Seven patients with recurrent malignant gliomas WHO Grade IV (NIV recurrent) .... The authors present a case of diffuse intrinsic pontine glioma presenting in a ...
Adjuvant lntraarterial Chemotherapy With Nimustine in the Management of World Health Organization Grade IV Gliomas of the Brain Experience at the Department of Neurosurgery of Dusseldorf University NORBERT ROOSEN, DRMED, DR, JURGEN c . w. KIWIT, DRMED, EVALDO LINS, PROF DRMED, MICHAEL SCHIRMER, PROF DRMED, AND WOLFGANG J. BOCK, PROF DRMED
A protocol with postoperative adjuvant intraarterial (ia) chemotherapy using nimustine (ACNU) was followed at the University of Dusseldorf (Federal Republic of Germany) after histologic confirmation of malignant glioma of the brain. The first iaACNU procedure was performed within 10 days of surgery, and immediately before postoperative irradiation. After radiotherapy further iaACNU courses were given. The study population consisted of 35 primarily treated malignant gliomas World Health Organization (WHO) Grade IV, i.e., glioblastomas (NIv). Of these tumors 11 showed early progressive disease (PD) (NIV whereas 24 had stable or responsive disease (NlvSDBm). Seven patients with recurrent malignant gliomas W H O Grade IV (NIv recurrent) were also treated plus six patients with malignant gliomas W H O Grade 111 (NIlr). Experience with 50 treated patients resulted from this study. The median survival time (MST) for the group NIV was 14.2 months; 41.0% of patients were long-term survivors. The M S T for the group NIv primPD was 7.8 months; 9.1% of patients were long-term survivors. For the group NIvsDaRD a M S T of 18.3 months and 66.7% of long-term survivors were determined. Patients with recurrent tumors on this treatment protocol had an additional MST of 6.1 months. The total M S T after first surgery was 16.2 months. The incidence of complications was low. Systemic complications were infrequent or rare. Retinal disturbances were seen in two patients; leukoencephalopathy was not seen in our patients. In 10% of patients cerebral complications were found, which were irreversible in 2% of patients. Complications could not be assigned unequivocally to the nitrosourea. These results compare favorably with what is reported in the literature, demonstrate the potential value of iaACNU in the treatment of malignant gliomas W H O Grade IV, and should encourage the initiation of a randomized clinical trial of adjuvant iaACNU in the therapy of these tumors. The authors propose iaACNU as a valuable approach in the management of primarily diagnosed malignant gliomas W H O Grade IV, but cannot recommend the delay of iaACNU until the recurrence of a brain tumor. Cancer 64:1984-1994, 1989.
T
HE PROGNOSIS for
patients with malignant gliomas of the brain is still very poor, despite intensive basic and clinical research on the treatment of these tumors.Ie4 The mainstay of the management of malignant cerebral gliomas certainly is surgical excision and postoperative r a d i ~ t h e r a p yThis . ~ ~ ~has been demonstrated in
large randomized controlled clinical trials by the Brain Tumor Study Group (BTSG).7.8These same studies i i s well as others showed a positive effect of chemotherapy on the course of the disease too, although the increase in median survival time (MST) and in the proportion of long-term survivors remained relatively m o d e ~ t . Other ~-~
From the Department of Neurosurgery, Hospital of the University of Dusseldorf, Dusseldorf, Federal Republic of Germany. Supported by Grant no. 500 018 87 from the Ministerium fur Wissenschaft und Forschung des Landes Nordrhein-Westfalen. The authors thank Professor W. Wechsler, Institute of Neuropathology. University of Diisseldorf. for doing the neuropathologic studies; Mrs. U. Hilbricht, Department of Neurosurgery, for preparing the artwork photographs: our colleagues. especially the nursing staff, for their help and efforts in the daily care of the brain tumor patients at the Department
of Neurosurgery;the radiological technicians for their execution of followup studies and the assistance during the intraarterial procedures; and Dr. H. Hiittmann, ASTA Pharma AG. Frankfurt, Federal Republic of Germany, for encouragement and support of brain tumor research at the Department of Neurosurgery of Diisseldorf University. Address for reprints: Norbert Roosen, DrMed, Dr, Department 'of Neurosurgery, Hospital of the University of Dusseldorf, Moorenstrasse 5 , D-4000 Diisseldorf 1, Federal Republic of Germany. Accepted for publication June 6, 1989.
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1984
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No. 10
INTRAARTERIAL
ACNU FOR GLIOBLASTOMA*
therapeutic approaches, such as immunotherapy, thermotherapy, ctc.. have not been conclusively proven to be Most studies with chemotherapy have used the systemic administration of various cytostatic agents, often in the context of clinical trials? However, antimitotic drugs may be infused locoregionally into the artery supplying a tumor, and this intraarterial (ia) administration might increase the tumoricidal efficacy of the drug as follows from theoretical considerations and as evidenced by clinical findings.I4-" The ia infusion may cause an increased incidence of local complications,'s319and the selection of an appropriate drug is important. We were encouraged by preliminary reports on the therapeutic safety of the nitrosourea nimustine (ACNU, ASTA Pharma AG, Frankfurt am Main, FRG, in license of Sankyo Co., Ltd., Tokyo) on ia administration.20,21 After using ACNU in an expeiimental model and looking at the pharmacokinetics of the agent in vivo,22we used ACNU to evaluate its efficacy and toxicity during adjuvant ia chemotherapy (iaACNU) of malignant cerebral gliomas. Here we present our experience with a series of 50 patients treated with iaACNU. Methods
Patient Charucteristics and Follow- Up During the last 3 years all patients with World Health Organization (WHO) Grade IV cerebral gliomas diagnosed at the Department of Neurosurgery of Diisseldorf University (Federal Republic of Germany) were evaluated for ia chemotherapy with ACNU. Some WHO Grade 111 gliomas were treated with iaACNU, too, but will not be considered extensively in the current analysis. The inclusion criteria to be fulfilled are described. A positive neuropathologic diagnosis of WHO Grade IV glioma was required, and this necessitated gross surgical debulking, partial resection, or at least stereotactic biopsy of the tumor. Generally, surgery was performed to reduce the tumor mass as completely as possible depending upon the extent of the glioma and the involvement of so-called eloquent areas of the brain. Patients younger than 18 years or older than 70 years were excluded. as well as patients with obvious atherosclerotic disease, severe general medical disease, or neoplastic disease other than the cerebral glioma. Pregnant female patients also had to be excluded. Routine laboratory studies for blood count, hepatic and renal function had to be within normal limits at the beginning of iaACNU chemotherapy. Performance status of our patients was carefully documented and those with a Karnofsky performance score of 4 0 were excluded from iaACNU.23Early in 1986 we introduced a more neurologic performance status evalu-
Roosen el d.
1985
ation according to Duff et a1.,13and those patients already entered were rescored retrospectively. Patients with a neurologic status grading of >3.0 (maximal score, 4.0) or a neurologic performance level of > 4 (maximal score, 6) were not considered for iaACNU chemotherapy. Follow-up consisted of regular clinical neurologic examination, and neuroradiologic studies such as computed tomography (CT) and/or magnetic resonance imaging (MRI), both including precontrast and postcontrast studies. In selected cases positron emission tomography (PET) of these tumors was performed, and preliminary results of these metabolic studies have been reported by our Laboratory investigations, in particular blood counts, were performed weekly. The occurrence of tumor regrowth was diagnosed according to clinical and neuroradiologic findings." The tumor response was classified into three categories and estimated at least each time at the occasion of a clinical and neuroradiologic follow-up examination: responsive disease (RD), stable disease (SD), and progressive disease (PD). The combination of >20% tumor volume growth on CT and/or MRI with an unchanged neurologic grading or increasing neurologic deficit was diagnosed as PD. Patients with RD demonstrated a decrease in tumor volume of >50% and an unchanged or decreasing neurologic symptomatology. Patients revealing no changes in neuroradiologic findings or clinical symptoms were designated as having SD. An increase in tumor volume of 18 months) was 27.9%. The surviving fractions of this group of patients at 6 months, 12 months, 18 months, and 24 months are listed in Table 2. The results for patients with primarily treated disease are depicted in Figure I and listed in Table 2. The MST is 14.2 months and 4 I .O% of patients can be considered long-term survivors. The patients with primPD and those with SD & R D are also described in Figure 1 and tabulated in Table 2. The MST for the group NIVpnmpD is 7.8 months with only 9.1% long-term survivors. The initial part of the Kaplan-Meier survival curve is extremely steep. The patients with SD & RD, on the contrary, demonstrated a MST of 18.3 months and a large proportion of long-term survivors (66.7%). The patients with secondarily treated malignant gliomas WHO Grade IV (NIvrecurrent) did not very well after iaACNU chemotherapy. The MST after diagnosis of tumor recurrence was 6.1 months with only 14.3% surviving at 12 months and none of these patients reaching the 18-month limit. If the maximal survival time of these patients is considered, it.., the time after initial diagnosis, results are better: a MST of 16.2 months and 42.9% long-term survivors. These results, however, are biased and should be interpreted very cautiously, as discussed later. The NIv group of primarily treated tumors consisted of 27 glioblastomas and eight WHO Grade IV gliomas
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CANCER November 15 1989
1988
6
12
18
24
30
36
t (months 1 primPo
6
12
18
24
30
36
t ( months 1 .
.
NIV
1.0
SD6RD
................................... 6
12
18
24
30 36 t (months 1
FIG. 1. Kaplan-Meier survival curves for the patients with primarily treated malignant gliomas WHO Grade IV. (A, upper) Overall results for all patients (NIv = 35). (B, middle) Survival graph for patients with primPD (NTV pnmPD = I I). (C, lower) Results for patients with SD & RD (NIV SD& R D 24).
with some less dedifferentiated areas. Although the MST for both these groups was different ( 16.6 and 13.9 months, respectively), it is remarkable that the glioblastomas had the better MST of both. The statistical comparison of both survival data revealed no difference between both groups (0.95 > P > 0.90). Therefore, both groups will be considered together in the current report. There was no significant difference between the survival statistics of patients with primarily treated WHO Grade
VOl. 64
IV gliomas and the whole group of Grade IV patients: 0.60 > P > 0.50. The similarity of survival statistics for patients with primarily treated gliomas WHO Grade IV and patients with secondarily treated tumors, considering the survival time after initial diagnosis, is remarkable: 0.975 > P > 0.950. Comparison of the survival statistics of patients with primPD and those with SD & RD revealed a highly significant difference: 0.005 > P > 0.00 1. A drfference of both these groups with regard to the survival statistics of the whole group of primarily treated patients may be noted, too, although not statistically significant: 0.10 > P > 0.05 (Nlv versus Nlv pnmpD) and 0.15 > P > 0.10 (Nlv V ~ ~ S Niv U S ~D~RD). In our series of 50 patients treated, a total of 174 iaACNU infusions were performed. The side effects and complications of iaACNU that we encountered are listed in Table 3. These were related either to the catheterization procedure itself or to the chemotherapeutic agent, although it was not always possible to distinguish both causes with certainty. However, in seven instances the chemotherapeutic infusion was not given due to complications during the catheterization procedure such as an epileptic fit, transient hemiparesis, or ICA occlusion. The frequency of general side effects such as hematopoetic disturbances, hepatopathy, and systemic infection, is listed as the percentage of patients involved, whereas the other complications and side effects are tabulated both as the percentage of patients and the percentage of iaACNU infusions. The neurologic performance status and neurologic function score remained relatively stabile in the group of patients with SD & RD (Fig. 2). Their level was generally TABLE3. Frequency of Complications in I74 Intraarterial Ninustine Procedures Into the Ipsilateral Internal Carotid Artery of 50 Patients Percentage of iaACNU Percentage of procedures patients General complications 12.07 14 Anorexia 17.82 Nausea 16 Nausea & emesis 10.34 10 Leukopenia ( ~ 1 . 5 -10y/l)and/ or thrombopenia 4 ( 4 0 . 1Oy/I) 4 Hepatopathy 2 Systemic mycosis ~
~
Locoregional complications Visual impairment Epilepsy Cerebral edema TIA-like symptoms (reversible stupor and hemiparesis) Irreversible hemiparesis Asymptomatic ICA occlusion
1.15 0.57 1.15
4 2
1.72 0.57 0.57
4 2 2
iaACNU: intraarterial chemotherapy using nimustine. See Appendix I for explanations for acronyms.
4
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INTRAARTERIAL ACNU FOR GLIOBLASTOMA
No. 10
PERFORMANCE LEVEL
STATUS GRADING
3.0. 0.5
2.0.
0.0-
1.0L
"
'
"
1
iaACNU 1 2 3 4 5 6 7
.-.
"V
-
iaACNU 1 2 3 4 5 6 7
SD&RD
"
primPD
%%@&Is
FIG.2. Neurological performance level and status grading for patients with primPD or with SD & RD are separately depicted as they were determined at the occasion of each iaACNU course. The mean value with standard deviation was calculated and is graphically demonstrated. better than in the group with primPD; only later during treatment a decrease in performance status and neurologic function score were noted. The patients with primPD clearly did worse (Fig. 2). Discussion
Relevance of Neuropathologic Classification of Malignant Gliomas The exact histopathologic classification of the malignant gliomas, that are treated according to a particular management protocol, is very important. The usual classification that currently is adopted by most investigators, is a three-tiered system.26.28,29,41 The astrocytic gliomas are categorized as astrocytomas, anaplastic astrocytomas, or glioblastoma multiforme, as proposed by the BTSG, the Radiation Therapy Oncology Group, and the Eastern Cooperative Oncology or as astrocytoma WHO Grade 11, astrocytoma WHO Grade 111, or astrocytoma WHO Grade IV, as proposed by the WH0.26,28 Almost all published studies on chemotherapy of malignant gliomas include both anaplastic astrocytomas (or astrocytoma WHO Grade 111) and glioblastoma multiforme (or astrocytoma WHO Grade IV) in the study population.' The proportion of glioblastomas (WHO Grade IV) versus astrocytomas WHO Grade 111 including other more rare types of gliogenous tumors may range from or more.43-45Some reports 46% to 54%42to 90%to even do not differentiate between different types of malignant g l i o m a ~ . However, ~ ~ . ~ ~ the biological clinical behavior of these different types of malignant gliomas clearly results in differences in survival time.29 The combined life-table survival curves comparing anaplastic astrocytoma (N = 175) verstis glioblastoma multiforme (N = 1265) for three Phase 111 studies of the BTSG demonstrate this: the MST for anaplastic astrocytoma was about
Roosen et a/.
1989
2 1 months, for glioblastoma multiforme about 10 months.29 The larger proportion of patients with anaplastic astrocytoma than with glioblastoma multiforme surviving at 1 year and 2 years was statistically highly ~ i g n i f i c a n tThese . ~ ~ figures are the result of a lumped analysis of the various treatment groups in these three Phase I11 studies29:this must be kept in mind in comparing these figures with the actual results of our study. However, the inherent prognostic difference depending upon the histologic diagnosis is nicely illustrated by this large analysis of the BTSG.29 These literature reports encouraged us to select only those patients for statistical analysis that had an astrocytoma WHO Grade IV, i.e., a glioblastoma multiforme. This should ensure the selection of a group of patients with a tumor population as homogeneous as possible.
Influence of Radiotherapv and Systemic Chemotherapy on Prognosis of Malignant Gliomas The dismal prognosis of patients with malignant gliomas receiving only supportive care, has been demonstrated convincingly by the BTSG.7 Forty-two patients were analyzed in that study7: the MST was 14.0 weeks (3.3 months) in the valid study group, and 17.0 weeks (4.0 months) in the adequately treated group.7 Sixteen percent of patients survived 6 months, whereas none of these patients reached the 18-month limit.7 An important increase in MST resulted from postoperative radiotherapy in 93 patients ofthe same study7: 36.0 weeks (8.4 months) in the valid study group and 37.5 weeks (8.75 months) in the adequately treated group. A further report by the same investigators on 1 18 patients treated with postoperative irradiation showed a MST of 37 weeks (8.6 months) in the total randomized population and 36 weeks (8.4 months) in the valid study group.8 The proportion of longterm survivors was found to be 4%,7or 19.4%resp. 15.1%.' The most important chemotherapeutic agent, which has been used already in the first clinical chemotherapeutic trials and still is one of the most active drugs for chemotherapy of brain tumors available today, is the nitrosourea derivative carmustine or 1,3-bis(2-chloroethyl)-1nitrosourea (BCNU).' Early studies unequivocally demonstrated that the results of intravenous (iv) BCNU chemotherapy as an adjuvant treatment of radiotherapy are superior to the results of either ivBCNU or radioIn 68 patients treated with ivBCNU a therapy MST of 18.5 weeks (4.3 months) or 25.0 weeks (5.8 months) was found, valid study group versus adequately treated group.7 Combination of ivBCNU with radiotherapy in 100 patients resulted in a MST of 34.5 weeks (8.0 months) or 40.5 weeks (9.45 months), valid study group versus adequately treated group, in the first BTSG s t ~ d y . ~ The second study of this group revealed in 120 patients
1990
CANCERNovember 15 1989
Vol. 64
Animal studies too, support the concept of superiority a MST of 49 weeks ( 1 1.4 months) or 5 1 wecks ( I 1.9 of ia versus iv ~hemotherapy.~”’~ Others, however, emmonths), total randomized population versus valid study group.8 The proportion of long-term survivors was 1970 phasize that due to the special characteristics of every drug applied, no general recommendation in favor of a specific resp. 28.8% or 27.2%.’.’ Other chemotherapeutic agents application mode can be made.’’ The therapeutic concept of the nitrosourea group, as well as antimitotic drugs of that with an ia administration high drug levels can ‘be differing pharmacologic classes such as cisplatin, epipoachieved in tumor tissue,56therefore is not generally acdophyllotoxins, etc., have been used in the chemotherapy cepted. On the other hand, PET studies on the pharmaof malignant gliomas but up to now a clear superiority of cokinetics of ia administered drugs revealed a much higher one of these agents could not be demonstrated at all.’ local concentration than after iv infusion.16317 The nitrosourea ACNU has been examined in a combination therapy of irradiation and iv a d m i n i ~ t r a t i o n . ~ ~ . ~ ’ During the last decade a wealth of articles reporting on clinical series of ia chemotherapy were pubTakakura el al. found a MST of 14 months in 26 patients lished.20,21,57-74 Although most of these reports suggested with gli~blastoma.~’ The proportion of long-term survithat ia chemotherapy was beneficial, their patient series vors was about 27%.48Surprisingly better results were rewere usually small and sometimes rather heterogeneous. ported by Voth et al., who obtained a MST of about 18 All kinds of intracranial tumors have been included: months and a 2070 5-year survival in 36 patients with glioblastomas, anaplastic gliomas, other gliomas, meglioblastoma treated with this combination chemoratastases, etc. The cytostatic agent commonly used was diotherapy involving ~vACNU.~’ The important difference BCNU,57-63.65.66.68 but ACNU,20,?l1.6Ocisplatin,6 I .62,64--66 between the results of both of these s t ~ d i e s ~warrants ~,~’ meth~trexate,~’ and aziridinylbenzoquinone (AZQ)69also a cautious interpretation. Although currently a real suhave been infused into the ICA. periority of a combination radiotherapy and ivACNU One of the largest series was reported by Hochberg et chemotherapy over a combination of radiotherapy and ~71.’~They treated 79 patients with glioblastoma multiivBCNU chemotherapy has not been pr0ven,4’*~~ the niforme: 30 had recurrent tumors, whereas 49 had primarily trosourea ACNU seems to cause considerably less side effects than ivBCNU.” treated neoplasms. The MST in the latter group was 64 and 49.5 weeks (14.9 and 11.5 months, respectively) fix The use of a multidrug regimen has been advocated, and these reports claim an increased chemotherapeutic infraophthalmic or supraophthalmic artery iaBCNU, respectively.” With the exception of the infraophthalmic efficacy,although the incidence of side effects with serious iaBCNU group these results are not significantly better morbidity and mortality is markedly increased, too, using than in comparable series with adjuvant ivBCNU chesuch an aggressive approach.’ motherapy.’ The same investigators reported on preirIntraarterial Administration of Chemotherapeutic Drugs radiation iaBCNU in 28 patients.58In that study a MST With Particiilar Emphasis on Intraarterial Niinirstine of 37 weeks (8.6 months) for all evaluable patients and >56 weeks (> 13.1 months) for those completing the The tumoricidal efficacy of a particular cytotoxic agent treatment protocol was determined.58A randomized condepends among other factors upon the drug concentration trolled study of iv versu.~iaBCNU conducted by the BTSG reached at the site of the tumor cell, i.e., upon drug dewas prematurely terminated because interim analysis relivery. Drug delivery to solid tumors is influenced by tuvealed a much higher complication rate in the ia group mor blood flow, the capillary surface area and permeand could not demonstrate a therapeutic difference beability, cellular permeability, the cellular-to-extracellular tween both groups.59The MST in that study was 50 weeks drug ratio, the extracellular and intracellular drug half(1 1.7 months) in the iaBCNU and 2370 of patients were life. the drug diffusion coefficient, and the total time of long-term survivor^.^' It should be considered however, drug e x p ~ s u r e . Some ~ ~ , ~of ~ these factors are related to that the iaBCNU dosage had to be reduced already early the tumor tissue: e.g., tumor vascularity and blood-tumor in the beginning of that study because of an unacceptably barrier; other factors are related to the drug itself e.g., high incidence of complications; therefore, the initial goal liposolubility, molecular weight, and mechanism of acof comparing equivalent BCNU doses could not be retion. Furthermore, the amount of drug delivered to a neoalized anyway.59Furthermore, all tumors were presented plasm is dependent upon the total amount of drug adas malignant gliomas without more details on the histoministered to the patient, which determines the occurrence logic cla~sification.~’ and severity of side effects and complications. To improve Our own results with iaACNU in malignant gliomas the therapeutic efficacy and decrease the burden of sysWHO Grade IV compare favorably with the results of temic side effects, all of these parameters have been studied in theoretical models of brain tumor chemotherapy, and iaBCNU, especially if one bears in mind the relative low incidence of complications caused by the iaACNU prosuggestive evidence in favor of the ia route for chemotocol. Indeed, only the group of patients of Hochberg et therapy was d e d ~ c e d . ’ ~ , ~ ’
No. 10
INTRAARTERlAL ACNU FOR
GL~OBLASTOMA * Roosen et a/.
1991
al. with infraophthalmic artery iaBCNU infusion had a The total MST of 16.2 months after first diagnosis is of MST similar to our own result^.^' the same order of magnitude as in the group of primarily ACNU is a small lipophilic and hydrophilic drug with treated patients. These recurrent tumors underwent sura short plasma half-life,30-32*34 which therefore possesses gery too: i.e., not all recurrent tumors seen in clinical good properties with regard to ia chemotherapy of brain practice may profit from this type of management because tumors. This nitrosourea derivative has been shown to only a minority are suitable candidates for second surgery. penetrate in brain tumors and to reach rather high intraIn general, therefore, we can not advocate a delay of tumoral concentrations after iv and ia a d m i n i ~ t r a t i o n . ~ ~iaACNU chemotherapy until a glioblastoma recurs. It is well known that patients with glioblastoma benefit The first results with iaACNU were obtained with a hetfrom chemotherapy.' Usually this is evaluated in terms erogeneous population of nine2' resp. I 3 patients2' comof long-term survivors. We found 41% of long-term surprising glioblastomas as well as anaplastic gliomas, malignant lymphomas, and metastatic tumors. These previvors in our series of primarily treated gliomas WHO liminary reports suggested high efficacy of iaACNU .20,2' Grade IV, which compares favorably with other reports. Eleven patients had early PD (primPD), within weeks of The survival curve for the iaACNU patients was better than for the ivACNU patients, although this difference diagnosis, seemingly uninfluenced by therapeutic meawas not significant." The MST of these nine patients was sures. As seen in Figure l and Table 2 these patients had 13 months.*' Ten of the 13 patients reported by Yumitori a very unfavorable outcome: their MST was 7.8 months et al. showed a disappearance or reduction of tumor and only 9.1% were long-term survivors. The remaining 24 patients, on the other hand, had SD & RD: their MST mass?' Papavero et al. discussed the intracarotid adminwas 18.3 months and 66.7% were long-term survivors. istration of ACNU and BCNU in 30 patients, but the The primPD patients received less radiotherapy than SD relative importance of both these nitrosoureas upon the results was not unequivocally apparent from their study.60 & RD patients, which might account for some of the difThe reports on iaACNU published up to now concern a ference in MST and percentage of long-term survivors. small series of patients2'*'' or a combination approach On the other hand, these considerable differences between both groups also indicate the potential importance of adwith BCNU.60Therefore, up to the present, our own report equate patient selection, e.g.. by tumor chemosensitivity represents the largest available experience on iaACNU Early selection of patients with responding chemotherapy of malignant gliomas WHO Grade IV. This tumors would greatly ameliorates the results of a particular means, of course, that the results reported in this article therapeutic a p p r o a ~ h , ~whereas ~ , ~ ' nonresponding tumors cannot be compared directly to those of Yamashita el should be treated with other therapeutic modalities, pera1.,20Yumitori et al.," and Papavero et aL6' haps even with a completely different therapeutic apWith regard to the results of ivACNU reported by Takproach. Up to now the main result of in v i m testing is akura et the MST of 14.2 months in our series is the establishment of chemoresistance. Furthermore, a firm comparable to the 14 months in their series. However, correlation between in vitro and clinical in vivo results our proportion of long-term survivors, 41%, is considerhas not been investigated prospectively in brain tumors. ably larger than that of Takakura et at., 27%.48The results Our own studies on chemosensitivity testing are based of Voth et al.49are extremely good, and much better than upon the in vivo determination of changes in glucose meour own findings as well as those of Takakura et aL4' or tabolism with PET during chemotherapy, as reported other results in the literature.' This difference remains el~ewhere;~but recently the study of in vitro chemosenunexplained, especially in view of earlier reports by the sitivity with early passage glioma cell culture has been same group with results which were not as good,75but initiated in our group, too. might be due to different or changing criteria of neuropathologic diagnosis, or may be due to longer continuation of therapy with a consequently higher total drug dosage. Complications of Adjuvant Intraarterial Nim ustine Chemotherapy Critical Analysis of Survival Statistics in Patients As with most chemotherapeutic agents, anorexia, nauTreated With Intraarterial Nimustine Chemotherapy sea, vomiting are known to occur with nitrosoureas, and therefore with ACNU t00.~'~~' Table 3 presents the inciThe results in primarily treated patients should be condence of these minor side effects, which was relatively low sidered separately from those in recurrent tumors. in our series as compared with reports on ivACNU." This The group of recurrent tumors with adjuvant iaACNU is at least partially due to the relatively low systemic burwas small. Therefore, statistical analysis is not very conden of iaACNU chemotherapy. fident. However, the results suggest that only about 6 Severe hematopoietic depression with marked thrommonths of additional MST is given to these patients by a bopenia and leukopenia is not uncommon with ivsecond operation and subsequent iaACNU chemotherapy.
CANCERNovember 15 1989
1992
ACNU,50.sobut was seen in only 4% of our patients, and thrombocyte transfusion was necessary in just one patient. An increased incidence of infections was not found in our study. In one patient both corticoids and chemotherapy, although only one course of iaACNU, probably were etiologically related to severe systemic mycosis. In contrast to the above mentioned general complications of chemotherapy, there are locoregional complications specifically seen with ia infusions."." These include neurotoxicity and retinotoxicity and they are due to the catheterization procedure and/or the particular cytostatic agent infused. The retinotoxicity of iaACNU seems to be very minor. Visual impairment was found in only 4% of patients. In one of these patients retinal emboli were identified by fundoscopy and were considered the cause of amaurosis; in the other patient no pathologic changes of the retina could be detected. Orbital pain, ecchymosis, redness, as very often seen during iaBCNU,8' have never occurred during iaACNU chemotherapy. The high incidence of retinal and orbital complications caused by iaBCNU or by ia cisplatin, has lead to the introduction of supraophthalmic ia infusions of these drug^"',^^.'',^^ However, this is a more invasive catheterization procedure, which bears a higher risk of catheter-related complications involving the ~ e r e b r u r n . ~ ' ~ ' ~ . ~ ~ The risk of cerebral ischemia, of transient ischemic attacks or of stroke, is known to exist during catheterization, in particular during selective catheterization. In 2.86% of our catheter procedures, i.e., in 10% of patients, cerebral complications occurred. These were major and persistent in 0.57% of catheterization procedures (2% of patients). The most feared complication of iaBCNU, however, i.e., hemorrhagic leukoencephalopathy,'9.85was never observed. The same holds true for hypodensity areas on CT, which were described after iaBCNU.7" All cerebral complications in our patients were seen during or immediately after iaACNU chemotherapy: therefore, in most cases, a catheterization complication, which can possibly be prevented by improving catheterization technology, cannot be differentiated with certainty from a toxicologic effect. On the whole, iaACNU as used in our management protocol, seems to possess a low neurotoxicity.
Conclusion The management protocol of malignant gliomas WHO Grade IV, which is followed at the University of Dusseldorf Department of Neurosurgery. and is described in this report, has lead to a favorable MST and a high proportion of long-term survivors. These results were obtained with an invasive approach using adjuvant iaACNU chemotherapy in addition to surgery and radiotherapy. Our series
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demonstrates an acceptably low frequency of both systemic and locoregional complications. Further progress can be made, as we believe, by modification of this protocol. The number of iaACNU courses may be increased and/or the single dose of iaACNU increased, thereby profiting from a relatively high therapeutic/toxic ratio of ACNU. Another way of improvement is the early selection of patients with responding tumors. This involves the development of reliable predictive chemosensitivity testing procedures, either in viiw (e.g., P E T ) or in vitro. Our results encourage us to investigate further the use of iaACNU in such modified treatment schedules in order to determine the optimal therapeutic approach. Because of these encouraging results of iaACNU and because of its high therapeutic/toxic ratio, even when administered iv, it seems mandatory to evaluate this substance in a controlled randomized clinical trial. which should be conducted at institutions with demonstrated routine and expertise in brain tumor chemotherapy in general and in ia chemotherapy in particular, REFERENCES I . Cobb CA, Youmans JR. Glial and neuronal tumors of the brain in adults. In: Youmans JR, ed. Neurological Surgery, vol. 5, ed. 2. Philadelphia: WB Saunders, 1982; 2759-2835. 2. Vick NA, Wilson CB. Total care of the patient with a brain tumor with consideration of some ethical issues. Neurol Clin 1985; 3:705-710. 3. Chatel M. Darcel F, Pecker J. Brain Oncology: Biology, Diagnosis and Therapy. Dordrecht: Martinus Nijhoff. 1987; 1-459. 4. Bamherg M, Sack H. Therapie Primarer Hirnturnoren. Miinchen: Zuckschwerdt. 1988; 1-465. 5. Ransohoff J, Kelly P, Laws E. The role of intracranial surgery for the treatment of malignant gliomas. Semin Oncol 1986; 13:27-37. 6 . Halperin EC, Burger PC. Conventional external beam radiotherapy for central nervous system malignancies. Neurol Clin q 1985; 3:867-882. 7. Walker MD. Alexander Ejr, Hunt WE el a/. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative trial. J Neurosurg 1978: 49:333-343. 8. Walker MD. Green SB, Byar D P ef al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N E n g l J J ~ e d1980; 303:1323-1329. 9. Kornblith PL, Walker M. Chemotherapy for malignant gliomas. J Nciiroxiu~?1988; 6:l-17. 10. Lee Y , Bigner DD. Aspects of immunobiology and immunotherapy and uses of monoclonal antibodies and biologic immune modifiers in human gliomas. Neurol Clin 1985; 3:901-917. I I . Silberman AW. Rand RW, Storm K, Drury B. Benz M, Morton DL. Phase I trial of thermochemotherapy for brain malignancy. Canc,?r 1985; 56~48-56. 12. Naruse S, Horikawa Y, Tanaka C el al. Evaluation of the effects of photoradiation therapy on brain tumors with in vivo P-3 I MR spectroscopy. Radiology 1986; 160327-830. 13. Duff TA, Borden E, Bay J, Piepmeier J, Sielaff K. Phase I1 trial of interferon+ for treatment of recurrent glioblastoma multifonne. J Neiirositrg 1986; 64:408-4 13. 14. Eeckman WW, Patlak CS, Fenstermacher JD. A critical evaluation of the principles governing the advantages of intra-arterial infusions. J Pharinacokinet Biophann 1974; 2:257-285. 15. Blasberg RG, Groothuis DR. Chemotherapy of brain tumors: Physiological and pharmacokinetic considerations. Senzin Onrol 1986: 13170-82. 16. Tyler JL, Yamamoto YL. Diksic M et a/. Pharmacokinetics of
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