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RADIATION THERAPY IN HEPATIC

MALIGNANT TUMORS

Prof. Dr. Rodica AnghelInstitute of Oncology “Al. Trestioreanu” Bucharest

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HEPATIC MALIGNANT TUMORSHEPATIC MALIGNANT TUMORS

About 10% of hepatic cancer patients may benefit of radical surgery.

But 45-75% develop reccurencies after total tumor removal.

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That is why attention is focused on nonsurgical treatments, including radiation therapy.

Radiotherapy aims to improve quality of life and survival.

HEPATIC MALIGNANT TUMORS

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Radiation therapy modalities

External beam radiotherapy: conventional radiotherapy; conformal three-dimensional radiotherapy; stereotactic radiotherapy; proton radiotherapy.

Internal radiotherapy: selective internal radiotherapy using yttrium;

microspheres(SIRT); metabolic radiotherapy with Iodine 131 marked lipiodol; brachytherapy.

Radiotherapy associated with other treatment modalities : radiochemotherapy; radioimunotherapy; radiotherapy associated with hyperthermia.

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microspheres(SIRT); metabolic radiotherapy with Iodine 131 marked lipiodol; brachytherapy.

Radiotherapy associated with other treatment modalities : radiochemotherapy; radioimunotherapy; radiotherapy associated with hyperthermia.

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External beam radiotherapy:External beam radiotherapy:conventional radiotherapyconventional radiotherapy

Conventional radiotherapy has only palliative role in hepatic malignant tumors, especially in whole liver irradiation.

The usual technique is whole liver irradiation through two antero-posterior fields.

High energy photons (6-15 MV) or Cobalt 60 are used.

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The level of dose calculation is half the antero-posterior liver diameter.Both fields are irradiated daily .

Whole liver irradiation through two antero-posterior fields using the linear accelerator 15 MV.

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Irradiation of primitive hepatic tumors or metastatic, unique or multiple but grouped can be accomplished by techniques using:

- 3-4 fields; - wedge filters; - boost through arc fields.

Dose distribution in the tumoral volume by fields combinations.

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Better normal hepatic parenchyma protection is achieved when using these techniques. The whole liver irradiation with 20 Gy in 2 weeks, then the fields are limited strictly to the tumor, up to 45 Gy, depending on the unimpared hepatic volum.

Whole liver irradiation and field reduction after 20 Gy, strictly on the hepatic tumor.

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External beam radiotherapy:External beam radiotherapy:conventional radiotherapy.conventional radiotherapy.

Dose of radiation is limitted by hepatic tolerance and tumor volume. Better results are obtained using higher doses on smaller volumes.

When total hepatic irradiation with standard fractionation is used, liver tolerance is about 25 Gy with 2,5 Gy/fraction . Stillwagon G, Order S, Guse C,

Klein JL, et al, J. Radiot. Oncol. Biol. Phys. 1989 Doses greater than 30 Gy on the whole liver Doses greater than 30 Gy on the whole liver

lead to complications.lead to complications.

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The most fearful complication is the radio-The most fearful complication is the radio-induced liver disease, produced by veno-induced liver disease, produced by veno-oclusive mechanism. oclusive mechanism.

Two to four months after irradiation, an increase Two to four months after irradiation, an increase of the abdomen volum may apper, due to of the abdomen volum may apper, due to hepatomegalia and ascitis, associated with hepatomegalia and ascitis, associated with medium or severe pain in the right medium or severe pain in the right hypocondrum. hypocondrum.

The laboratory tests in the radio-induced The laboratory tests in the radio-induced hepatic disease show increased alcaline hepatic disease show increased alcaline phosphatasis, ALAT, ASAT, bilirubina, TP and phosphatasis, ALAT, ASAT, bilirubina, TP and thrombocytopenia.thrombocytopenia.

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There is no efficient therapy for the radio-There is no efficient therapy for the radio-induced lesions. induced lesions.

In order to prevent radio-induced liver disease, In order to prevent radio-induced liver disease, special attention has to be paid to radiation special attention has to be paid to radiation dose and irradiated volume, (at 35 Gy, there is dose and irradiated volume, (at 35 Gy, there is a 50% risk of radio-induced liver disease). a 50% risk of radio-induced liver disease). Cheng JC, Cheng JC,

Wu JK, Huang CM et al, Radioter.Oncol. 2002 Wu JK, Huang CM et al, Radioter.Oncol. 2002

Protection of at least 25% of the liver allows Protection of at least 25% of the liver allows greater doses of radiation, with a lower risk of greater doses of radiation, with a lower risk of radio-induced liver disease, but quite often, with radio-induced liver disease, but quite often, with a diminished therapeutic effect.a diminished therapeutic effect.

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External beam radiotherapy:External beam radiotherapy: conventional radiotherapy; conformal three-dimensional radiotherapy;conformal three-dimensional radiotherapy; stereotactic radiotherapy; protons radiotherapy.

Internal radiotherapy: selective internal radiotherapy using yttrium microspheres(SIRT); metabolic radiotherapy with Iodium 131 marked lipiodol; brachytherapy.

Radiotherapy associated with other treatment modalities: radiochemotherapy; radioimunotherapy; radiotherapy associated with hyperthermia.

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Conformal three-dimensional radiotherapy

Provides dynamic adaptation to the tumors shape during irradiation,

which leads to:

increased protection of normal tissues arround tumor; decreased irradiation volume; and consequently, less side effects and complications due to and consequently, less side effects and complications due to

radiation therapy and a higher dose administratted to the target radiation therapy and a higher dose administratted to the target volum, with improved local controlvolum, with improved local control.

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ConformalConformal three-dimensionalthree-dimensional radiotherapyradiotherapy

Matching the irradiation fields to the tumor shape is accomplished by using a multileaf colimator, made of 40-60 pairs of opposite leaves 1 cm wide, independently activated.

This colimator is adaptated to linear accelerator gantry. An improvement to conformal radiotherapy has been

brought by irradiation with beam intensity modulation. Thus, not only the field shape is adapted to the tumor

shape, but also the intensity of the beam is different at the periphery from the center of the tumor, so that a uniform distribution of the radiation dose, in the tumor and a quick decrease nearly normal tissues to be obtained .

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Beam delimitation through MLC

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Three-dimensional represantion of target volume, critical organs and MLC

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Beam delimitation through MLC and isodose 90% curve

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Conformal tridimensional radiotherapy

Avoids unneccesary exposure of unimpared liver and critical organs to radiation, thus becoming one of the safest treatment in unresectable hepatocarcinoma.

Tridimensional reconstruction of the tumor and surrounding organs, with dose distribution (isodoses 90%-green; 80%-violet)

Irradiation fields represented on the skin

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The therapeutic effect is directly correlated with radiation dose.

Photons beam 6-10 MV is used. The irradiation field encompasses the tumoral

volum and wide enough safety limits. Radiation doses of 48-72 Gy can be delivered.

Local control rate is 50% and medium survival is 16-20 months.

Wei-Chung, Po-Ming Wang, Kung-Shin Ying, et al, Chin J Radiol

2002

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Recent results suggest that the delivered radiation dose is an important prognostic factor for local control as well as for survival at patients with primary hepatobiliar cancers.

The administratted dose reached as much as 90 Gy, depending on the normal unirradiated tissue fraction, calculated according to modern radiobiological models such as normal tissue complications probability (NTCP). Dawson L.A, McGinn N.J.,Ensminger W. et al, ASCO 1999

Patients who received doses greater than 70 Gy had a medium survival of 17 months, similar to results obtained after surgery. Minsky B.D. Textbook of Radiation Oncology, 1998

Conformal three-dimensional radiotherapy can be used associated with systemic or locoregional (intrahepatic artery) chemotherapy.

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External beam radiotherapy:External beam radiotherapy: conventional radiotherapy; conformal three-dimensional radiotherapy; sterotactic radiotherapy;sterotactic radiotherapy; proton radiotherapy.

Internal radiotherapy: selective internal radiotherapy using yttrium microspheres (SIRT); metabolic radiotherapy with Iodine 131 marked lipiodol; brachiterapy;

Radiotherapy associated with other treatment modalities: radiochemotherapy; radioimunotherapy; radiotherapy associated with hyperthermia.

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Stereotactic radiosurgery-a single high dose of radiation is given, the procedure being done in one day, the great majority being treated patients.

Stereotactic radiotherapy- this gives the radiation treatment over many days ranging from 3-5 to 28-30.

STEREOTACTIC RADIATION

STEREOTACTIC RADIATION

BRACHYTHERAPY

STEREOTACTIC RADIATION-EXTERNAL

RADIOTHERAPY

TEMPORAR IMPLANT PERMANENT IMPLANT RADIOSURGERY RADIOTHERAPY

Stereotactic radiationStereotactic radiation

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Stereotactic radiotherapy

A tehnique used, at first in brain tumors, in order to deliver a unique high radiation dose, very accurately in a small target volume, using a particular kind of cobalt unit.

Afterwards, linear accelerators were used, being equiped with special colimators, which allow a high radiation dose to be delivered in a small tumor volum (about 3 cm).

Some stationary fascicules associated with arciform rotations focus the radiation dose in the tumoral tissue, protecting normal surrounding tissue.

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Extracranial stereotactic radiotherapy indications:

Hepatoma and hepatic metastases

Pancreatic malignancy Prostatic malignancy Pulmonary lesions

Spinal lesions

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Body immobilization and localization system


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Irradiation fields Dose distribution

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Stereotactic radiotherapyStereotactic radiotherapy

• In order to diminish error due to liver movements during breathing special modalities of patient contention and numerous CT scanns are needed. • Based on the concept that in malignant tumors treatment fractionated radiation doses are more efficient than single dose, in solitar hepatocellular carcinoma, fractionated stereotactic irradiation and arc-therapy have been used. • Total doses of 52 Gy have been delivered in 13 fractions in 29 days.

Koichi T.,Minako S., Hiroshi I., et al, Japanese Journal of Clinical Oncology , 1997

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Radiation therapy modalitiesExternal beam radiotherapy:External beam radiotherapy:

conventional radiotherapy; conformal three-dimensional radiotherapy; stereotactic radiotherapy;

proton radiotherapy.proton radiotherapy.Internal radiotherapy:

Selective internal radiotherapy using yttrium microspheres (SIRT); metabolic radiotherapy with Iodine 131 marked lipiodol; brachytherapy;

Radiotherapy associated with other tratment modalities: radiochemotherapy; radioimunotherapy; radiotherapy associated with hyperthermia.

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Proton radiotherapyProton radiotherapy

The characteristics of these particules make the irradiation using

protons the most accurate nowadays modality of radiotherapy: (a) protons energy keeps almost constantly in their way throughout

the tissue proximal to tumors; (b) at the end of their way, protons show down or stop, quickly giving

their energy to secundary electrons, the biological efficiency beingmaximal in this area (Bragg curve peak) ;

(c) after that, the energy goes down abruptly, so that the normal tissues distal to the tumor get a neglectable dose of radiation, which means a total dfferent behavior compared to photons ;

(d) usually, this biological efficiency peak is smaller than the tumors diameter, which requires the use of different energies in the tumor irradiation (beam intensity modulation) for an optimal dose distribution.

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Proton radiotherapy

Allows foccusing the beam to the target volume and minimal irradiation of normal tissue by combining proton beams, in the same way as photon ones, but with a threefold decrease of normal tissue irradiation.

Due to such protons beams characteristics, the treated volum gets smaller, together with decrease of treatment linked morbidity.

Reduced treated volume allowed higher doses to be administrated to the tumor (50-87 Gy), with minimal sides effects.

Thus, protons irradiation is a new treatment option, safe and efficient for patients with unresectable hepatocellular carcinoma.

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Proton radiotherapy

Proton radiotherepy can be associated Proton radiotherepy can be associated with chemoembolization using lipiodol. with chemoembolization using lipiodol.

A study comparing radiotherapy using A study comparing radiotherapy using protons alone versus associated with protons alone versus associated with chemoembolisation with lipiodol versus chemoembolisation with lipiodol versus chemoembolisation alone at patients chemoembolisation alone at patients with hepatocellular carcinoma shows 4-with hepatocellular carcinoma shows 4-years survival: 67%, 81%, 36%.years survival: 67%, 81%, 36%.

Matsuzaki Y., Chiba T., Shoda J., et al, Elsevier Science, 1997

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Internal radiotherapy:Internal radiotherapy: selective internal radiotherapy using yttrium microspheres selective internal radiotherapy using yttrium microspheres

(SIRT);(SIRT); metabolic radiotherapy with Iodium 131 marked lipiodol; brachitherapy;

Radiotherapy associated with other treatment modalities: radiochemotherapy; radioimunotherapy. radiotherapy associated with hyperthermia.

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Selective internal radiotherapy (SIRT)

The method can be used in primitive hepatocarcinoma as well in metastatic tumors.

Hepatic metastases are irrigated only by the hepatic artery, while the normal tissue by both hepatic artery and portal vein.

Consenquently, introducing a radioactive substance in the hepatic artery will aim tumoral tissue.

This kind of target effect can be improved by simultaneous administration of a vasoconstricting drugs, such as angiotensin II, which produces selective vasoconstriction on normal tissue vessels and does not affect vessels inside the tumor, with a relative increase of tumoral blood flow.

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The technique implies administration in the The technique implies administration in the hepatic artery of sort radioactive particles , hepatic artery of sort radioactive particles , that is yttrium-90 microspheres. This is beta-that is yttrium-90 microspheres. This is beta-emitter, with 2,5 cm penetrability, half time emitter, with 2,5 cm penetrability, half time 64,5 hours, medium energy electrons 2,23 64,5 hours, medium energy electrons 2,23 MeV. MeV.

Normal heatic tissue support much greater doses (50-324 Gy) when using SIRT compared to external beam radiotherapy.

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Results depend also microspheres composition (glass, resin) The first microspheres with resin have been associated with

complications, even lethal, because of microspheres breaking and radioisotope release. Local control rates have been between 50% and 90% when SIR-sphere used

Another Yttrium-90 containing product is called Thera-Sphere and it contains millons of glass microspheres 20-30 microns diameter, with Yttrium-90 in there mattrix.

SIRT produces a response consisting in 100% reducing SIRT produces a response consisting in 100% reducing alphafetoprotein level and 26% reducing tumor dimensions. In clinical alphafetoprotein level and 26% reducing tumor dimensions. In clinical trials cases of conversion to operability have been reported.trials cases of conversion to operability have been reported.

Andew S. Kennedy, Riad Salem, 14 IACT, Paris-France, February 2003

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This technique is well tolerated, without significant complications.

SIRT with SIR-Sphere can be associated with SIRT with SIR-Sphere can be associated with intraarterial chemotherapy, without significant increase of intraarterial chemotherapy, without significant increase of toxicity, with benefit concerning local control.toxicity, with benefit concerning local control.

Thera-Sphere infusion in hepatocellular carcinoma is an Thera-Sphere infusion in hepatocellular carcinoma is an efficient method with minimal toxicity for patients refusing efficient method with minimal toxicity for patients refusing other treatment modalitiesother treatment modalities

SIR-Sphere therapy is mostly an embolic type therapy, SIR-Sphere therapy is mostly an embolic type therapy, unlike There-Sphere therapy which have a much more unlike There-Sphere therapy which have a much more intense activity per sphere, thus beeing more alike intense activity per sphere, thus beeing more alike classic brachitherapy.classic brachitherapy.

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Internal radiotherapy:Internal radiotherapy: Selective internal radiotherapy usin yttrium-90 microspheres (SIRT); Metabolic radiotherapy with Iodine 131 marked lipiodol;Metabolic radiotherapy with Iodine 131 marked lipiodol; brachytherapy;

Radiotherapy associated with other treatment modalities: radiochemotherapy; radioimunotherapy. radiotherapy associated with hyperthermia.

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Metabolic radiotherapy with Iodine 131 marked lipiodol

Lipiodol has been used initially for hepatocarcinoma diagnostic and longer perssistency in tumoral tissue compared to normal one has been observed (half time 5,7 days compared to 3,7 days). Consequently, lipiodol has been used as a vehicle for radioactive iodine for selective irradiation of hepatic tumors.

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Metabolic radiotherapy with iodine Metabolic radiotherapy with iodine 131 marked lipiodol131 marked lipiodol

The use of iodine 131 marked lipiodol led to tumoral mass reduction, decrease of alphafetoprotein and a better patient general condition.

In patients who refused surgery or this could not be performed, tumor mass reduction has been observed by using metabolic radiotherapy of 88,9% for tumors smaller than 4 cm; 65,5% for tumors 4-6 cm; 25% for tumors greater than 6 cm.

Raoul JL, Bretagne JF, Caucanas JP, et al, Cancer, 1992

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External beam radiotherapy: conventional radiotherapy for the whole liver; conformal three-dimensional radiotherapy; stereotactic radiotherapy; proton radiotherapy.


microspheres(SIRT); metabolic radiotherapy with Iodium 131; brachytherapy.

Radiotherapy associated with other treatment modalities : radiochemotherapy; radioimunotherapy; radiotherapy associated with hypertermia.

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Brachytherapy

Brachytherapy involves the direct injection of a radiation source into the tumor, either percutaneously or at the time of laparotomy.

Various radionuclides have evaluated, including radioactive I125, Ir192, Y90.

Method limits are difficult access to the tumor and invasivity.

radioactive substance can be lost in the peritoneal cavity and can reach the lungs by lymphatics.

Ho S, Lau WY, Leung TWT, et al, Cancer 1998

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External beam radiotherapy: conventional radiotherapy; conformal thredimensional radiotherapy; stereotactic radiotherapy; proton radiotherapy.


microspheres(SIRT); metabolic radiotherapy with Iodine 131; brachytherapy.


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RadiochemotherapyRadiochemotherapy

Radiotherapy and chemotherpy are complementary and they can increase each other efficiency.

Radiotherapy can be associated with systemic chemotherapy and also with locoregional chemotherapy in the hepatic artery.

Due to multiple association modalities, results are Due to multiple association modalities, results are extremely variable, with response rates between 22% extremely variable, with response rates between 22% and 83%.and 83%.

Drugs that can be administrated intraarterial are 5FU, Drugs that can be administrated intraarterial are 5FU, epirubicin, doxorubicin, cisplatin, mitomycin, mitoxantron.epirubicin, doxorubicin, cisplatin, mitomycin, mitoxantron.

Drugs for sistemic administration are : doxorubicin, Drugs for sistemic administration are : doxorubicin, cisplatin, mitoxantron, iphosphamid, 5 FU, vinblastine, cisplatin, mitoxantron, iphosphamid, 5 FU, vinblastine, etoposide. etoposide.

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Radioimunotherapy Radioimunotherapy

This approch involves coupling of a radionuclide to an antibody that can be used to target tumors.

Iodine 131 and Yttrium 90 are the usual radioactive isotopes.

Monoclonal antibodies target are the carcinoembrionic antigen, alphafetoprotein and feritin.

There in an important risk to irradiate the hematopoetic marrow, with leukopenia and trombocytopenia.

Order S, Pajak T, Leibel S, Asbell S, et al, Int J Radiat Oncol Biol Phys 1991

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Radiotherapy associated with Radiotherapy associated with hypertermiahypertermia

It is used limited by difficulties of foccused application, being rarely used in hepatic tumors treatment.

Most work in this area involves external radiation in combination with radiofrequency capacitive heating.

Seong J, Lee HS, Han KH, Chon Cy, et al, Yonsei Medical Journal 1994

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Radiotherapy associated with hypertermia

External beam irradiation 30,6 Gy with hypertermia thruogh radiofrequency 8 MHz which produces a temperature of 40,8 C in the tumor. Objective response of 40,3% and subjective response at 78,6% of patients have been obtained.

The most common side effects have been local pain and adipose tissue necrosis, considered acceptable.

The possible association between hypertermia and one of focused radiotherapy methods is under evaluation.

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Indications of radiotherapy in hepatic malignant tumors

Patients with disease limited to the liver; no extrahepatic metastases are accepted.

Patients with an acceptable hepatic function; patients with advanced chirosis will not undergo radiotherapy.

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Indications of radiotherapy in hepatic malignant tumors

Patients who would benefit of better quality of life or/and survival by hepatic metestases control.

Adjuvant therapy after surgery, together with chemotherapy.

Conversion to operability in patients with unresectable disease .

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Limitations in radiation therapy of Limitations in radiation therapy of hepatic malignant tumorshepatic malignant tumors

The main causes which limit the use of radiotherapy are:

Difficulties in administration of tumoricide doses without damages to normal hepatic tissue; external liver irradiation with doses greater than 30 Gy causes radio-induced hepatic disease;

Association with preexistent cirrhosis;

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Limitations in radiation therapy of Limitations in radiation therapy of hepatic malignant tumorshepatic malignant tumors

Radioresistant micrometastases; Carcinogenetic agent persistance; Big tumors with necrotic center weak

responsive at selective internal radiotherapy;

Radioimunotherapy limited by the fact that not all tumors and tumor cells express their antigenes

Often disease is not limited at liver.

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Complications of radiotherapy in hepatic tumors

The main complications after liver irradiation are:

Radio-induced hepatic disease; Biliary sclerosis; Portal vein thrombosis; Portal hypertension.

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Damage to normal tissues radiations are passing through: skin, small bowles, stomach, right kidney, pancreas, extrahepatic biliar ducts;

Yttrium microspheres can produce damages to stomach or duoden;

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Radioactive substance loss in peritoneum; Radioactive substance may through arterio-

venous shunts; Haematological complications: trombocytopenia,

leukopenia, pancytopenia-especially in radioimunotherapy or radiochemotherapy.

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Conclusions

Radiotherapy is rarely curative in hepatic tumors,

it is mostly used for paliaton.

Radiotherapy as adjuvant treatment or for

conversion to operability is under evaluation.

Clinical ongoing trials will have to establsh the

best irradiation tehnique in these tumors.

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Documents

conformal radiotherapy

liver irradiation

irradiation fields

total hepatic irradiation

hepatic disease

radioinduced liver disease

liver tolerance

dose of radiation