  n  a   l   Y  e  s   P  r   i  m  a  r  y   A   l   i  v  e  w   i  t   h   l  o   b  e   2   7   %      ≠    1   8   %      Ø    f  u   l   l  n  e  s  s ,   d   i  s  e  a  s  e ,  p  a   i  n   1   7    +   m   P  t ,  p  a  t   i  e  n  t  ;   T   A   C   E ,  t  r  a  n  s  c  a  t   h  e  t  e  r  a  r  t  e  r   i  a   l  c   h  e  m  o  e  m   b  o   l   i  z  a  t   i  o  n  ;   R   T ,  r  a   d   i  o  t   h  e  r  a  p  y  ;   A   F   P ,  a   l  p   h  a -   f  e  t  o  p  r  o  t  e   i  n  ;   N   A ,  n  o  t  a  s  s  e  s  s  a   b   l  e  ;   D   O   D ,   d   i  e   d  o   f   d   i  s  e  a  s  e  ;   N   E   D ,  n  o  e  v   i   d  e  n  c  e  o   f   d   i  s  e  a  s  e  ;   A  g ,  a  n  t   i  g  e  n  ;   A   b ,  a  n  t   i   b  o   d  y  ;  m ,  m  o  n  t   h  s  ;   A  n  t   i -   H   B  c ,  a  n  t   i   b  o   d  y  t  o   h  e  p  a  t   i  t   i  s   B  v   i  r  u  s  c  o  r  e  a  n  t   i  g  e  n  ;   A  n  t   i -   H   C   V ,  a  n  t   i   b  o   d  y  t  o   h  e  p  a  t   i  t   i  s   C  v   i  r  u  s  ;   H   B  s   A  g ,   h  e  p  a  t   i  t   i  s   B  v   i  r  u  s  s  u  r   f  a  c  e  a  n  t   i  g  e  n .   *   C   h   i   l   d -   P  u  g   h  c  r   i  t  e  r   i  a   b  e   f  o  r  e  a  n   d  a   f  t  e  r  r  a   d   i  o  t   h  e  r  a  p  y . Figure1 Computed tomography (CT)-assisted radiationtreatment planning of patient no.2.This patient had recurrenthepatocellular carcinoma in the left lobe of the liver after right lobectomy.He also had history of trauma with previousright nephrectomy.The CT-assisted radiation treatment wasplanned to avoid irradiation of the surrounding organs,suchas stomach,left kidney and the remaining hepatic tissue. Table3 Radiation treatment guidelines for hepatocellularcarcinomaIndocyanine greenNon-tumorous liver10%10.1–20%20.1–30% < 1/340GyNo RTNo RT1/3–1/250Gy40GyNo RT > 1/260Gy50Gy40Gy  with the patient.The probability of survival and recur-rence was calculated according to the methods of Kaplan and Meier. 20 RESULTS Tumour response Tumour response after 3-D conformal RT is shown in Tables1,2.Partial regression of the tumour wasobtained in 58% (seven of 12) patients,minimalresponse was obtained in additional 25% (three of 12)patients.One patient (patient 4) could not be evaluatedbecause of the development of hepatic failure 1 monthafter completion of RT.Eight patients had elevation of AFP before 3-D conformal RT:AFP levels declinedmore than 50% in four of them (range 77–100%).Subgroup analysis revealed that the partial responsein group A patients was 63% (five of eight) and in group B patients 50% (two of four,further volumereduction after TACE).In patient 12 (group A),whohad main portal vein thrombosis initially (Fig.2),thetumour regressed 98% (Fig.3) and AFP decreasedfrom 801700 to 4.6ng/mL.The residual tumour under-went local excision 6months after 3-D conformal RTand the resection specimen showed only fibrotic tissuewithout microscopic tumour remaining.This patient isstill doing well to date,15 months after RT.In group B,all patients underwent combinationTACE and 3-D conformal RT and lived for at least 1year,the longest surviving patient has been followed for40 months and,to date,has no evidence of tumour pro-gression in the liver although he developed pulmonarymetastases at 38 months of follow-up (Table2). 3-D conformal radiotherapy in unresectable HCC  1029 Treatment-related toxicity Radiation-related complications were mild andreversible (Tables4,5).Alanine transaminase (ALT)usually rose within 3 months after completion of radiotherapy and showed grade 4 toxicity in twopatients,one of whom (patient 8) had simultaneoustumour rupture,while the other (patient 4) developedhepatic failure (Fig.4).Leucopenia (seven of 13) andanaemia (seven of 13) were the most commonlyobserved extra-hepatic side-effects,grade 3 leucopenia(white blood cells < 2000/ m L) and anaemia (haemoglo-bin < 7.5g/dL) were observed in two of 13 (15%) andone of 13 (8%),respectively.A late complication associated with the treatmentswas gastrointestinal bleeding,which occurred in threepatients.The first patient (no.12) developed caecalbleeding 5 months after RT,which was apparentlyrelated to RT to the ascending colon because theprimary tumour extended downward to the pelviccavity.This bleeding was finally controlled by bowelresection.She was the one in whom pathological com-plete regression was observed and was alive with no evi-dence of disease at this reporting.The second patient(no.6) had variceal bleeding 12 months after RT.Portalhypertension was associated with either the naturalcourse of liver cirrhosis or radiation-induced hepaticfibrosis.The third patient (no.13) developed diffusehaemorrhagic gastritis confirmed by endoscopy 4months after RT.On reviewing the radiation portals,only the duodenum was in the radiation treatment fieldsand the radiation dose to this area was 4000cGy in 20fractions.The diffuse haemorrhagic gastritis may or maynot be associated with RT. Figure3 Patient no.12.Computed tomography of theabdomen shows an 11 ¥ 10 ¥ 21cm tumour of the right lobeof the liver.This tumour also invades the portal vein withthrombosis (data not show). Figure2 Six months after radiotherapy,repeat computedtomography of the abdomen reveals residual tumour in theright lobe of the liver.Subsequent surgical excision of thislesion showed only fibrotic tissue without microscopic viablecancer cells.Hypertrophy of the left lobe is present.
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