Intratumoral Adjuvant Chemotherapy With Doxorubicine In ...

Turkish Neurosurgery 4: 145 - 149, 1993 Oktar: Intratumaral Adjuvant ADM Chematherapy

Intratumoral Adjuvant Chemotherapy With DoxorubicineIn Glioblastoma Multiforme and Anaplastic Astrocytoma

NEZIH OKTAR. ISMAIL TANER. IZZET ÖVÜL. EREN DEMIRTAS

Ege University, Medical School. Departments of Neurosurgery (NO, IT, IÖ), and Pathology (ED), Bornova, Izmir, Türkiye

Abstract : Intratumoralloeal chemotherapy was applied as adju­va nt treatment to 20 patient with reeurrent types of anaplasticastroeytoma (AG3-4) and glioblastoma multiforme (GBM). Amultiport catheter was implanted into the tumour and a portableAmmaya reservoir was plaeed under the sealp over the ap eneraniotomy bone flap. Doxorubidne (Adriamydne) was given0.5mg per day for ten day s ,and a total of ten treatments wereprogrammed monthly for each ease. Pre-operative Karnofsky per­formanee score was between 60 and 70%.Control CT seans of the

patients showed the tumour to be progressive in 40 %. regressive

INTRODUCTION

Several chemotherapeutic drugs have been usedeither as single agents or as combinationchemotherapy in the treatment of malignant gliomas.The antineoplastic activity of doxorubicine(Adriamycine=ADM) (an antiturnoral agent of an­tibiotic origin isolated from streptomyces peucetiusvar. caesius) has been clearly demonstrated (1).it hasthe ability to show specific immunosuppressive ac­tivity as an inhibitor of reverse transaiptase enzyme.ADM is not a phase-specific agent. Besides bone­marrow depression, stomatitis and hyperurichaemiahave been reported as known side effects. Becauseof its poor penetration into blood-brain barrier andsevere neurotoxicity. ADM is not considered suitablefor systemic brain tumour chemotherapy (18).On theother hand. its effectiveness in the prevention ofsystemic metastases and in combination therapy asadjuvant chemotherapy has been reported (23.24).

Instilling drugs directly into the CSF or gliomatissue has been repeatedly shown to inaease survival

in 30%, and stable in 30%. In two patients alacal sealp infectionand a eerebellar abseess due to Noeardia asteroides developed ascomplieations of the treatment, but no other sistemie or loeal sideeffeets were deteeted. Mean survival in the anaplastic astroeytomaand GBMgroups was 98.9 and 46.1 weeks respeetively. In conclu­sion, intratumoral doxorubidne treatment was found to be effee­

tive against systemie Lv. administratian in the anaplasticastroeytoma group rather than the GBM group.Key words: Chemotherapy, intratumoral, Doxorubidne, Cerebellarabseess

and improve quality of life by diminishing the disad­vantages due to the blood-brain barrier (4.7,9).Previous attempes at intratumoral chemotherapy forbrain tumours have been reported for a variety ofdrugs. including bleomycin (2),methotrexate (MTX)(7,10,24.28,29). cisplatin (3), interferon andnitrosoureas (17.32).

In this study. the antiturnoral effect of dox­orubicine (Adriamycine=ADM) as intratumorallocalchemotherapy was investigated in twenty anaplasticastrocytoma and glioblastoma multiforme (GBM)pa­tients.

MATERIALS AND METHODS

Twelve anaplastic astrocytoma and eightglioblastoma patients were included in the pro­gramme. Theyall had been irradiated and receivedCCNU chemotherapy with 1iomglm2 doses beforerecurrent tumour was diagnosed in control CT-scans.There were II women and 9 men with a mean ageof 48 years and mean performance status of 64.4%

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Turkish Neurosurgery 4: 145 - 149, 1993

on the Karnofsky scale. Histopathological diagnosiswas based on the WHO classification of 1990 with

an malignant astrocytoma i GBM rate of 60%. Twopatients had been operated four times, six threetimes. and ten patients twice.

Intratumoral chemotherapy was started on the se­cond post-operative day after a control of CT-sean forthe prompt site of the catheter. Microinjections ofdoxorubicine were administered per-operatively toeach recurrent glioma case. Doxorubicine(Adriamydne. Farmitalia), was given post-operativelythrough the Ommaya reservoir (20)in doses of 0.5mgdaily for LO days and repeated monthly ten times.ECG.blood uric acid. creatinin. white blood cells and

platelets were monitored routinely throughout thedrug administration.

In addition, ADM 60-75mglm was administeredintravenously in ten recurrent anaplastic astrocytomaand ten GBM as a consequent comparison group. Inthese systemic ADM treated groups , Karnofsky per­formance scale mean score were 68,3% and 60%.

respectively.

CT-scanning was performed bimonthlypostoperatively with and without cantrast enhance­ment to measure the size of the the tumour. Median

survivals were ca1culated using the Kaplan-Meiermethod (12).For statistical analysis , student t , F ande tests were used for the significant differences.

RESULTS

CT-seans of a right-sided occipital anaplasticastrocytoma case before and after the intratumorallocal chemotherapy treatment was shown in Figure1 a. b. The maximal total dose of 50mg ADM was

Oktar: 1ntratumoral Adjuvant ADM Chemotherapy

reached only twice in two anaplastic astrocytoma pa­tients. The mean total dose was 22.5mg.

Mild side effects were headache in three patients.and slight hyperurichaemia in one. In one patient.local irritative infection due to leakage of ADM to thescalp was observed. In another patient. an asepticmeningitis occurred and was treated with cor­ticasteroids. One patient developed a left sidedcerebellar abscess which was removed by suboc­dpital aaniectomy (Figure 2).Culture of the spedmenrevealed Nocardia astroides as a severe complicationof the treatment. This camplication developed otherthan the local site of the administered drug may beexplained in terms of its immunosuppressive effect.All other side effects disappeared in the first 72hours.Mean survival was 98.9 weeks in the anaplastic ast­rocytoma (AG3-4)group and 46.1 weeks in the theGBM group, Comparison of the survival rates of thepatients receiving systemic (i.v.) and intratumoralADM chemotherapy revealed a signincant effective­ness of local as opposed to the systemic chemothe­rapy in the anaplastic astrocytoma group (p<0.5). Nosignincant statistical difference was found in the GBMpatient group (p > 0,5) (student t test) (Table I).

Median survivals were ca1culated as 67.5 weeks

in locally treated and 60 weeks in intravenouslytreated malignant astrocytoma groups, and 44.5 and45 weeks in the GBMgroups. respectively (Figure 3).CT seans of the patients showed: tumours to be pro­gressive 40%, regressive 30% and stable 30% .

Histopathological investigation ofbiopsy materialafter intratumoral ADM administration revealed

some tissue necrosis and hyalinisation processes inthe vessels. as shown in Figures 4a. b.

Fig. la, b: CT-sean showing decrease in the size of an anaplastic astrocytoma before (a)and six montbs alter (b)mtraturn oral ADM treatment.

146

Turkish Neurosurgery 4: 145 - 149, 1993 Oktar: Intratumoral Adjuvant ADB Chemothetrapy

Fig. 3 : Kaplan-Meler survival curves for Anaplastic astrocytoma(AA) and GBMpatients treated with intratumoral or syste­

mic ADM chemotherapy

(62.0)

Groups & Median Survlval <in w··"i·

~ iniralumoral AA (67,5)

-+-Inlratumoral GBM (44,5)

Weeks

15 30 45 60 75 QO 105120135150165180195

10

TumoaB NofofIdean ageIdeanIdeanIdedianp

paoents

KmiofslySamia!Samia!iINdemi

(n)

Perioiiiwiceiinweeks'inweeks'resi'

SeoreIntratumoral ADM Chemotherapy Anaplastic

1246.166%93,9'675 weeksp<O.5

astrocyioma

weeks

'(Wopaoen~are stillhl'IOgGSM

8SU633%46,1 weeks44, weeksp>0,5

Systemic (Lv,) ADM Chemotherapy Anaplastic

10474683%62,0 weeks60,0 weeksp<0,5

astrixytoma GBM

10,2)60%42,9 weeks450 weeksp>0,5

Fig.2: Ct sean of a patient showing a left sided cerebellar abscess

during intratumoral ADM chemotherapy as a complicationof the procedure,

Table i: Comparison of Mean and MedianSurvivals of Cases Treated With Adjuvant

Intratumoral and Systemic ADM Chemotherapy

Fig. 4 a, b: Tissue necrosis (A) and hyalinisation processes in the vessels (B)after intratumoral ADM chemotherapy in biopsy materiaL.

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Turkish Neurosurgery 4: 145 - 149, 1993

DlSCUSSION

During the pa st decade there has been great in­terest in identifying the best drug for thechemotherapy ofbrain tumours, The basic prindpleof chemotherapy is that the drug mu st reach all partsof the tumour. and the side effects must be minimaL.

The blood-brain barrier prevents the delivery ofchemotherapeutic agents into the brain tissue andCSF is not an adequate pathway to reach solidtumours within the brain (29), In 1968, Ommayadescribed his initial experience with the insertion ofa CSF reservoir and a manual pump, In that earlyreview, there was a complication rate of 28% in 60patients. consisting largely of seizures and infection;in addition. pump failure occurred in 23% (23). Thesurgical technique was altered in subsequent years.showing more favourable complication rates inrecently published articles (8.16). Direct delivery ofdrugs into a brain tumour through multiple im­planted catheters by a stereotactic procedure hasbeen tried (9).but a few biopsi es have be en perform­ed after intratumoral chemotherapy (19). MTX.Bleomydn. Cisplatin. BCNUand other water-solublenitrosoureas and ADM were the antineoplastic drugsused for this purpose (5,8.13.20.26.27.28.32.33),

We believe that 0.5mg ADM was not adequateas a single dose. In same studies,mainly carried outby the Japanese researchers (11.25.30.31). the totaldose of ADM in intratumoral administration was

reported as 5-lOmg. Our total dose was much higher.ranging from 30 to 50mg (mean 22,5 mg), Throughoutthe study the postulated total dos e of 50mg was notachieved and no seizures.cardiotoxidty or nephrotox­idty occurred in any of the cases, Yoshida reportedalocal chemotherapy study in 79 patients; 63 withADM. 5 with a combination of ADM and bleomydn,7 with bleomydn and 4 with MTX and reported 8local infections and 4 meningitis cases as complica­tion s of this procedure (33).Mean survival was 806days in the AG3 and 757 days in the AG4 groupwhich was close to our findings (692 days in theanaplastic astrocytoma group).

Surgical implantation of biodegradable polymercontaining chemotherapeutic drugs into the tumourmay be considered as a therapeutic option (8 ). Withthis technique Kuba reported 91%of 18 months' sur­vival in 91% of 20 anaplastic astrocytoma cases and12 months in 47% of 23 GBM patients with in­tratumaral ADM treatment (14).Median survival of

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Oktar: Intratumaral Adjuvant ADM Chematherapy

patients treated with surgery alone is approximate­ly 20 weeks in GBMpatients. and surgery plus radia­tion therapy. 45-50 weeks (6).With our method themedian survival was 44.5 weeks in the GBMand 67.5

weeks in the anaplastic astrocytoma group.

Apart from unexpected complications. our studyshowed that the dose and side effects of the drugwere minimal in intratumoral chemotherapy. Serialstereotactic biopsies may help to determine the doseof the drug in the tumour and pathological foilow-up.

In conclusian. evaIuatian of the mean survival

rate of the patients, though the sizes of the groupswere smail. showed that intratumoral ADM treat­

ment was significantly more effective in the recur­rent anaplastic astrocytoma group than the GBMgroup.

Correspondence, Dr. Nezih OktarEge University Medical schoolDept. of NeurosurgeryBornova· 35100. Izmir. Türkiye

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