CANCER RESEARCH(SUPPL.)55. 5952s—5956s.December 1. 995]

Abstract

Two murine monoclonal antibodies, BC-2 and BC-4, raised againsttenascin and labeled with ‘@‘Iwere infused locally in the site of neoplasticdisease by means of a removable (16 patients) or indweffing (34 patients)catheter. Fifty patients bearing a malignant glioma were treated. Twentysix of these were suffering from recurrent disease; their tumors relapsedwithin 9 months (median) after treatment. The remaining 24 cases had anewly diagnosed tumor, and local radioimmunotherapy (RIT) was givenimmediately after surgery and radiochemotherapy. All efforts were madeto reduce the tumor before the infusion of the radiopharmaceutical.Therefore, 22 cases with relapsing glioma underwent additional debuiltingsurgery, which led to total or subtotal removal of tumor in 9 of thepatients. Altogether, 28 patients had intralesional RIT when the diseasewas minimal or microscopic. Conversely, 22 cases underwent local RITwith a tumor the diameter of which was >2 cm. In many cases, theinfusions were repeated up to six times to achieve complete destruction ofthe neoplastic tissue. The local treatment did not give rise to systemic orto cerebral adverse effects. The labeled monoclonal antibodies, givendirectly in the site of the lesion, concentrated in very high amount in theneoplastic tissue and remained fixed in the target for a long period of time.For these reasons, the radiation dose to the tumor was remarkable (onaverage >30,000 cGy/cycle) and consequently led to promising results. Themedian survival was, in total, 20 months (18 in recurrent tumors and 23in newly diagnosed lesions). Moreover, median survival was 17 months inpatients with bulky tumors (both recurrent and newly diagnosed tumors)and 26 months in patients with minimal or microscopic disease. Themedian time to progression was 3 months in recurrent and 7 months innewly diagnosed gliomas. Finally, RIT produced 3 CRs (all in recurrenttumors), 6 PRs (4 in recurrent and 2 in newly diagnosed), and 11 stabilizations of disease (4 in recurrent and 7 in newly diagnosed). In 19 cases(13 recurrent and 6 newly diagnosed) the progression of tumor wasrecorded.

Eleven patients (2 recurrent and 9 newly diagnosed) who were treatedby lilT when their disease was minimal and nondetectable by radiologicalmethods remained disease-free and were classified as NED. The overallresponse rate (NED plus CR plus PR) was 40% (34.6% recurrent and45.8% newly diagnosed). These data provide evidence for the capability of

this new therapeutic technique to achieve, in a significant number of cases,

lasting control of malignant gliomas and suggest the opportunity to applyusia treatment in an adjuvant setting.

Introduction

Current therapeutic modalities (surgery, external radiotherapy, and

chemotherapy) currently utilized control malignant gliomas and canprolong patients' survival, achieving a median duration of 12 months(1—3)and as long as 17 months (4). Nevertheless, they do not lead tocomplete remission of these tumors, which in almost all cases recur(5). Therefore, local techniques to selectively destroy the neoplastic

I Presented at the “Fifth Conference on Radioimmunodetection and Radioimmuno

therapy of Cancer,―October 6—8.1994. Princeton. NJ. This work was supported by aIstituto Oncologico Romagnolo. Cesena (Italy) grant from the National Research CouncilProgram: Clinical Applications in Oncology.

2 To whom requests for reprints should be addressed. Phone: (547) 352664; Fax: (547)

352660.

tissue without affecting the normal brain have been developed or areunder study (6—9).The locoregional administration of radiolabeledmonoclonal antibodies (10, 11) reacting specifically with antigenspresent in the tumor represents a promising approach in this field.Experimental (12, 13) and clinical (14, 15) studies have demonstratedthat the intratumoral injection of specific immunoglobulins linked toa suitable isotope yields a very favorable biodistribution of the radiopharmaceutical. In fact, the accretion of radioimmunoglobulins in the

lesion as well as their residence time in the neoplastic tissue areenhanced in comparison with that achievable by iv. administration.Moreover, the direct application of radiolabeled MoAbs3 into thetumor delivers a very high radiation dose to the target cells. Promisingoutcomes were obtained in a Phase I clinical study in patients withrecurrent tumor (16, 17). A second group of patients with newlydiagnosed malignant gliomas was given intralesional Rif, and thebiological and clinical effects of the treatment were evaluated andcompared in both groups.

Materials and Methods

MoAbs. Two murineIgGl antibodies,BC-2 andBC-4, the biological andhistopathological characteristics of which have been described previously (18)were used. Their target is TN, an exameric glycoprotein that is found inimpressive quantity in the stroma as well as in the cytoplasm of tumor cells ofmalignant gliomas (19, 20). Conversely, normal cerebral tissue completely

lacks TN antigens (21). This feature is favorable for glioma targeting by meansof MoAbs because a high concentration of these biological probes can beachieved in the tissue (22). The MoAbs were labeled with ‘@‘Iby means of thelodogen method, as published (23), with good labeling efficiency; immunoreactivity was preserved satisfactorily (24, 25).

Patients. Altogether50 evaluablepatientswere accruedin this study, theprotocol of which was approved by the Ethical Committee of “M.Bufalii―Hospital (Cesena, Italy) and by the Italian Health Ministry. The patients weresubdivided into two groups: group A, patients with recurrent malignant gliomas (26 patients); and group B, patients with newly diagnosed malignantgliomas (24 patients).

The mean age of the patients in group A was 49.6 years and ranged between26 and 70 years. In group B, the patients' mean age was 52.5 years (range,26—68years). In the majority of cases of groups A and B, the tumor diameterevaluated by CT scan before the first surgical operation was >3 cm, as shownin Table 1. Large tumor size represented an unfavorable prognostic factor (26,

27). Tumors were located in all lobes of the brain: temporal (11), parietal (10),frontal (8), parieto-occipital region (5), parieto-temporal region (5), frontoparietal region (5), occipital (3), fronto-temporal region (3), 3rd ventricle (1),and spinal cord (1).

The histology of the tumors, classified according to the WHO (28), in groupA were glioblastomas (19) and anaplastic astrocytomas (5). The Karnofskyperformance status (29) was 100—80in 35 cases (70%), 70—50in 10 cases(20%), and 40—30 in 5 cases (10%). Patients with recurrent malignant glioma

(group A) had a clinical course which can be summarized as follows: (a)surgical operation to resect their newly diagnosed primary tumor; (b) external

3 The abbreviations used are: MoAb, monoclonal antibody; TN, tenascin; CT, com

puted tomography; SPECT, single-photon emission computed tomography; DTPAdiethylenetriaminepentaacetic acid; HAMA, human antimouse antibody; PD, progressivedisease; NED, no evidence of disease; CR, complete remission; PR. partial remission.

5952s

Local Treatment of Malignant Gliomas by Direct Infusion of Specific Monoclonal

Antibodies Labeled with 131!: Comparison of the Results Obtained in

Recurrent and Newly Diagnosed Tumors1

Pietro Riva,2 Agostino AriSta, Giancarlo Franceschi, Massimo Frattarelli, Carmelo Sturiale, Nada Riva, Michela Casi,and Rosetta Rossitti

Nuclear Medicine Department and Istituto Oncologico Romagnolo. 47023 Cesena (FO), Italy fP. R., G. F., N. R., M. C., R. RI, and Neurosurgery Department, “M.Bufalini―Hospital. Servizio Multizonale di Medicina Nucleare, Via Ghirotti n 286, 47023 Cesena [A. A., M. F., C. S.] italy

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Table ITumor diameter (cm) atthe time of the firstoperationTumor

diameter(cm)1—2345>5Patients

Groups―Groupb―Total2

245

3814

15293

362

13

INTRALESIONALRIT OF MALIGNANT GLIOMAS

therapy to a total dose of 5400 cGy; in addition, she was given chemotherapy.Finally, she was given intralesional RIT according to the following schedule:first course (‘31I-labeled MBq 1850), on December 1993; second course

(‘311-labeledMBq 1443), on February 1994; and third course (‘31I-labeledMBq 1258), on April 1994. At the end of this period, the brain CT scan andSPECT (99mTclabeled DTPA) showed no sign of tumor. Nevertheless, she had

additional infusions on August 1994 (‘31I-labeledMBq 1961) and December1994 (‘311-labeledMBq 2479) as a precautionary measure. The patient iscompletely free of disease 26 months from diagnosis and 21 months from firstRIT course (Fig. 1).

Pharmacokineticsand Dosimetry Evaluations. Thebiodistributionof theradiopharmaceutical in the neoplastic lesion and in the rest of the body wasassessed with several different modalities: continuous whole body radioactivity recording by means of a Geiger-Muller probe set over the patient's bed;

serial measurements of blood and urine radioactivity; and sequential planar andSPECT scintigraphies of the brain, chest, and the abdomen immediately afterthe infusion and daily up to 7—10days (16, 31, 32). These data led to thecalculation of the percentage of injected dose concentrated in neoplastic andhealthy tissue as well as the effective half-life in these sites. The size of tumorswas obtained by CT scan examination.

In patients bearing a minimal lesion who were treated immediately aftersurgery and external radiotherapy, the tumor volume was assumed as a narrowzone adjacent to the bed of the primary lesion with an assumed depth no larger

Fig. 1. A 58-years-old female patient. This patient was operated on July 1993 for ahuge and infiltrating left temporo-parietal glioblastoma (bottom). Intralesional RIT wasadministered immediately after surgery and radiochemotherapy as an adjuvant setting.The patient received five MoAbs infusions. The cumulative ‘@‘Iwas MBb 8991 (i.e., 243mCi). The total radiation dose to neoplastic tissue was 242.000 cGy. The patient does notpresent, thus far, any sign of disease (top) 26 months after operation and 21 months afterthe beginning of the locoregional treatment.

a Group a, patients with recurrent tumor.

b Group b, patients with newly diagnosed tumor.

radiotherapy at the maximum tolerated dose (60—70Gy) delivered to a limitedfield; (c) chemotherapy given in 20 patients by combining different drugs; (d)in all cases the tumor relapsed after a median time of 9 months; (e) thus, theywere referred for intralesional RIT; (f) 22 of 26 patients underwent an

additional surgical operation that was carried out with the support of the

operating microscope, aiming to achieve total or subtotal removal of theregrowing glioma tissue before the local infusion of radioactive drug. This goalwas achieved in 9 cases, whereas in the remaining 13 patients a neoplasticremnant, the diameter of which was, on average, 4.08 cm (range, 2.2—6.1cm),remained; and ( g) finally, MoAbs conjugated with ‘@‘Iwere infused intratumorally. Conversely, the patients in group B with a newly diagnosed malignantglioma had intralesionai RIT immediately after surgical operation and radio

chemotherapy. In this group, surgery achieved more effective reduction oftumor burden. In fact, 15 of 24 patients had a minimal or microscopic residualdisease after surgery. In the remaining nine cases, the mass left by theintervention had an average diameter of 2.95 cm (range, 2—4.1cm). In allpatients, immunohistochemistry (30) confirmed the expression of TN in sufficient amount (at least three plus). All patients gave their informed writtenconsent before the infusion of radiolabeled MoAbs.

Protocol of RIT. The methodology used has been described in detail (16,3 1, 32) and is briefly summarized here. The patients were pretreated withantiepileptic drugs, steroids, antibiotics and thyroid-blocking agents. To injectthe MoAbs exactly in the site of the disease, an indwelling Rickam catheter,with a reservoir located under the skin, was utilized in the majority of cases (34of 50). This device was set up by the surgeon during the operation whichproduced a cavity at the site of the tumor. The tip of the catheter was placedinside the cavity. In this way, antibodies injected through the external reservoirreached the cavity and homogeneously diffused through it to reach and bindtheir specific target. In 16 cases, 12 of these bearing recurrent lesions (group

A) and 4 with newly diagnosed tumors (group B), a removable catheter wasused. It was inserted surgically or stereotactically and had to be removedwithin 2 weeks to avoid local infections. The radiolabeled MoAbs were bolus

administered within 30 s. The volume ofradiopharmaceutical was always <1.5

ml to prevent an increase of the intracranial pressure. In the first 26 patients,escalating doses of “Istarting from 185 MBq and reaching 2405 MBq,increasing 185 MBq at each level, were administered. In this way, the maximum tolerated dose was determined to be 2405 MBq. In the second series ofcases (24), higher ‘@‘Idoses ranging from 1850 to 2405 MBq (mean, 2146

MBq) were used. This amount of radiopharmaceutical proved to be safe andeffective and was chosen to be utilized in subsequent applications. Theprocedure of injection and the subsequent management of the patients were

carried out according to radioprotection regulations.

Multiple lilT Cycles. RIT courses were repeatedmany times, when thecourse of the disease made it possible. The first three therapeutic injectionswere given at short intervals (30—60days). Subsequent injections were givenafter 3—4months with respect to the response of the tumor to the treatment. In

17 cases, patients' RIT infusions were interrupted owing to the progression ofthe tumor.

In those patients who experienced a favorable response, RIT courses wereinterrupted only when the patients did not have evidence of disease for at least

6 months. This was assessed by radiological investigations (CT scan, magneticresonance imaging, and brain SPECT with @“Tc-labeledDTPA), which had to

be completely normal. This rule was adopted empirically, on the basis of theexperience gained during the course of the trial. The maximum number ofinjections given to the same patient was six; four cases had six administrations.As an example of this particular strategy, the clinical course of the patient isreported. She was operated on July 1993 to remove a huge left temporoparietal (diameter, 3.69 cm) glioblastoma. Then she underwent external radio

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TabIc 2 llAMAproductionCycleHAMA

@aGroup a1'Group b'Titer median a'@Titer medianbeI

2345

6I

7/5017/3819/2512/164/74/47/26

10/1911/136/82/22/210/24

7/198/126/82/52/21

:81:321:321:321:641:321:8

1:321:2561:1281:161:64

Table 3 Pharmacokinetics and dosimetry(meanvalues)All

patientsGroup aUGroupb―ID

% X gCeff.T/2―2.42±

1.858±322.11

±1.862.3±352.8±2 54.3±27.1cGyC42,300

±30,00030,000 ±26,00054,000 ±26,000

Group a'@%bTime'Groupb@'%TimeTotal%TimePD13505625919386SDC415.412729.29II2210PR415.41028.31161210CR311.5423642NED27.720937.511112213

INTRALESIONALRif OF MALIGNANT GLIOMAS

pharmacokinetics of the anti-TN antibodies when they were administered again.

Pharmacokinetics and Dosimetry. The MoAbs, injected directlyin the site of the tumor that contained large amounts of specific TNantigens concentrated in high quantity in the target and did not spreadto the normal brain or distant organs. Moreover, the residence time ofthe radiopharmaceutical in the tumor was long (Fig. 2) because theintralesional route of injection avoided the removal of the MoAbs.

As a consequence, the radiation doses that were given to thepatients with newly diagnosed malignant glioma were remarkablyhigh. The irradiation of the lesions of the patients with newly diagnosed malignant glioma were higher than that in patients with recurrent tumors, the fact that the tumor load was less in the former group

Fig. 2. Planar scintigraphy obtained. in anterior view, 63 days (i.e. more than 2months) after the intralesional injection of radiolabelled antibodies BC-2 and BC-4 (4 mg.of protein and 2220 MBq, i.e., 60 mCi, of ‘@‘I).This image demonstrates that the MoAbsintralesionally injected remain in the site of injection for a period of time extremelyextended. About 2% of injected dose is still concentrated in the cavity left by surgery,which was performed 21 months before. Only a small amount of free radioiodine has beenpicked up by the thyroid. This patient, who underwent the surgical removal of left frontalglioblastoma, received 5 Rif applications and is in complete remission 23 months sincethe first MoAb injection.

a I-IAMA +, number of patients who became HAMA positive after one or more RIT

courses, compared to the total number of cases who received one or more MoAbsinfusions.

b Group a, number of patients with recurrent tumor who became HAMA positive afterone or more RIT courses, compared to the total number of cases who received one or moreMoAbs infusions.

C Group b, number of patients with newly diagnosed tumor who became HAMA

positive after one or more Rif courses compared to the total number of cases whoreceived one or more MoAbs infusions.

d Titer median a, HAMA median titer recorded in cases with recurrent malignantglioma after one or more RIT applications.

CTiter median b, HAMA median titer recorded in cases with newly diagnosedmalignant glioma after one or more R]T applications.

than 1mm. By means of these data, the doses delivered to the neoplastic tissueand to the liver, kidney, bone marrow, urinary bladder, and thyroid etc. werecalculated applying both Medical International Radiation Dosimetry and

Monte Carlo formalisms (33, 34).Follow-up. Every montha physicalexaminationand a complete hemato

logical investigation were performed. In particular, a HAMA (35) assay wasdone using an ELISA method (36). Brain CT scan and brain SPECT (@“@Tclabeled DTPA) were carried out every 3 months. When the patient became freeof disease for at least 1 year, the clinical and radiological controls wereobtained every 6 months. The median survival time of all patients weremeasured from the time of initial diagnosis until death or last follow-up visitand was statistically evaluated according to Kaplan et a!. (37). The mediantime to tumor progression was calculated beginning from the first RIT course,applying the methodology described by Kaplan et al. (37). The objectiveresponse to the treatment was assessed clinically and radiologically (CT scan,brain SPECT with ‘@“Tc-labeledDTPA, and, ifnecessary, magnetic resonanceimaging), utilizing the WHO score (38). In this respect, objective measure

ments of the three main diameters of the lesions obtained both by CT scan andby SPECT were carried out. On the basis of the results of these investigationsthe responses to treatment were classified as PD, stabilized disease, PR, andCR (38). Twenty-fourpatients(9 in groupA and 15 in groupB) receivedlocalRIT after radical removal of the neoplastic tissue and subsequent radiochemotherapy. In these cases, the radiological examinations before R1T did notprovide evidence of macroscopic tumor. In fact, these patients had a postop

erative cavity, macroscopically free of disease, although occult neoplastic cellsaround the cavity were almost certain.

If these patients did not relapse after one or more RIT infusions, this resultwas classified as NED.

Results

Toxicity. The local administrationof large amounts of ‘@‘Iandimmunoglobulins did not produce systemic or cerebral adverse effects. All hepatic, renal, metabolic, and hematology functions wereunchanged. A few patients suffered mild and transient ailments, suchas headache and nausea after the therapeutic infusions, which spontaneously decreased and disappeared no later than 24 h afterwards.

HAMA. Sixty-nine % of the patients developed HAMA owing tothe spread of the murine IgG or of their degradation products into theblood stream. HAMA output was recorded in 64% of cases belongingto group A (16 of 25) and in 75% of group B (18 of 24). HAMA wasdose dependent because in cases who had three or more cycles, it wasalways present. Conversely, HAMA was observed in only 35.4% ofthose patients who underwent 1—2administrations (Table 2). Thepatients who became HAMA positive and were given additionaladministrations of MoAbs did not show allergic or anaphylacticsymptoms. Moreover, HAMA did not cause any modification of the

a Group a, patients with recurrent tumor.

b Group b, patients with newly diagnosed tumor.C ID. % x g., percentage of injected dose concentrated/g of tumor 24 h after the

injection.d eff. T/2, effective half-life of the radiolabeled MoAbs in the tumor (in hours).e cGy, radiation dose delivered to neoplastic tissue/cycle in cGy.

Table4 Objective response zoRIT (WHOcriteria) in 50 cases

a Group a, number of patients with recurrent tumor.

b ,,,, percentage of patients who experienced the response.C time, (median value) of the duration of the response. in months.

d Group b, number of patients with newly diagnosed tumor.eSD,stabilizationofthedisease.

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Table 5 Malignant glioma relapse afterRUTum.

bed―%bTime'Outside'@%TimeGroup

(Group 1/2 414.2 28.56 83 521.4 35.77.35Total642.77857.19

INTRALESIONALRIT OF MALIGNANT GLIOMAS

indwelling catheter utilized for the infusion was made of plasticmaterial so that it was tolerated by the tissues and could be left in

place for two or three years. At the same time, it guaranteed deposition of the radiopharmaceutical in neoplastic tissue, avoiding unwanted spread to normal brain. Thus, the intralesional administrationof radiolabeled MoAbs seemed to approach the features of the “magicbullet―proposed by Ehrlich (40). Repeated RIT applications could besafely performed.

This represented a therapeutical advantage with respect to otherlocoregional radiating techniques that can be used only one time (41,42). HAMA was observed in many cases but did not affect tumortargeting when repeated courses were carried out. (3-Rays of@@ 1! havea restricted energy and cannot penetrate into tissue >1 mm. Thepresence of physiological or anatomical obstacles could prevent thetargeting of tumor clusters. “Barriers―were represented by areas ofnecrosis, hemorrhagic infiltrations, and tumor zones with high interstitial pressure. For these reasons, relapse in the tumor bed occurred insome cases. In spite of these limitations, the clinical outcomes can bejudged as promising and are similar or better than the outcomesobtained with other aggressive approaches. For example, Wen et a!.(43) by utilizing stereotactic brachytherapy with 1251seeds, in additionto customary regimens, obtained a median survival of 18 months in 56patients with newly diagnosed glioblastoma. Moreover, in cases undergoing reoperation the median survival was 22 months. By usingstereotactic radiosurgery, in 5 1 cases a 10-month survival was re

corded (44), but in small, radiographically well-defined malignantgliomas a median survival of 26 months was observed (45, 46).Similarly intraoperative radiation therapy delivering a large radiation

dose to the neoplastic tissue in a group of 30 cases led to a survival of25 months (47). The use of a radiosensitizer combined with hyperfractionated irradiation (48) did not give a significant benefit to thepatients (median, survival 11 months). Finally, the i.v. injection ofradiolabeled MAbs (49) produced only one CR and two PRs of briefduration in 14 cases.

The survival thus far recorded in our patients points to evidence thatthe prognosis of this disease can be ameliorated and the patients' lifespan made longer in group A (18 months) and group B (23 months).Moreover, the application of intralesional MT to small or microscopiclesions, in an adjuvant setting, yielded additional prolongation of thesurvival (26 versus 17 months recorded in bulky diseases). Theobjective response to intralesional RIT was quite good, taking intoaccount the aggressive and invasive nature of these tumors.

In fact, 11 NED, 3 CR, and 6 PR were obtained altogether, corresponding to a 40% response rate. Moreover, in group B the percentageof NED and CR was higher with respect to group A (37.5 versus19.2%, respectively), whereas the progression of the disease (PD) wassignificantly lower (25% group B versus 50% group A). This repre

sents the most interesting issue of our study. The clinical experienceacquired during 4 years gave evidence that this innovative therapeutic

technique is able to reduce or completely destroy the neoplastic tissue,

to prevent the regrowth of the tumor, and to control the progression ofmalignant gliomas for a long time. The best model for the application

of intralesional RIT is represented by patients with newly diagnosedtumors in whom previous treatment (radical surgery, radiochemotherapy, and chemotherapy) has reduced neoplastic tissue to minimalor microscopic disease. Additional progress could be achieved by theuse of 90Y, the energetic f3particles of which can penetrate up to 1 cminto the tissue, thus, reaching more distant neoplastic elements andenhancing the probability of destroying the glioma cells. At the same

time its physical properties (absence of y emission and quite shorthalf-life, 2.5 days) greatly reduce the length of hospitalization.

a Turn. bed, nurnber of patients, who received RIT when their disease was apparently

absent and was not shown by radiological examinations, in whom the malignant glioma

relarsed in the bed of primitive lesions after one or more RIT courses.%, percentage of patients who presented a tumor relapse either in tumor bed or

outside the primary lesion.C Time, time (median value in months) elapsed from first RIT application to relapse.

d Outside, number of patients who received Rif when their disease was apparently

absent and was not shown by radiological examinations, in whom the malignant gliomarelapsed far from the seat of primitive lesions after one or more RIT courses.

C Group a, number of patients with recurrent tumor.

@Groupb, number of patients with newly diagnosed tumor.

B owing to previous aggressive surgery (Table 3). The irradiation

dose to liver, kidney, and bone marrow did not exceed 150 cGy/cycleand did not produce untoward effects.

Survival. The intralesional RIT approved to prolong the lives ofthe patients in comparison with the values usually reported for currenttreatments (surgery and radiochemotherapy), wherein median survivalis usually <12 months (39). In fact, the overall RIT median survival

was 20 months; in group A it was 18 months and in group B it was 23months. In cases (belonging to both groups A and B) who were treatedwith a tumor remnant with a diameter >2 cm, median survival was 17months. By contrast, median survival was 26 months in patients whounderwent RIT with minimal or microscopic lesions. The median timeto tumor progression was 3 months in group A and 7 months ingroup B.

Clinical Response. Altogether, the local infusion of radiolabeledMoAbs led to 3 CRs (all in recurrent tumors), 6 PRs (4 in recurrentand 2 in newly diagnosed), and 11 stabilizations of disease (4 inrecurrent and 7 in newly diagnosed). In 19 cases (13 recurrent and 6newly diagnosed), PD was recorded. Eleven patients (2 recurrent and9 newly diagnosed) who received intralesional RIT when their lesionwas minimal and not detectable by means of radiological examinations, remained disease free and were classified as NED (Table 4; Fig.1). The overall response rate, which included PR plus CR plus NEDresults, was 40% (34.6% recurrent and 45.8% newly diagnosed).

Relapse of the Tumor after lilT. In 14 cases who receivedone ormore RIT courses, the tumor, which was apparently absent at the timeof first RIT course, relapsed in spite of administration of radioactiveantibodies. The recurrence of glioma occurred in five patients ofgroup A and in nine patients of group B. Moreover, in 6 patients (2group A and 4 group B) the neoplastic tissue reappeared in the bed ofthe primary lesions. By contrast it reoccurred outside the site of theoriginal tumor in eight cases (Table 5).

Histological Modifications Produced by Local lilT. Seventeenpatients, 6 in group A and 11 in group B, underwent an additionaloperation because they presented radiological and clinical data thatwere judged as suspicious of relapsing disease after one or more RITapplications. In all cases, large areas of necrosis were found in the site

of the primary tumor. In three cases, neoplastic cells were completelyabsent and few malignant cells were present in the remaining cases.

Discussion

This study is still in progress and a larger number of cases has to be

treated to improve the significance of the results. Nevertheless, someconclusions can be drawn. The local infusion of radiopharmaceuticalproved to be a safe technique that was well tolerated. This was due tothe particular route of administration, which restricted the radioactiveantibodies to neoplastic tissue, thus preventing or greatly reducingtheir diffusion to normal brain or critical organs. In particular, the

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INTRALESIONALRif OF MALIGNANT GLIOMAS

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