THERAPY OFBENIGN THYROID DISEASES
Recently the human Na+/I-symporter (hNIS), which is responsible for iodine uptake in thethyroid gland, has been cloned and characterised16. Thistransporter is located on the basolateral membrane of the thyroidfollicular cells and iodine transport is made possible by an energy(Na+ / K+-ATPase) dependant co-transport mechanism that is drivenby an inwardly directed Na+ gradient. This transporter is the basisof thyroid scintigraphy and radioiodine therapy, which isclincially used since more than 50 years since the initial131I human thyroid uptake studies performed by Hamiltonand Soley25,57.
131I hasbecome the most commonly used therapy for Graves'disease in adultsin the United States, but this predominant 131Itherapeutic use is not followed in Europe and Asia whereantithyroid drug therapy is initiallypreferred69.
Once the diagnosis ofGraves'disease is established the physician must discuss with thepatient likely therapeutic outcomes of the various availableoptions, antithyroid drug therapy, surgery or radioiodine therapy.Each of these modalities has advantages and disadvantages. Nooption is clearly superior or inferior to the other modality.Because a lot of studies demonstarted clearly that a antithyroiddrug therapy of at least one year offers a sponataneouslong-lasting remission for the patients, Europeans prefer to treatfirst with antithyroid drugs, if after one year hyperthyroidismrecurs or antithyroid drug therapy cannot be stopped or evenreduced in dose, a definitive treatment of hyperthyroidism isdiscussed with the patient, where actually two options, near totalthyroidectomy and radioiodine therapy has to bediscussed.
The situation in Europedue to the iodine deficiency areas all over the continent isdifferent. In the USA most of the patients with Graves'disease havenormal sized glands, in Europe and especially in Germany patientshave additionally goiters sometimes with nodules. In this situationsurgery should be preferred to radioiodine therapy, if there areadditional cold nodules being suspicious to be malignant, largegoiters with mechanical problems in the neck and situations wherean immediate stop of hyperthyroidism and antithyroid drug therapyhas to be guaranteed, such as allergic or liver and hematologicside effects of antithyroid drugs.
In all the othersituations radioiodine therapy is the treatment of choice, becausethere is no real side effect, no hypoparathyroidism, no voice cordparalysis and no risk of anesthesia.
The radiation risk isneglectible, because the radiation burden of the patients receiving185MBq of 131I is comparable to one or two x-ray studiesof the kidneys.
Due to the Europeanpreferred antithyroid drug pretreatment, most of the patients areeuthyroid under ongoing antithyroid drug therapy. But beforeradioiodine dosimetry and radioiodine treatment antithyroid drugtherapy should be stopped, because it is well documented that thisleads to an increase of intrathyroidal halflife ofradioiodine58. The explanation for that is thatantithyroid drugs inhibit thyroid peroxidase which binds iodine tothyroid hormon preceders. If iodine and also radioiodine is notbound to i.e. monoiodothyrosin it rapidly is excreted out of thethyroid cell. Also prevented must be the use of iodine containgcontrast agents or other drugs such as cordarex, because then thethyroid gland would be overloaded with iodine and no sufficientradioiodine uptake would be any longer possible fortherapy.
Radioiodine is given as astandard activity or as an individually calculated activity.Standard activities are more common in the United States, probablydue to the most likely normal-sized thyroid glands, whereindividual dosimetry is preferred in Europe. A prospective study inGermany52 demonstrate that standard doses of 555MBq131I lead to a higher number of hypothyroidism in smallglands, a higher number of treatment failure in large glandsetc.
For the dosimetry theMarinelli algorithm:
Activity = thyroid volume(sonography)(ml) x dose (100-300Gy) x 24.8
highest% radioiodine uptake x biological half-life(days)
is used. For dosimetry,which is performed as a 24 h uptake test or optimally as a 5 daysradioiodine uptake test, between 3.7 to 7 MBq radioiodine areadministered.
Since 1997 in the USA theNCR has appropriately liberalized the previous 30mCi restrictionfor outpatient therapy by promulgating the so-called PatientDischarge rule. Patients may now be released when the total dose ofa member of the public exposed to the patient is not likeley toexceed 5mSv in a year. This allows nearly all Graves'patients inthe USA to be treated on an outpatient basis. This is more strictlyregulated in most European countries with the maximal permissabledose to outpatients varying from 185MBq (Switzerland, Austria, TheNetherlands) 555MBq (Poland, Finland, Greece, Hungary) 740MBq(Belgium, France, United Kingdom) to 1100MBq in Italy. In Germanyevery intention to treat a patient with radionuclides makes himobligatory an inpatient for at least 48 hours. He may be thenreleased with a restactivity of less than 250MBq.
Resultsand side effects
The comparison of theresults of radioiodine therapy in the literature is difficult,because the way to treat the patients is very different.
After low doses to thethyroid between 20 and 50 Gy about 35% of the patients remainhyperthyroid after 1 year of follow-up. Only after repeatedapplications of therapeutic 131I activities, which arenecessary in 20% to 70% of the cases, the percentage ofhyperthyroidism can be lowered to approximately 4% after 5 years offollow-up. The incidence of hypothyroidism increases from 18% afterthe first year to approximately 25% after 5 years. In long-termfollow-up after 10 years, 50% of the patients develophypothyroidism, the remaining 50% being euthyroid.
For intermediate dosesbetween 60 and 100 Gy, the percentage of patients with persistenthyperthyroidism is about 10% after 1 year. Also in this grouprepeated doses are necessary to abolish hyperthyroidism. After 5years of follow-up approximately 35% of the patients arehypothyroid. As in the low dose group this percentage increases to50% after 10 years remaining 50% of euthyroid patients.
In the high dose groupwith doses between 120 and 150 Gy hyperthyroidsim can be rapidlycontrolled. Only 5% of the patients show hyperthyroidism after 1year. 1% of patients remain hyperthyroid after 5 years. On theother hand 70% of these patients are hypothyroid after one year andthis increases to approximately 80% after 5 years. Possible furtherincrease of the hypothyroidism rate are not available in theliterature. These figures have been taken from three already olderstudies in the literature covering about 4,700patients19,31,32,60. In the own department we have touse 300 Gy for hyperthyroidism to come the same results as arepublished in the high dose group. Perhaps this general Germanexperience is due to the difficulties to differentiate betweenGraves'disease and disseminated functional autonomy. From thesedata it clearly can be concluded, that the higher the dose is, thehigher is the elimination of hyperthyroidism, but the higher isalso the induction of hypothyroidism.
So it depends from thestrategy to treat patients, whether you prefer to have a highsucces rate in elimation of hyperthyroidism and subtitute most ofthe patients life long with thyroid hormon drugs or whether takeinto account to treat them several times with radioiodine and toguarantee half of them to be euthyroid for the rest of thelife.
As all other treatmentsalso radioiodine has risks and side effects. The general ruleshould be to use for an individual the modality with the lowestrisk and the highestbenefit7,8,10,11,18,23,24,26,30,32,40,49,54-56. Mainrisks of surgery are irreversible paresis of the laryngeal nerveand hypoparathyroidism (risk of 3th order).Perioperative mortality which increases with age and accompanyingdisease is a risk of 4th order.
Radiation inducedcarcinogenesis and mutagenic effects have to be taken intoconsideration as possible risks of 131I-treatment. Ithas to be stressed that these risks are hypothetical since theyhave not been proven to be of statistical significance in allavailable follow-up studies.
So in conclusionradioiodine therapy of Graves' disease is safe without severe sideeffects.
Graves'ophthalmopathy isan autoimmune process initiated and maintained by antigen(s) sharedby the thyroid and the orbit. A matter of argument concerns thechoice of the method of treatment of Graves'hyperthyroidism whenclinically evident ophthalmopathy is present. Restoration ofeuthyroidism appears to be beneficial for ophthalmopathy. Therational for a definitive therapy of Graves'hyperthyroidism is apermanent control of the hyperthyroidism, ablation of thyroidtissue may result in the removal of both the thyroid orbit crossreacting antigens and the major source of thyroid autoreactivelymphocytes.
The relationship betweenradioiodine treatment and the course of ophthalmopathy is a matterof controversy and some authors have suggested that radioiodineadministration may be associated with a worsening of preexistingophthalmopathy61. This is not observed when radioiodinetreatment was associated with a three month oral course ofprednisone4.
This development orprogression of ophthalmopathy in Graves'patients might be due tothe release of thyroid antigens following radiation injury and tosubsequent exacerbations of autoimmune reactions directed towardsantigens shared by the thyroid and the orbit.
The glucocorticoidtreatment should be limited to patients with evident ophthalmopathyand to those without ophthalmopathy but with other known riskfactors, such as smoking43.
Therapy oftoxic nodular goiter (thyroid autonomy; Plummersdisease)
Besides Graves'diseasefunctional thyroid autonomy (Plummers'disease) is still the mostfrequent cause of hyperthyroidism, especially in iodine deficiencyareas. In these countries thyroid autonomy is four to fivefold morefrequent than in areas with a sufficient iodine supply. Thyroidautonomy can be further differentiated into uni-, multifocal ordiffuse (disseminated) TSH-independent thyroidal hyperfunction byquantitative thyroid scintigraphy with 99mTcpertechnetate.
The aim of radioiodinetherapy (RIT) in autonomy is the destruction of autonomous tissuewith restoration of euthyroidism. Some groups have successfullyused standard activities46. Others modify the fixed doseby giving larger activities per gram multiplied by the estimatedthyroid weight and normalised to the 24 hours uptake value. InGermany radiation protection authorities require the estimation oftherapeutic activity by a radioiodinetest. For dose estimationMarinelli's formula is generally used:
MBq 131I = Gy desired x weight of target thyroidtissue x 24.8
maximal uptake (%) x effective half life (d)
Many investigators usedultrasonogaphic volumetry in the determination of the weight of thetarget volume in patients with unifocal autonomy. Agreement existsthat in these patients an empirical dose of 300-400 Gy should bedelivered to the autonomous tissue. Because it is impossible tomeasure the autonomous voulme in multifocal or disseminatedautonomy by ultrasonography with certainity, the sonographicapproach to determine the target volume has been replaced by a socalled «compromise». For this concept the thyroid glandas a whole was taken as the target volume and the target dose wasreduced to 150-200 Gy. Using this concept sufficient therapeuticsuccess could only be achieved in patients whose TCTU was smallerthan 3.2%, indicating that higher doses were necessary in a certainthyroid volume if the amount of autonomous tissue exceeded acritical limit. As a consequence the original approach was modifiedby adapting the target dose in autonomy to the TcTUs-values. Thismodified concept uses the total thyroid volume as a target withstepwise increasing the target doses between 150-300 Gy which aregiven dependent of the pretherapeutic TcTUs. Recently preferableresults were publihed for this method.
A more functionalapproach in the determination of the target volume was developpedby authors who made an attempt to estimate the «autonomousvolume» directly by a linear correlation between thesonographic volume of unifocal thyroid autonomy without anyregressive changes and their corresponding TcTUs values. In orderto estimate the autonomous volume independently of its distributionform of thyroid autonomy.
Thyroid autonomy is verycommon in longstanding goiters, so not only the diagnostic proof ofa thyroid autonomy is an indication to radioiodine therapy or evensurgery as the most common alternative treatment regimen. Thyroidautonomy should definitively be treated in patients havinghyperthyroidism, borderline thyrotoxicois, because of proven highercardiac risk, and euthyroid patients where the TCTU undersuppressive conditions (TCTUs) is higher than 2.0%.
Own results demonstratethat after a 18 months follow-up radioiodine therapy is successful(TSH > 0.5 and or TCTUs < 1.6%) in 84%. Of these patients 91%were euthyroid with or without thyroxine and 9% borderlinehypothyroid (TSH > 4 uU/ml). A dose of 350-450 Gy to theautonomous tissue resulted in a success rate of 97% in the unifocaland 78% in multifocal or disseminated autonomy. A negativeinfluence comes from high therapeutic volume of the gland, highpretherapeutic TCTUs, multifocal and disseminated autonomy and lowtarget doses.
The results are normallygiven after 6 to 12 months with a complete elimination of theautonomous tissue.
Treatment startegiesdiffer from country to country. Also the possibility of anoutpatient or inpatient treatment is different and is the same asdescribed for Graves'disease.
Treatment ofnon toxic goiter
Radioiodine is notclassically used in the first-line treatment of non toxic goiter.Surgery is more common. However there may be a great benefit forsome patients from radioiodine therapy, particulary when surgery iscontraindicated as in elderly patients with cardiopulmonarydiseases or not accepted by the patient for variousreasons.
A thyroid relapse aftersurgery represents another indication for radioiodine therapy. Theuse of 131I in nontoxic goiter has certainly beenreinforced by the general safety of this treatment.
Overall median thyroidvolume reduction averages 50% after 24 months. In this indicationalso standard activities and dosimetric activities are reported,using the Marinelli algorithm.
Again modalities oftherapy differ from country to country in Europe.
Therapy ofinflammatory joint diseases (radiosynovectomy)
The principle ofradiosynovectomy means, that the inflammed synovia will benormalized or cured after application of radionuclides in the jointand the inflammatory process will be stopped.
Radionuclides and activity
For radiosynovectomy onlybeta-emitting radionuclides are applied. The beta-emitters have topenetrate and cure the swollen synovia and the underlying cartilagehas to be protected. The radioisotopes have to be fixed toparticels small enough to be phagocytosed, but large enough for notleaving unspecifically the joint. The optimal size seems to be 2-5um21.
For this reason differentradionuclides are available and used because the thickness of theynovia in different joints is different. In smaller jointsradionuclides with a short pathway in larger joints radionuclideswith a longer pathways are used.
The mean beta-energy of186Re is 1.07 MeV and additional a gamma-energy of 137keV is available, which allows gammacamera imaging. The pathway ofthe beta-energy is 3.7 mm and the physical halflife is 3.7 days. Asa chelating agent sulfat is used. 186Re is used forwrist, ellbows and ankle joints with an activity of 74 MBq and forshoulders and hip with a dose of 111 MBq.
The mean beta-energy of90Y is 2.26 MeV with a maximal pathlength of 11 mm insoft tissue. The physical halflife is 2.7 days. Due to itspathlength it is only used for injection into the knee joints withan activity of 185 MBq.
The maximal beta energyof this low activity isotope is 340 keV with a short pathway of 1mm in soft tissue. The physical half life is 9.5 days. The lowenergy is optimal for small joints just as in finger joints.Normally no more than 37 MBq are injected per joint.
Autoradiographic studieswith colloidal coupled radionuclides show a preliminary superficialbinding of the radionuclides and shortly afterwards also a deeperaccumulation without damageing the cartilage of the joint. Inaccordance with an external radiation beam therapy the effect ofradiation synovectomy can be described as an initial hyperemia,increased capillary leakage, increased leucocyte migration and deadwith a subsequent increased cellular and humoral defense reaction.The final consequence can be described as reduction of localhyperemia with reduction of inflammation and inactivation ofinfiltration. Following this first step fibrosis of the synoviawithout damage of the cartilage are the consequence. The fibrosiscan first be detected 2-3 months after instillation of theradionuclides. One of the consequences is the reduction offiltration and resorption of synovial fluids. After therapy it isrecommended to fix the joint for at least 48 h via lying thepatient in the bed or via a cast to prevent efflux of theradionuclides out of the joints into the lymphatic vessels and theregional lymphnodes.
The application should beperformed under x-ray controll or preinjection of99mTc-pertechnetate under gammacamera to make sure thatthe radionuclide homogenously distributes. At a single time pointmore than one joint can be treated, but a total administeredradioactivity of more than 400 MBq should not given peryear.
Indications for therapy
Radiosynoviortheses isindicated in different joint diseases, such as rheumatoid arthritisand other inflammatory joint diseases, hemarthros in patients withhemophilia, villonodular synovalitis and osteoarthritis.
Before therapy an activeinflammation in the joint to treat has to be documented via threephase bone scintigraphy with increased blood pool activity or in apertechnetate scintigraphy of the joint. This diagnosis of activityallows a semiquantitative reevaluation of the joint after therapy.Via sonography the inflammatory activity can be judged by thedetermination of the thickness of the synovia.
In all the patients after6 months a reduction of the thickness of the synovia of about 50%can be documented, whereas the reduction of the inflammatoryprocess starts earlier and is about 40% after the first month. Thiscan be documented by three phase scintigraphy and sonography. Painrelief starts early at 1 month after application and reaches itsmaximum at three months posttherapy.
If a reflux or aninstillation of part of the radionuclid happens into the puncturechannel skin necrosis may happen. In 2% of the patients increasedbody temperature is described. Also in about 2% joint effusionhappens immediately, which is not permanent. This can be preventedby a coinjection of steroids. Systemic side effects are notreported.
Therapy ofspondylitis ankylosans
Spondylitis ankylosans isa common rheumatoid disease with inflammation of the small jointsof the spine and the ileosacral joints with pain and immobilisationof the spine as well as inflammation of the tendons of the centralskeleton.
Recently the old, but fora long time not longer avaible 224Ra-chlorid (224-Ra) isavailable again. The injection of this drug leads to a target doseat the surface of the bones of 6 Gy.
The use of224Ra-chlorid is based on a low dose scheme with a 10times weekly repeated injection of 1 MBq. A repetiton of thetherapy is recommended not earlier than 10 yearsafterwards.
Indicationfor 224Ra-Radiumchlorid and results
The indication is onlygiven, if the disease is proven but should be performed early inthe course of disease. This is important to start radiation at thetime of inflammation and not when inflammatory lesions have gone.The treatment results in good pain relief and better mobilisationof the spine. Earlier described tumor induction is based onsignificantly higher activities used in earlier times.
THERAPY OFMALIGNANT DISEASES
Therapy ofthyroid cancer
Thyroid cancer is a raremalignancy with wide interethnic and geographic variations. Theoverall incidence is increasing slightly in recent years.The mostcommon types of cancer are papillary (60-80%) and follicularcancers (10-20%). The relevant prognostic indicators are tumorstage and distant metastases. The mean survival rates in papillarycancer usually exceed 90%, whereas in follicular cancer the amountis about 80%.The standard treatment procedure in these thyroidcancer types are total thyroidectomy followed by adjuvant ablativetherapy with radioiodine and thyroid hormone suppressive therapyafterwards. Only in papillary thyroid cancer stage pT1 No Molobectomy alone is considered to be appropriate. In patients withlocally invasive differentiated thyroid cancer stage pT4 adjuvantpercutaneous radiation therapy is a treatment option.
Indicationand treatment strategy
Patients withdifferentiated thyroid cancer first are treated with athyroidectomy (exception papillary thyroid carcinoma pT1, N0, M0)and afterwards the thyroid 131I-uptake of the remnantshould be measured with a test activity. If the 24 h remnant uptakeis higher than 20% the patient should be reoperated to furtherreduce the remnant. Sonographic evaluation is not reliablyimmediatley after surgery and significantly overestimates theremant volume. Then the ablative therapy with radioiodine131I is initiated if the TSH level is higher than 30mU/l. The short ranging beta-radiation (maximum range 2 mm in softtissue) of 131I (8 days half-life) allows to administertumor doses of higher than 500 Gy in tumor tissue. Percutaneousradiation therapy only achieves about 70 Gy. The basis for thistherapy is the same as for benign thyroid diseases, it is theexpression of the sodium-iodine-symproter, which specificallyaccumulates radioiodine in benign and malignant thyroid tumortissue.
The expression is lowerin tumors as in normal thyroid tissues, which explains thatpresurgically these nodules always are cold, because thesurrounding benign tissue accumulates nearly all of the iodine. Butafter removing the normal thyroid tissue thyroid cancer tissueaccumulates enough radioiodine for therapy.
The indications for aroutine ablative dose after surgery for patients havingdifferentiated papillary or follicular thyroid cancerare:
-- Elimination of thebenign or potentially malignant remnant in the neck as a good basisfor thyroglobulin follow-up.
-- The adjuvant therapyof potential small circulating tumor cells or tumor cell clustersin lymphnodes or other organs.
-- Curative or palliativetreatment of inoperable tumor or metastases.
-- Staging procedure,because high radioiodine doses are significantly better than lowdoses for imaging small metastases such as small disseminatedpulmonary metastases in lymphangioses carcinomatosa of thelung.
In patients withmedullary and anaplastic thyroid cancers no radioiodine uptake hasto be expected. In oncocytic differentiated carcinomas an effectiveradioiodine accumulation can be demonstrated not very often, so itshould be tried to treat these patients because they may benefitfrom radioiodine therapy.
The effect of radioiodinetherapy is inversly correlated with the tumor mass. The higher thetumor volume, the lower the therapeutic benefit. So beforeradioiodine therapy it should always be considered together withthe surgeon to remove as much tumor tissue as possible.
The only contraindicationfor radioiodine therapy is pregnancy. So pregnancy should beexcluded before therapy and also breast feding has to be stopped,because radioiodine is excreted in breast milk.
In the ablativesituation the patients is treated between 3 to 4 weeks aftersurgery. At this time the TSH level is usually higher than 30 mU/lwhich is accepted to be high enough for radioiodine uptake in tumortissue. Between surgery and radioiodine therapy thyroid hormones,iodine containg drugs and contrast agents are contraindicated. Theurine iodine excretion should be checked, if possible.
The radioiodine uptaketest should be done with low activites of radioiodine to preventstunning15. Activities of 10-20 MBq arerecommended.
300 Gy are sufficient toablate thyroid remnants48. 1-3 GBq 131Ideliver doses of more than 300 Gy if the tissue of the remnant issmall enough. Some authors prefer to administer radioiodine on adosimetric basis of the Quimby-Marinelli formula. But in generalthis is impossible, because the volume of the remnant can not bedetermined exactly.
The therapy itself shouldbe combined with high hydratation of the patient to facilitateurinary excretion and by oral stimulus of salivary gland excretion,i.e lemon juice, to keep the radiation exposure of the patients aslow as possible. Recently Amifostine has been used to reduceradiation exposure to the salivary glands12. In patientswith large local remnants and with no further option of surgerynon-steroidal antiphlogistics should be administered to preventradiation induced thyroiditis.
In curative orpalliative therapy of tumor residues, recurrences lymphnode ordistant metastases if not performed immediately after surgery,the thyroid hormone suppressive therapy has to be stopped for 3-5weeks to achieve TSH stimulation of higher than 30 mU/l. In thefuture perhaps recombinant human TSH may be injected to induceradioiodine uptake.
In general diagnostic ordosimetric studies should not be performed immediately beforeradioiodine therapy, because stunning could prevent acceptableradioiodine uptake in the tumor tissue. So most of the authorsadminister standard activities between 5-10 GBy.
In patients with highthyroglobulin but without radioiodine positive diagnostic scanssome authors recommend also to perform radioiodine therapy. Thebenefit of the patients is around 50-60% of the cases47,but the benefit is only measured as a disappearence of an elevatedtumor marker. In patients with faint radioiodine uptake in thetumor tissue retinoic acid for some weeks may induce131I uptake again59, but these data havestill to be confirmed.
The targeting ofneuroblastoma with radiopharmaceuticals is based on thecharacteristic features of neuroblastoma such as the metabolism ofMIBG, via receptor binding or via antibodytargeting27-29. The active uptake-1 mechanism at thecell membrane and the neurosecretory storage granules in thecytoplasm of the neuroblastoma are responsible for the uptake of131I- or 123I labelled MIBG. Theradiopharmaceutical may be released from the granules', but areuptake mechanism prolongates the retention in the tumor cells. Innon adrenergic tissue there is a passive diffusion only. Thepeptide receptors on top of neuroblastoma cell lines, which havebeen used for neuroblastoma imaging are the somatostatin receptorand the vasoactive intestinal peptide receptor. Reubi53has shown that somatostatin receptor is expressed in 86% and VIPreceptor in 57% of all the cases.
Goldman ycols.20 and Cheung y cols.14 reportedsuccessful radioimmunoscintigraphy with a 131I-labelledUJ13A and a 131I-labelled 3FB antibody (oncofetalantigen ganglioside GD2). Nowadays studies in nude mice demonstratea high specific tumor uptake with an antibody against a cellsurface glycoprotein chCE722. First clinical resultshave been reported. Potentially due to the high radiationsensitivity of neuroblastoma cells MIBG therapy, peptide therapywith 90Y-DOTATOC or labelled VIP and radioimmunotherapywould be possible approaches.
The largest experiencenowadays is based on 131I-MIBG therapy. The indicationfor such a therapy are TNM stage III and IV, where chemotherapy andsurgery, sometimes high dose chemotherapy with stem celltransplantation are the basis of therapy. Radiation therapy mayfollow. Due to the bad prognosis of the disease other therapystartegies are warranted.
Contraindications for131I-MIBG therapy are severe myelosuppression and renalfailure. Unstable clinical conditions which do not allow to isolatethe patient in a specific unit is a relativecontraindication.
131I-MIBGtherapy is given in the following clinical settings: in recurrentor progressive disease after all other modalities have been used,preoperatively at the start of the treatment protocoll ininoperable stage III and IV disease and in combination withhyperbaric oxygen therapy.
Generally a fixed does of3.7-7.4GBq (100-200mCi) of 131I-MIBG with a highspecific activity (up to 1.48 GBq/mg) is intravenously injectedduring 30 min to 60 min. For thyroid protection 200 mg potassiumiodide is given orally daily.
Different results insmall series have been published and demonstrate a low responserate but sometimes a very impressive palliativeeffect27-29,37,62,63. The review of pooled results of intotal 273 treated patients indicated an overall objective responserate of 35%. Most of these patients had progressive and intensivelypretreated diseases in stage IV disease.
The therapy and theisolation of the patients is generally well tolerated.Thrombocytopenia may selectively occur due to a radiation of thebone marrow but also due to selective uptake of MIBG in platelets.In patients with bone marrow involvement the use of stem cells orbone marrow for transplantation is recommendable.Troncone62,63 described hypertensive crisis shortlyafter administration of the drug.
The objective ofintroducing 131I-MIBG therapy as the first therapy wasto reduce the tumor volume, enabling adequate surgical resectionand to avoid toxicity and the induction of early drug resistance.An additional advantage of such an approach was that the child'sgeneral condition is unaffected or improved before it undergoessurgery. In this approach chemotherapy is reserved to treat minimalresidual disease. In their inital results Hoefnagel ycols.28 demonstarte that the objective response rate wasbetter than after conventional treatment and 70% had complete or> 95% resection of the primary tumour or did not require surgeryat all. The toxicity after such a first-line therapy was only mildthrombocytopenia and moderate myelosuppression, because in thesepatients the bone marrow was not infiltrated. In conclusion thefirst line treatment is at least as effective as combination withchemotherapy but is combined with significantly less toxicity. Thecombination of both was reported to be associated with severetoxicity45.
Several new applicationsare nowadays discussed, such as the use of Auger-electron emitterslike 125I-MIBG or alpha-emitters like At-211-MABG. Alsothe combination with other uptake and retention increasingradiopharmaceuticals are discussed, i.e interferon, retinoic acidsetc.29.
First results have alsobeen reported on the use of radioimmunotherapy as is describedabove.
Therapy ofpheochromocytoma and paraganglioma
Pheochromocytomas andparagangliomas are rare catecholamine-producing tumors which arisefrom chromaffin tissue. When there is the suspicion of apheochromocytoma the biochemical confirmation is based on 24 hoururinary excretion rates of catecholamines and their metabolites(metanephrines, VMA etc.). Non invasive imaging techniques such asCT and MRI and123I-MIBG scintigraphy are performed tolocalize the tumor and / or metastases. 111In-octreotidemay also be applied, especially in head and neck chemodectomas.Malignant paragangliomas of adrenal or extraadrenal origin show avariable natural history from a locally invasive indolent tumor toa highly agressive tumor. Surgery with complete resection ordebulking of the primary tumor is standard treatment. Externalradiotherapy or chemotherapy are not very effective. An alternativetherapy is here the use of 131I-MIBG.
Indications and contraindications
131I-MIBG ismainly indicated in disseminated and unresectable pheochromocytomawith a good tracer uptake, so that 131I-MIBG is able todeliver at least 20 Gy to the target. Another indication is thetreatment of small postsurgical residual tumors to completesurgery.
The aims of the treatmentare 1) symptom palliation 2) reduction of tumor function due to thesecretion of catecholamines 3) stable disease, partial or completeresponse42.
Imaging studies with123I- or 131I labelled MIBG shoulddemonstrate a good tracer uptake and retention and dosimetry arerecommended before therapy.
Before imaging anddosimetry drug intake interferring with MIBG uptake has to bestopped 7 days before starting scintigraphy or therapy, thyroid hasto be blocked with Potassium-perchlorate or high doses of iodine(200 mg) or Lugols solution. 18.5-37 MBq 131I-MIBG isslowly intravenously injected and whole body and spot images areperformed. Dosimetry should be performed according MIRDformulations41 taking into account 131I-MIBGtumoral uptake (% of 24 hr), retention of the tracer dose(effective halflife), the tumor volume estimated by CT orultrasound.
3.7-9 GBq of131I-MIBG is infused controlling heart rate, bloodpressure and ECG.
The treatment can berepeated within of 4 to 6 weeks, but usually within of 3-12months.
Cumulative doses of 30GBq have been reproted. Reinjection of treatment doses should bedependent from the toxicological profile (platelets > 150000/l).
Troncone andRufini62,64 report in a multicenter metaanalysis of 137treated patients a biochemical response in 52 patients, a completeresponse in 8, partial response in 25, stable disease in 60patients progressive disease in 29 and not evaluable were 15patients. But it is important to keep in mind that the therapeuticresponse depends on the tumor size, the number of metastases, theMIBG uptake and retention etc.
In advanced stages nearlyin all treated patients a symptomatic improvement could beachieved. A partial response (6 months to 4 years) was observed in68% of the patients. Soft tissue lesions better responded than bonemetastases. Smaller lesions responded better than larger lesions.Therefore debulking should always precede MIBG therapy. In theseadvanced stages a complete resonse was rare (5.8%). In patientswith less advanced disease longer lasting complete responses havebeen achieved.
In malignantparagangliomas partial responses were observed in most cases andsymptom palliation in all of them5,6,13,36. The largestseries is reported by Virotta y cols.65 with 22 patientswith chemodectoma. 10 patients were only evaluable but all showedsubjective benefit, 1 had tumor shrinkage and 9 showedstabilisation of disease.
Sideeffects and toxicity
Some patients complainimmediatley after infusion nausea and anorexia accompanied byvomating, which easily can be handeled by diet and antiemeticdrugs. Some patients demonstrate increase of blood pressure, due tocatecholamine displacement in the periphery, but this can behandeled by reducing infusion rate. Myelotoxicity is low, but a fewpatients have minor and transient myelosuppression with leucopeniaand thromocytopenia. This typically occurs 4 to 6 weeks aftertherapy. The risk is highest in patients with bone metastases. Thedevelopment of hypothyroidism has also beenreported1.
Therapy ofneuroendocrine tumours with somatostatin analogues
It is well known thatpeptide receptor scintigraphy with the radioactivesomatostatin-analogue (111In-DTPA) octreotide is asensitive and specific technique to show in vivo thepresence and abundance of somatostatin receptors on various mainlyneuroendocrine tumours. With this technique primary tumours andmetastases of neuroendocrine tumours as well of other cancer typescan be localized39. Based on this knowledge the use ofpeptide receptor radionuclide therapy, administration of high dosesof 111In- or 90Y-labeled octreotide analoguesis now in prospective clinical trials. Due to the experimentalstatus of this therapy the comments on it will be short, becausethe therapy is only available in a few centers.
The Rotterdam grouptreated thirty end-stage patients with mostly neuroendocrineprogressing tumours with 111In-DTPA octreotide with upto a maximal cumulative patient dose of about 74 GBq in a phase Itrial. There were no major clinical side effects after up to 2years treatment except that a transient decline in platelet countsand lymphocyte subsets can occur. Promising benefical effects onclinical symptoms, hormone production and tumor proliferation werefound. Of the 21 patients with progressive disease at baseline andwho received a cumulative dose of more than 20 GBq111In-DTPA octreotide 8 patients showed stabilisationand 6 a reduction of tumor size. There is a tendency to a betterresult in patients having higher tumoruptake17.
In a phase II study 40patients were treated in the Basel group with 4 intravenousinjections of a total of 6000MBq/m2 Y-90-DOTATOCadministered at intervals of 6 weeks. 82% of patients suffered froma tumor progression before therapy. According to WHO criteria thetumor response was as follows: complete remissions in 3%, partialremission in 20%, minor response in 13% stable disease in 50% andprogressive disease in 15%. The tumor response according to WHOcriteria was 23%, and 36% in case of endocrine pancreatic tumors.Up to now these results have been calculated after a nine monthsfollow-up. More than 90% of the patients had improvement of thesubjective syndromes. Side effects were only mild lymphopenialasting 3-5 weeks after injection in 20% of thepatients68. It could be nicely shown that in patientswith a positive antitumor effect there was a good correlation withthe dose to the tumor, calculated with 90Y-DOTA TYROctreotide34. A coinfusion of aminoacids is renalprotective, which is very important, because the kidneys are thecritical organ with the highest dose.
This therapy is one ofthe most promising therapies and has to be forwarded to patientswith smaller tumor load, who probably have better theapeuticresults.
Metastaticbone pain palliation
Pain is both a blessingand curse for humanity. The onset of pain serves as a benefactorwhen it convinces the patient to seek medical aid early, at a timewhen the pathophysiologic process is still reversible. However, thesame benefactor becomes a curse in the terminal stages of patient'slives, especially for those with metastatic bone cancer.
The therapy of bonemetastases with radionuclides is known since 40 years. Besidesosteotropic radiopharmaceuticals especially the pure beta emitterwill be used such as 89Sr and 90Y.Disadvantage of 89Sr is the long physical half-life of50.6 days. This is the reason why 90Y was preferred,which itself is incorporated in the bone metabolism, has a shorterhalf-life of 2.7 days and a higher betaenergy. Comparable resultswere known from P-32 but due its incorporation in the bone marrowas well myelosuppression is the consequence.
A new group is thecombination of bone seeking radiopharmaceuticals such as186Re-HEDP and 153Sm-EDTMP. For all thisradiopharmaceuticals the aim is bone pain palliation, which leadsto a lowering of the dose of drugs and increases lifequality.
After a conventionel bonescan, where the metabolic activity of metastases have been proventhe therapy can be started. The scintigraphic control can beperformed with a gammacamera using the Bremsstrahlung and the gammaenergy of the radionuclides.
The usual activities are:40-150 MBq (1-4 mCi) for 90Y, 35-100 MBq (1-3 mCi) for89Sr, 1.3GBq (35 mCi) for 186Re-HEDP and 2.6GBq (79 mCi) for 153Sm-EDTMP. These doses arerecommended for patients with 70 kg.
This kind of therapy isindicated in advanced stages of bone metastases mainly of prostaticand breast cancer, but all kinds of cancer metastases can betreated. The only relevant question is the metabolic activity ofthe osteoblastic metastases, which has to be proven by bonescintigraphy. About 80% of the injected radiopharmaceutical ismetabolized in the bone metastases whereas the rest is excreted viathe kidneys very fast, so a treatment as an inpatient isrecommended but not necessary.
The effect of bonepalliation is hard to document because most of these patients arein an advanced stage of the disease. Normally pain relief startsafter some days (doses to the metastases 4 Gy). The duration ofthis effect is strongly correlated to the dose to the metastases.If the tumor to bone ratio is 10 : 1 a dose of up to 40 to 50 Gycan be delivered.
The rate of success isvariable and ranges between 60 and 90%.
Side effects andcomplications are rarely documented. After several injections bonemarrow depression is reported. This therapy is mainly indicated andof benefit, if the pain is diffuse of larges areas of the bonewhere local external radiation is not possible toperform.
Some authors report theuse of higher doses of the radiopharmaceuticals to controll notonly pain but also the disease. 153Sm-EDTMP was injectedin five cycles using 30 mCi each9 and a significantdecrease in the number of bone metastases and a decrease of PSA inpatients with prostate cancer was reported. This remission of bonemetastes in the bone scan is remarkable and was also reported byMcCready y cols.9. He used 186Re HEDP in adose escalation study and found that metastases from prostatecancer in the bone can successfully ablated by therapy activitiesof rhenium-186 and that higher activities are even more effective.But in these cases bone marrow toxicitiy has to be considered andeven stem cell transplantation may be necessary.
Intraperitoneal and intrapleural therapy
Another palliativeapproach is the intraperitoneal or intrapleural injection of90Y-colloids. The colloids prevent resorption. Theapplication of the radionuclide is performed under sonographiccontrol in the left lower quadrant of the abdomen, or at thetypical side of pleuralpunction. Very important is the primarilyreduction of the volume of the ascites or the pleural effusion toprevent a dilution of the injected radionuclide. Before thetherapeutic radionuclid is injected the homogenous distribution ofthe injected radionuclide should be demonstrated using99mTc labelled colloids. After the therapeutic injectionthe distribution should be controlled with aBremsstrahlungsimage.
The indication for thiskind of therapy is a recurrung ascites or pleural effusion inmalignant diseases. The aim of the therapy is to stop or to reducethe volume of ascites or pleural effusion. In about 50-80% of thetreated patients the result starts but not earlier than 3 monthsafter injection. Patients with chylic effusion, large tumor massesin the abdomen or chest or patients with circumscribed fluid cystsshould not be treated.
Polycythemia is amyeloproliferative syndrome and mainly gets manifest in elderlypatients. The disease leads to splenomegaly and proliferation ofred cells but also platelets. The aim of the therapy isnormalisation of the blood cell counts to reduce the danger ofthrombosis and normalisation of the size of the spleen. Primarilyblood letting and chemotherapy is used.
After intravenousinjection of 32P as natriumdihydrogenphosphat, which isincorporated in cells with high turn over, predominantly in bonemarrow cells and in the calciumphosphat of the bone. Before therapyblood lettings should be performed to stimulated proliferationactivity of the bone marrow cells and increas the rate ofincorporation of 32P into the stem cells when stem cellproliferation starts.
The recommendedactivities are empiric. At the beginning 70-110 MBq (2-3 mCi)32P / qm body surface or a standard activity of 185 MBq(5 mCi). After 3 to 4 months therapy could be repeated if notherapeutic results can be detetced. It is recommended to inject a25% increased activity. A repetion of therapy is possible if thesingle dose is not higher than 250 MBq (7 mCi). The effective halflife is about 20 days and the absorbed dose is 5-14 mGy/MBq for thebone marrow. 5 to 10% of the activity is renally excreted within ofthe first 24 h. The cumulative urinary excretion is up to 50%. InGermany a 48 h indoors therapy is necessary.
Indications and results
A primary success of thetherapy can be expected in 60-85% of the patients with a time ofremission of 6 to 24 months. The mean survival time increases from1 to 2 years up to 11 to 16 years. There is no significantdifference in comparison to chemotherapy.
Acute side effects justas bone marrow aplasia and pancytopenia are rare, but due to thisfact blood specimens for control are recommended. Late side effectsis leukemia. The frequency increases from 1 to 2% up to 10 to 15%.Chemotherapy with Busulfan chemotherapy shows the same effect. Butnowadays other chemotherapeutics are recommended.
Pregnancy, age under 40years and leuco- or thrombocytopenia are contraindications. Thiskind of therapy can be performed in polycythemia but also inthrombocythopenia.
Intraarterialhepatocellular carcinoma therapy with 131I-labelledlipiodol
Recently in differentasian, french and german group the use of131I-lipiodoltherapy was reported. The131I-lipiodol has to be delivered via an intrarterialcatheter during hepatic angiography. The therpeutic efficacy isdependant on tumor mass. Side effects due to theradiopharmaceutical were tolerable and mainly consisted of atransient rise of liver enzymes.
These results areencouraging for tumors up to a moderate mass.
Localradioimmunotherapy of malignant gliomas
The high grade malignantgliomas (anaplastic astrocytoma and glioblastoma) have a very badprognosis since the available methods of treatment (surgery, radiotherapy and chemotherapy) are unable to control the progression ofthe disease for long. The use of specific monoclonal antibodieslabelled with a suitable isotope (iodine-131 and yttrium-90)represents an effective approach to hamper tumour regrowth. Someauthors have injected the antibodies intravenously, or have triedto increase the tumour / background ratio with the avidin / biotinsystem. In many cases the monoclonal antibodies were injecteddirectly into the tumoral bed after surgery. The largest seriesuses antitenascin antibodies labelled with 131I andrecently with 90Y for direct local injection. Theclinical results demonstrate the ability of this technique tocontrol, for a long time, the growth of the tumour. Theglioblastoma median survival was prolonged to 25 months(131I-therapy) or 31 month (90Y-therapy). Theresponse rate which comprises partial response, complete responseand no evidence of disease was 47.1% (glioblastoma131I-therapy) or 40% (glioblastoma 90Ytherapy). The use of 90Y proved to be more favourable inbulky lesions and reduced the radioprotection problems.
Radioimmunotherapy of Non-Hodgkins-Lymphoma
Few patients withrelapsed non-Hodgkin's lymphoma are curable with conventional dosesof chemotherapy or radiotherapy2,3,33. In contrast, highdoses of chemotherapy and radiotherapy in conjunction withautologous peripheral stem cell or bone marrow transplantation canoffer long term disease-free survival for between 20 to 50% of suchrelapsed patients2,3,33. However conventionalchemotherapy conditioning regimens used for autologoustransplantation are associated with high morbidity and 3-15%treatment-related mortality from infections, venoocclusive diseaseof the liver, interstitiell lung disease, and renal failure.Furthermore relapse rates remain high, with 40 to 80% of patientseventually developing progressive lymphoma.
Based on this backgroundthe clinical promise of radiolabelled antibodies has been recentlyverified by several authors.
Press ycols.50,51 have documented in an131I-labelled murine monoclonal anti CD20 (anti-B1)trial with myeloablative doses of 131I completeresponses in 83% of their patients and many of these responses havebeen durable. The patients received therapeutic infusions of 234 to777 mCi of 131I labelled antibody (58 to 1168 mg). In amedian follow-up time of 42 months the overall and progressionfree-survival rates were 68% and 42%.
The use of a coldchimeric anti-CD-20 antibody (IDEC-C2B8) is also well documented.Maloney (44) injected 375 mg / m2 and documented 46%response rate with 8% complete responses.
Kaminski35,67y cols. administered non-myeloablative doses of131I-anti-B1 (anti-CD20) mAb (34 -161 mCi) anddocumented 50% complete response. The median duration of responseexceeded 16.5 months. The therapy in these patients is dosimetrybased. Delivering 75 Gy to the tumor, this group reported a 57%response rate, a complete response in 35%. The median duration ofresponse was 9.9 months.
Knox y cols.38reported a 72% overall response rate and a 33% complete responserate with a non-myeloablative dose (13.5-50 mCi) of an90Y labelled murine anti-CD20 antibody (IDEC-Y2B8).Later on the same group with the same antibody (0.4 mCi/kg)reported an overall response rate of 67% for low grade disease aresponse rate of 82%, for intermediate grade 43% and for mantlecell disease 0%70.
Another approach is theuse of an anti-CD22 antibody. Vose y cols.66 report in adose escalating study a total response rate of 33%.
Dose dependant sideeffects were seen from the bone marrow, which had to be substitutedby stem cell transplantation in high dose therapy schemes. The sideeffects then are comparable to bone marrow aplasia after radiationor high dose chemotherapy. They were expected, because the antibodydelivers its activity also to the normal non malignant bone marrowcell. In a low number of patients hypothyroidism occured in theiodine labelled antibody therapy group although there was a highblocking of the thyroid uptake. Using murine monoclonal antibodies,a limited number of patients developped human antimouse antibodies(HAMA). The HAMA rate is low because all these patients areimmunocompromised due to their disease. Other side effects likemoderate fatigue, nause fever, vomating, pruritus and rash werereported in a frequency between 10% to 70%.
Patients with bulkydisease and splenomegaly were appointed as unfavourable in thebiodistribution, because in bulky disease the total uptake wasnormally low, in splenomegaly most of the injected antibody goes tothe spleen and for the rest of the tumour there is not enoughantibody left. But also in these situations responses arereported.
Summarizing the resultsof these published studies the highest number of responses andprogression free survival rates are reported in the high dose131I approach. The disadvantage is the handling of highdoses of 131I, the long inpatient status of thesepatients, whereas the low dose 131I has a shorter periodof inpatient stay and can be performed in some countries on anoutpatient basis. The use of yttrium-90 has the disadvantage ofhaving no gamma emission, which is also an advantage, because thisoffers a higher safety profile to medical personnel but doesnecessitate the use of another radioisotope (111In) forimaging studies.
Several independantgroups have now documented impressive efficacy with minimaltoxicity of anti-CD20 monoclonal antibodies andradioimmunoconjugates. Future studies will be aimed at integratingthis exciting group of radiopharmaceuticals in conventionalchemotherapy in the setting of minimal residual disease,investigating upfront therapy for previously untreated patients,amplifying radiation delivery to tumor cells using theavidiv-biotin pretargeting strategy and optimizing the applicationof these reagents to potentially curative high doseregimens.