ACTA NEUROCHIRURGICA 9 by Springer-Vedag 1978

Acta Neurochirurgica 41,287--299 (1978)

University of Pavia, Italy, Neurosurgical Clinic* (Director: Prof. P. Paoletti) and Clinica del Lavoro Foundation **, Division of Oncology (Director: Prof. G. Robustelli della Cuna)

Multidisciplinary Treatment for Central Nervous System Tumours With Nitrosourea Compounds By

P. Paoletti*, G. Robustelli della Cuna**, R. Knerich*, and M. R. Strada** Summary The authors report the results of a controlled clinical trial in patients with primitive and metastatic CNS tumours treated with combined therapy: surgery, radiotherapy, and chemotherapy (BCNU or CCNU). A total of 102 patients were treated, 50 with BCNU, and 52 with CCNU. The overall response (R. + P.R.) was 68% for the BCNU group, and 65% for the CCNU group. No significant differences were found between the two types of treatment, either in terms of response or in terms of quality and length of survival.

Introduction According to recent data 9, ~ Central Nervous System Turnouts (CNS) have an incidence rate of 4 cases per 100,000. The age distribution curve is biphasic. There are two peaks with the same incidence, one between 6-9 years and one between 40-60 years. The incidence, in percentages, of the various histological types were given in a study on 17,580 brain tumours (Walker 1976). Gliomas, at 430/0, were in first place, meningiomas followed at 16~ the other types occurred less frequently. The incidence of metastatic turnouts, given as 13%, appears incomplete considering that an always increasing number of patients bearing solid turnouts, live longer due to the progress m a d e in treatment. This longer survival time causes, inevitably, an increased possibility of secondary tumours in the CNS. Primitive brain turnours, in particular malignant gliomas, have a rapidly fatal course. The m o r t a l i t y rate is 500/0 at 6 months and 9 0 % at 18 months 4, 6, s, ~4 In spite of the progress of surgery,

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et aI.:

improved anaesthesiological techniques, and the use of radiotherapy, steroids, and dehydrating agents, the traditional therapeutic approach has proved incapable of significantly lengthening survival time. Treatment consisting of surgery and radiotherapy is considered as traditional. Surgery alone gives a 4-5 month survival time. Radiotherapy, now in use for more than 40 years, has an indubitable effect in treating these tumours, especially when used in combination with surgery. This combined efficiency was demonstrated in a controlled study by Walker and Gehan (1972). Data from retrospective studies are variable, however. While some deem that radiotherapy has an indisputable effect in lengthening the survival time of patients with glioblastoma ~, others believe it to be of little value 18. According to the results of the Brain Tumour Study Group in 1973, the combination of surgery and radiotherapy is able to lengthen the survival time by 7 months compared with 3 months for surgery alone. These limited results, along with the recent progress made in the medical therapy of other solid turnouts, justify the introduction of chemotherapy to the therapeutic strategy for CNS tumours. Correct planning for the chemotherapy of these tumours must take into account: A. The kinetic characteristics of the tumour population (slow growth fraction, lengthened generation time). B. Spacial distribution of the cellular growth (proliferating cells at the periphery, necrosis and tumour degeneration at the centre). C. Ability of the drug to penetrate the turnout (absence of a barrier in the center, valid barrier at the periphery). In view of the above mentioned characteristics of the cellular population, the elegible drug should not be cycle-specific, due to the slow growth-rate of brain tumour, and should be able to kill the cells even if they are not in a phase of active metabolism. From the viewpoint of the barrier, the ideal drug should be able to penetrate the barrier itself and arrive at the tumour in therapeutically effective concentrations. Such a capacity is tied to three particular characteristics: 1. high degree of lipid-solubility, 2. low degree of ionization, 3. small molecular dimensions. A retrospective evaluation of traditional drugs not having such characteristics 6 showed that methotrexate, bleomicine, TEM, mitramycine, the Vinca Rosea alkaloids, and hydroxyurea were active; other drugs were disappointing or scarcely active, except for procarbazine. Procarbazine is able to penetrate the blood-brain barrier and gives objective responses at around 52~ in malignant gliomas for an average period of 6 months v

Multidisciplinary Treatment for Central Nervous System Tumours

289

However, in general, the conventional antiblastic agents have not shown a real capacity significantly to lengthen the survival times of patients with CNS primitive tumours. If the treatment for primitive brain tumours remains disappointing in many aspects, it must unfortunately be admitted that palliative therapy for metastases of extracerebral primitive tumours is far from being established and seems even more frustrating, especially viewed in the light of the mediocre results obtained thus far. Even the data in the literature regarding this point do not help to clarify the problem: such data, often few and fragmentary, are almost always to be found among the case records of the CNS primitive tumours. The results available are often different, due to the different criteria used to select patients and to evaluate the therapeutic response. Their therapy is problematic for two reasons. One is the difficult operative choice (whether to treat the metastasis alone or whether to attack both the primary growth and the metastasis), and second is the marked difficulty in evaluating the response. In fact, the survival time of these patients depends more on the degree of generalized diffusion of the primitive tumour than on the real control of the brain lesion. Therefore, even in cases of real response, the patient is often lost due to cQmplications related to the systemic diffusion of the tumour. On the other hand, if the metastases remain untreated, the average survival time of the patient does not exceed one month. Briefly summarizing the traditionally available therapeutic possibilities, we can say that surgery, radiotherapy, and corticosteroids have been the most widely used methods to date. Chemotherapy in the last few years has developed and widened its field of action. Immunology, for the moment, is still in the experimental stage. Corticosteroids can give subjective and objective improvements in percentages that vary from 60 to 75o/0. They are capable of controlling the symptomatology of the metastatic brain localization for a brief period, then there is an inevitable progression of the disease. The existing data, which are not abundant, regarding the increase in survival time of patients treated compared with those treated show an increase of one month with corticosteroids 17 Radiotherapy can give from 60 to 700/0 of objective responses with an average length of 2-6 months, with a percentage of survivors up to 1 year between 3 and 200/0. The results obtained with surgery alone are analogous, with occasional long periods of survival time. Surgery alone gives objective responses of 3-5 months with survival up to 1 year in 15-20~ Even though there have been no controlled studies, it would seem that surgery has a certain advantage over radiotherapy in treating brain

P. Paoletti et al.:

290

metastases. However, this advantage must be evaluated considering the inevitable selection of the patients chosen for surgery (single metastasis without other signs of primitive tumour localization) 17 The chemotherapeutic approach, as is well known, has its own very particular aspects. Table 1. Therapeutic Modality in CNS Tumours

17 R

BCNU 1st cycle

D O

Z A T I

O N

R A D

___~

2nd-3rd cycles

I

O T H E CCNU 1st cycle

-->

support therapy

R

E S S

R

A P Y

P R O G

-+

2nd-3rd cycles

I O N

§

support therapy

* 5,500 rads in 6 weeks starting 15 days after the first cycle of chemotherapy.

Chemotherapy is commonly held to be applicable only after surgery with or without radiotherapy and in patients with multiple metastases, or those who are unsuitable for surgery. In theory, the primary reason for using chemotherapy should be prophylactic. The chemotherapy should eradicate as many micrometastases as possible. On the other hand, mono- or polychemotherapy for primitive turnouts has not proved effective in controlling metastatic foci in the brain. These loci are found frequently during continued chemotherapy for solid tumours. At this point, the problem arises of finding drugs that can penetrate the blood-brain barrier, since the failure of the common antiblastic agents to control intracerebral metastatic diffusion is caused by their inability to penetrate this barrier. Drugs endowed with the desired characteristics are Nitrosourea derivatives. Available since 1970, these compounds have markedly improved the prospects of chemotherapy for both CNS primitive and metastatic tumours. B C N U and C C N U * are very well suited for use in treating CNS * B C N U : NSC-409962; 1,3-Bis(2-chloroethyl)l-nitrosourea, C C N U : 79037; 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea.

NSC-

Multidisciplinary Treatment for Central Nervous System Tumours

291

tumours due to their chemical-physical characteristics and to their mechanism of action. First documented in experimental systems 2, 28, the therapeutic efficacy of these drugs have been confirmed clinically. Since the first clinical use in 1970 the first relevant results show objective regression in 44% of the cases treated with BCNU, and in 40% of those treated with C C N U ~, s, i2, 13, 1~, s0, st, s4, 2s Table 2. Characteristics of Patients Entered Into the Study Patients

Total

BCNU

CCNU

Entered Evaluable Males Females Median Age

117 102 63 39 58 (17-74) 18 17

58 50 31 19 52 (18-74) 13 8

59 52 32 20 47 (12-72) 5 9

N ~ > 60 Years Lost to follow up Turnout Removal (A1) Decompression, Biopsy and/or Shunt A - V (A2) No surgical Therapy (As) Metastatic (Ca)

33

15

18

21

10

11

5 43

3 22

2 21

Astrocytoma (Grade 2) Glioblastoma Meningosarcoma CNS. Metastatic Tumours

21 36 2 43

11 16 1 22

10 20 1 21

P a t i e n t s and M e t h o d s Our experience began in January 1973 with a randomized perspective study. It was intended to verify the influence on the length and quality of survival of surgery and radiotherapy associated with B C N U or C C N U chemotherapy. The randomized patients were carriers of CNS primitive or metastatic turnouts. There were four groups of patients, divided as follows: A~: removed intracraniaI glial tumours. A2: intracranial glial tumours with osteodural decompression, biopsy or extrathecal CSF shunt. Aa-" intracranial glial tumours without surgery. Ca: multiple intracranial metastatic turnouts without surgery. The treatment for operable malignant brain tumours (Table 1) consisted of surgery, postoperative chemotherapy, radiotherapy, and consolidating chemotherapy. 19"

P. Paoletti et al.:

292

Patients who did not undergo surgery were randomized immediately after the diagnosis was made. From January 1973 to June 1976, 117 patients were taken into the study. O f these, 102 were evaluahle (50 treated with B C N U , and 52 treated with C C N U ) . Table 2 shows the characteristics of the treated patients grouped according to the type of surgery and histological type. Table 3 shows the division of the 102 patients treated according to the prevalent brain localization.

Table 3. Turnout Location in Each Treatment Group

Site o f Tumours

No. Eval. Patierits

BCNU

CCNU

Frontal Temporal Parietal Occipital R. Temp.-Parietal L. Temp.-Parietal Posterior Fossa 3rd Ventricle

15 15 10 2 26 21 10 3

7 9 4 1 14 9 5 1

8 6 6 1 12 12 5 2

102

50

52

Total

Table 4. Clinical and Instrumental Devices During Chemotherapy

Chemotherapeutic cycles

Neuro- Skull logical X-ray tests

1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th

9

9 9 9 9 9 9 9 9 9 9 9

[ ] if necessary.

EEG

Isotope Neuro- D e s m o - B l o o d Brain radiol, sterol counts scan tests test and/or CT-Scan

9

9

9 9

9 9 9

9

9 9

9 9 9

9

9 9 9 9 9

9 9 9 9 9

9

Blast. Bone lymph. m a r r o w test biopsy

9

9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

9

9

9

9

9 9 9 9 9 9 9

Multidisciplinary Treatment for Central Nervous System Turnouts

293

Patient selection for the protocol was made according to the following criteria: clinical, neuroradiological and histological diagnosis. interval of at least 15 days between surgery and beginning of chemotherapy, theoretical survival of at least 8 weeks with possibility of follow-up, normal liver and kidney functions, minimum acceptable hemochromocytometric values: H t ~ 35~ WBC 4,500/ram 3, platelets >_ 150,000/ram 8, Table 5. Response to Treatment (Wilson 1975) Designation

Clinical condition

Brain scan

A. Responder B. Probable Responder

Improved 1. Improved 2. Unchanged 3. Unchanged (for 3 months with malignant turnout) Worse

Improved Unchanged Improved Unchanged

C. Non-Responder

Worse

Table 6. Haematological Toxicity. Combined Evaluation of Peripheral Blood

and Bone Marrow Changes Score Parameters

4 100%

3 75 %

2 50 %

1 25 %

Bone marrow Total cells Red cell series White cell series Megakaryocytes

+ + + +

+ + + +

-+ + --

+ -+ -+ -~-

@-+-

+ +

+ --

+ --

+-

+ +

+ --

+ --

+--

+ +

+ --

+ --

+ +

+ +

+ --

3-

B

C

Peripheral blood Hemoglobin --> 14 g% Erythrocytes _> 4.5• 10 mm 8 Leucocytes >-- 4.5 • 10 mm a Platelets 150• I0 mm 3 Class of toxicity A: B: C: D:

No toxicity. Moderate toxicity. Marked Toxicity. Severe Toxicity.

+ + + +

D

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294

during &emotherapy the use of urea, mannitol or other osmotic agents is not permitted. Routine antiepileptic treatment is permitted. During chemotherapy, clinical, instrumental and laboratory tests were performed, according to a fixed time-table (Table 4), that allowed us to evaluate the response to therapy. The criteria of response have been those suggested by Wilson (1975) (Table 5). Table 7. Dose Reduction Schedule Leucocytes/mm ~ (nadir)

Platelets/mm 8 (nadir)

Subsequent dose

> 4,000

> 140,000

< 4,000 > 3,000

< 140,000 > 80,000

< 3,000 > 2,000

< 80,000 > 50,000

< 2,000

< 50,000

BCNU 80 mg/m 2x3 CCNU 130 mg/m 2 BCNU 60 mg/m 2 x 3 CCNU 90 mg/m 2 BCNU 40 rag/me x3 CCNU 60 mg/m 2 Bone marrow biopsy

Delay further treatment until: Platelets return more than 110,000 mm z, Leucocytes return more than 3,500 mm 3. The next dose will be: B C N U 40 mg/m ~ • 3, C C N U 80 mg/m 2.

Table 8. Comparison of Response in Relation to Treatment and Type of Tumour Treatment

BCNU

CCNU

Type of turnout

No. Eval.

Type of response R. P.R.

N.R.

Astrocytoma (grade 2) Glioblastoma Meningosarcoma CNS. Metastatic turnouts

I1 16 1 22

6/11 9/16 1/1 5/22

4/11 2/16 0/1 7/22

1/11 5/16 0/1 10122

Total

50

21/50 (42%)

13/50 (26%)

16/50 (32%)

Astrocytoma (grade 2) Glioblastoma Meningosarcoma CNS. Metastatic turnouts

10 20 1 21

5/10 11/20 1/1 5/21

4/10 4/20 0/1 5/21

1/10 5/20 0/1 11/21

Total

52

22/52 (42%)

13/52 (23%)

17/52 (32%)

Multidisciplinary Treatment for Central Nervous System Tumours

295

Che&s for haematologicai toxicity were made at each cycle of therapy, and globally, according to the combined modality shown in Table 6. The dosages of the drugs were calculated at each cycle, based on the degree of toxicity caused by treatment (Table 7). Table 9. Mean Duration of Response (Months) in Relation to Treatment and Type of Turnout Treatment

Type of tumour

No. Eval.

Type of response R. P.R.

BCNU

Astrocytoma (grade 2)

11

Glioblastoma

16

CNS. Metastatic tumours

22

20 (17-22) 13.6 (11-17) 10 (7-15)

12 (7-21) 7 (9-11) 8.4 (6-13)

Astrocytoma (grade 2)

10

Glioblastoma

20

CNS. Metastatic turnouts

21

19 (14-21) 12.7 (8-14) 9.7

14.7 (11-23) 7 (5-10) 7.7

(8-13)

(5-10)

CCNU

Table 10. Mean Survival (Months) in Relation to Treatment, Type of Turnout, and Surgery Treatment

Type of tumour

No. EvaL

Type of surgery A1 A2

BCNU

Astroeytoma (grade 2)

11

Glioblastoma

16

17.25 (10-31) 17.33 (10-29)

22.71 (10-28) 13.33 (10-15)

Astrocytoma (grade 2)

10

Glioblastoma

20

19.10 (12-24) 15.55 (8-22)

17.14 (17-22) 10.66 (6-12)

CCNU

Results

Comparing the incidence, in percentages, of the response (R.) of the two treatment groups, an equal response is shown (42%). If considered globally (R. + R.p.), the responses were 68% for BCNU and 65% for C C N U (Table 8). The average length of response (Table 9) according to the tumour type and type of response did

P. Paoletti et al.:

296

not show significant differences for the two drugs. Analyzing the survival times in relation to the type of surgery (Table 10) no important differences based on the type of surgery used were found. Table 11. Survival Time in Relation to Chemotherapy Drug

Type of tumour

No. Eval.

Survival (months) Mean Median

Range

BCNU

Astrocytoma (grade 2) Glioblastoma CNS. Metastatic tumours

11 16 22

24.27 13.56 11.09

20 11.5 8.0

10-52 5--38 4-32

CCNU

3-strocytoma (grade 2) Glioblastoma CNS. Metastatic tumours

10 20 21

26.80 12.75 10.95

24 12,5 7.5

5-58 6-30 4--28

Table 12. Incidence of Haematological Toxicity in Patients With CNS Tumours Drug

Group

No. of cases

Class of toxicity A

BCNU

CCNU

A1 A2 A3 C3

15 10 3 22

Total

50

4 2 0 11

B

C

5 2 0 5

3 6 0 3

17 (34%)

12 (24%)

12

D 3 0 3 3 9 42%

A1 A2 A3 C3

18 11 2 21

9 4 1 8

1 1 0 5

2 3 1 5

Total

52

22 (42%)

7 (13%)

11

6 3 0 3 12 44%

Similarly, no significant differences appeared from analyzing the survival times starting from the beginning of chemotherapy (Table 11). Both of the nitrosoureas used seem to be able to lengthen, in a similar manner, the survival times of patients bearing CNS primitive or metastatic turnouts. We would like to emphasize the results obtained with metastases: for the global response 22/43, equal to 51.16~ and for the average survival time 10.5 months.

Multidisciplinary Treatment for Central Nervous System Tumours

297

The incidence of haematological toxicity (Table 12) was more or less identical for the two drugs, particularly the C and D toxicity classes. Perhaps C C N U had a slight superiority in percentage values for inducing cytopenia. Comments

Many authors 1, ta, iv, 19, 20, 2~, 25 agree that the combined strategy of surgery, radio- and chemotherapy with nitrosoureas represents an important step forward in treating CNS primitive and metastatic tumours. This progress has improved the quality and the length of survival times for patients thus treated in comparison to patients treated with conventional therapy. There are authors who maintain that the nitrosoureas do not improve the quality or the length of survival times obtained with traditional therapy 9, 19 Objective analysis of the results obtained permits us to agree with those who affirm that chemotherapy is effective when combined with traditional treatment for CNS tumours. Remaining within the confines of monochemotherapy, the results we obtained seem valid from the view-point of percentages, and from the type and length of responses. Therefore, supported also by the experience of others 21, 22, -~4,25, we maintain that the combined approach seems to be the most suitable treatment for these tumours. This work was supported by the United States Public Health Service Grant No. 080090/4 from the National Institutes of Neurology and Blindness, Bethesda, U.S.A., and by the National Research Council, Rome, Italy. References

1. Armentrout, S. A., Foltz, E., Vermund, H., Otis, P. T., Comparison of postoperative irradiation alone and in combination with BCNU (NSC 409962) in the management of malignant gliomas. Cancer Chemother. Rep. 58 (1974), 841 --844. 2. Barker, M., Hoshino T., Gurcay, O., Wilson, C. B., Hielsen, S. L., Downie, R., Eliason, J., Development of an animal brain turnout model and its response to therapy with 1,3-bis-(2-chloroethyl)-l-nitrosourea. Cancer Res. 33 (1973), 976--986. 3. Bouchard, J., Radiation therapy of tumours and diseases of the central nervous system, p. 244. Philadelphia: Lea and Febiger. 1966. 4. Brain tumors, Vol. II (Wilson, C. B., ed.), pp. 1--74. Seminars in Oncology. 1975. 5. Broder, L. E., Carter, S. K., BCNU (NSC 409962), Clinical Brochure, N.I.H., Bethesda, Md. 1970. 6. Broder, L. E., Rail, D. P., Chemotherapy of brain tumours. Prog. exp. Tumor Res. 37 (1972), 373--399.

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7. Chang, C. H., Some new radiotherapeutic approaches and combined protocol trials in the management of malignant gliomas. In: Gliomas: Current concepts in biology, diagnosis and therapy, pp. 135--149 (Hekmatpanah, J., ed.). Berlin-Heidelberg-New York: Springer. 1975. 8. Costans, J. P., Cioloca, C., Tumeurs c~r~brales e chimioth~rapie antimitotique. Paris: Masson et Cie. 1957. 9. Crivelli, G., Monfardini, S., Morello, G., Bonadonna, G., Controlled study with adjuvant chemotherapy following surgery plus radiotherapy in glioblastoma multiforme. XI. World Cancer Congress, Firenze 1974. 10. Cutler, S. J., Young, J. L. (eds.), Third National Cancer Survey: Incidence Data. Nat. Cancer Inst. Monogr. 41 (1975), 1--454. 11. Hansen, H. H., Selawry, O. S., Muggia, F. M., Walker, M. D., Clinical studies with 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea(NSC 79039). Cancer Res. 31 (1971), 223--227. 12. Hildebrand, J., Brihaye, J., Wagenknecht, J., Michel, J., Kenis, Y., Combination chemotherapy with 1-(2-chloroethyl)-3-cyclohexil-nitrosourea (CCNU), vincristine and methotrexate in primary and metastatic brain tumors. A preliminary rep[3rt. Europ. J. Cancer 9 (1973), 627--634. 13. Hildebrand, J., Brihaye, J., Malignant gliomas: Prognostic factors and criteria of response. In: Cancer therapy: Prognostic factors and criteria of response, pp. 3~7--318 (Staquet, M. J., ed.). New York: Raven Press. 1975. 14. Introzzi, G., Paoletti, P., Pezzotta, S., Robustelli della Cuna, G., Rodriguez y Baena, R., The use of BCNU in chemotherapy of tumors of the central nervous system. J. Neurosurg. Sci. 19 (1975), 223--225. 15. Mealey, J. Jr., Chen, T. T., Pedlow, E., Brain tumor chemotherapy with mytramicine and vincristine. Cancer 26 (1970), 360--367. 16. Morley, T. P., Does radiation therapy improve the treatment of intracranial gliomas? In: Ontario cancer treatment research brochure, pp. 54--70. Toronto, Canada. Nov. 1967. 17. Morley, T. P., The failure of radiation therapy to improve the survival period in gliomas: A controlled study. Presented at the American Association of Neurological Surgeons, April 1968, Chicago, Ill., U.S.A. 18. Posner, J. B., Shapiro, W. R., Brain tumor: current status of treatment and i~s complications. Arch. Neurol. 32 (1975), 781--784. 19. Reagan, T. J., Bisel, F. H., Childs, D. S., Jr., Layton, D. D., Rhoton, A. L., Jr., Taylor, W. F., Controlled study of CCNU and radiation therapy in malignant astrocytoma. J. Neurosurg. 44 (1976), 186--190. 20. Robustelli della Cuna, G., Paoletti, P., BCNU and CCNU chemotherapy of tumors of the central nervous system. In: Chemotherapy: Cancer chemotherapy II, Vol. 8, pp. 541--549 (Hellmann, K., Connors, T. A., eds.). Plenum Press. 1975. 21. Robustelli della Cuna, G., La Chemioterapia dei Tumori del Sistema Nervoso Centrale yon derivati della Nitrosourea. In: Progressi in Chemioterapia Antitumorale, pp. 143--153 (Ransa, L., Velo, G. P., eds.). Milano: Casa Editrice Ambrosiana. 1976. 22. Walker, M. D., Gehan, E. A., An evaluation of 1-3-bis(2-chloroethyl)-lnitrosourea (BCNU) and irradiation alone and in combination for the treatment of malignant glioma. In: Proceedings of the 63rd Annual Meeting of the American Association of Cancer Research. Proc. Amer. Assoc. Cancer Res. 13 (1972), 67. 23. Walker, M. D., Nitrosoureas in central nervous system tumors. Cancer Chemother. Rep. 4 (1973), 21--26.

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24. Walker M. D., Brain and peripheral nervous system tumours. In: Cancer Medicine, pp. 1385--1405 (Holland, J. F., Frei, E. III, eds.). Philadelphia: Lea and Febiger. 1973. 25. Walker, M. D., Gehan, E. A., Clinical studies in malignant gliomas and their treatment with the nitrosoureas. Cancer Treat. Rev. 60 (1976), 713--716. 26. Wilson, C. B., Chemotherapy: Current results and future prospects. In: Gliomas: Current concepts in biology, diagnosis and therapy, pp. 119--124 (I-Iekmatpanah, J., ed.). Berlin-Heidelberg-New York: Springer. 1975. 27. Withmore, G., Stanners, D., Till, J., Gulias, G., Nucleic acid synthesis and division cycle in X-irradiated L. strain mouse cells. Biochem. Biophys. Acta 47 (1961), 66--71. Author's address: P. Paoletti and R. Knerich, Neurosurgical Clinic, University of Pavia, Policlinico S. Matteo, Piazza Golgi, 1-27100 Pavia, Italy. G. Robustelti della Cuna and M. R. Strada, Clinica del Lavoro Foundation, Division of Oncology, University of Pavia, Via Severino 13oezio, 24, 5-27100 Pavia, Italy.

Multidisciplinary treatment for central nervous system tumours with nitrosourea compounds.

ACTA NEUROCHIRURGICA 9 by Springer-Vedag 1978 Acta Neurochirurgica 41,287--299 (1978) University of Pavia, Italy, Neurosurgical Clinic* (Director: P...
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