Int. J Kadiat~on Oncology Bid Phy., Vol. 35. No. I, pp. 103-I I I. 1996

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ELSEVIER

0 Phase I/II Clinical Trials

SSDI: 0360.3016( 95 )02379-g

IMPROVING CANCER RADIOTHERAPY WITH 2-DEOXY-D-GLUCOSE: PHASE I/II CLINICAL TRIALS ON HUMAN CEREBRAL GLIOMAS

BIDHU K. MOHANTI, M.D.,““iii’ GOURA K. RATH, M.D.,““3”‘I NARANAPPA ANANTHA, M.D., *I

V. KANNAN, M.D.,*‘: BHABANI S. DAS, M.CH.,‘” BANGALORE A. R. CHANDRAMOULI, M.CH.,““,,

AJIT K. BANERJEE, M.CH .,ssnl SARALA DAS, M.D.,“’

AMARNATH JENA, M.B., B.S., D.R.M., D.N.B., * *“I RAMAMURTHY RAVICHANDRAN, PH .D., *”

UDAY P. SAHI, M.D., “‘I11 RAJINDER KLJMAR, M.Sc .,‘I” “‘I NEERU KAPOOR, PH .D., * *-F-‘-

VIJAY K. KALIA, PH.D.,‘# BILIKERE S. DWARAKANATH, PH.D.*’ *‘i--’ AND

VINEY JAIN, DR. PHIL. NAT.* *‘x

*Kidwai Memorial Institute of Oncology, Bangalore. India. ’ Departments of Radiotherapy and ‘Radiation Physics, “National Institute of Mental Health and Neurosciences. Bangalore. India. ’ Departments of Neuropathology. ‘Neurosurgery,

and ‘Bio-Physics. q”tInstitute of Nuclear Medicine and Allied Sciences, Delhi. India, ” Department of Biocybernetics, ‘NMR Research Centre, ““All India Institute of Medical Sciences, New Delhi I IO 029. India, ” Department of Radiotherapy,

Institute Rotary Cancer Hospital, ““Department of Neurosurgery

Purpose: Evaluation of tolerance, toxicity, and feasibility of combining large fraction (5 Gy ) radiotherapy witheoxy-u-glucose (2DG), an inhibitor of glucose transport and glycolysis, which has been shown to differentially inhibit repair of radiation damage in cancer cells. Methods and Materials: Twenty patients with supratentorial glioma (Grade 3/4), following surgery were treated with four weekly fractions of oral 2DG ( 200 mg/ kg body weight) followed by whole brain irradiation (5 Gy). Two weeks later, supplement focal radiation to the tumor site (14 Gy/7 fractions) was given. Routine clinical evaluation, x-ray computerized tomography ( CT ), and magnetic resonance ( MR) imaging were carried out to study the acute and late radiation effects. Results: All the 20 patients completed the treatment without any interruption. The vital parameters were withinnormal limits during the treatment. None reported headache during the treatment. Mild to moderate nausea and vomiting were observed during the days of combined therapy (2DG + RT) in 10 patients. No significant deterioration of the neurological status was observed during the treatment period. Seven patients were alive at 63, 43, 36, 28, 27, 19, and 18 months of follow-up. In these patients, the clinical and MR imaging studies did not reveal any late radiation effects. Conclusions: Feasibility of administering the treatment (2DG + 5 Gy) is demonstrated by the excellent tolerance observed in all 20 patients. Further, the clinical and MR studies also show the absence of any brain parenchymal damage.

2.Deoxy-n-glucose, Cerebral gliomas, Radiotherapy.

INTRODUCTION

The prognosis of patients suffering from malignant cere- bra1 gliomas has remained dismal despite application 01 multimodal therapy and many advances in medical radia- tion technology ( I, 36, 5 1 ). The failure of radiotherapy in cerebral gliomas is primarily due to the presence of

hypoxic, intrinsically radioresistant, and repair proficient

subpopulations of cells in the tumor (56, 63, 64). Cere- bral gliomas are heterogeneous tumors exhibiting large variations in their genotype, DNA content, proliferation kinetics, and metabolic and immunological status (6. 20. 52). Amplification in the expression of cellular onco- genes like raf, myc, and N-ras, known to confer radiore- aistance (37), has been demonstrated in gliomas (49).

An analysis of the pattern of failure after conventional

Reprint requests to: Prof. Dr. Viney Jain, Director. Institute of Nuclear Medicine and Allied Sciences, Lucknow Marg, Delhi I IO 054, India. A(,kno~c,/edgernrnr.s-These studies were carried out under the project INM-175 within the framework of Indo-German re- search collaboration in science and technology. Z-DC was a generous gift from GSF. Munich. Germany. Thanks are due to

Prof. Dr. C. Streffer. Prof. Dr. W. Pohlit. and Prof. Dr. H. Sack for helpful discussions. We are grateful to Prof. Dr. G. N. Narayana Reddy, former Director, NIMHANS, Bangalore, Prof. Dr. M. Krishna Bhargava. former Director, KMIO. Bangalore and Prof. Dr. S. K. Kacker, Director, AIIMS for providing facilities and encouragement.

Accepted for publication I December 1995.

103

104 I. J. Radiation Oncology l Biology 0 Physics Volume 35, Number I, 1996

therapy comprising surgery, radiotherapy, and chemother-

apy indicates local regrowth of the tumor to be the major contributor, implying that the conventional treatment

( 1.8-2.0 Gy/fraction; 30-35 fractions; five fractions/

week; total absorbed dose 60-70 Cy) is inadequate in

local control of the tumor ( 1) . On the other hand, delivery of high radiation doses is limited due to damage to sur-

rounding normal brain tissues (50). Therefore, it has been

suggested that experimental approaches based on newer understanding of the biology of gliomas should be ex-

plored in Phase I/II clinical trials (5, 36). Strategies di-

rected towards differentially enhancing radiation damage

in tumor cells and reducing the damage to normal tissues

could significantly improve the treatment efficacy of ra- diotherapy leading to better local control (28, 31, 46).

Experimental evidence suggests that damage to DNA

is the major cause of cell death and cell loss induced by ionizing radiations in living organisms. A variety of DNA

lesions are induced in cells exposed to ionizing radiations;

most of these lesions (including double strand breaks) can be repaired by the various repair pathways. The bio-

logical end points such as cell death, mutations, and trans-

formations are, thus, determined by competitions between the processes of error-free repair, misrepair, and fixation

of DNA lesions ( 10, 30). Earlier studies have demon-

strated that the cellular processes leading to the repair and fixation of radiation damage require continuous flow of metabolic energy (26, 30, 32, 43) supplied by the

respiratory and/or the glycolytic pathways (32, 61). Be-

cause glucose usage in transformed cells and tumors is increased and tumor cells derive a large part of their

metabolic energy (ATP) from the glycolytic pathway (62), it was predicted that inhibitors of glucose transport and glycolysis could differentially inhibit repair processes

in these cells, leading to an enhancement of the radiation

damage (32). Subsequent studies demonstrated that the presence of 2-deoxy-D-glucose (2DG), an inhibitor of glucose transport and glycolysis, during the first few hours

following irradiation, could, indeed, inhibit the repair of DNA lesions and potentially lethal damage (PLD),

thereby enhancing the radiation damage in various cellu- lar systems with high rates of glycolysis like the cancer cells under euoxic as well as hypoxic conditions ( 18,

19, 27, 30, 34). Interestingly, under similar conditions, a decrease in radiation damage has been observed in normal cells (29, 3 1, 35, 54). Therefore, combination of ionizing

radiations with 2DG provides a unique opportunity to selectively destroy tumors by differentially enhancing the radiation damage in cancer cells and at the same time preventing radiation injuries to normal tissues. Experi- ments on animal tumor models have provided support for this suggestion (33, 48).

Human cerebral gliomas appear to be most appropriate to verify the validity of this approach, because studies using positron emission tomography (PET) have shown that “F-deoxy-o-glucose accumulates in most of the cere- bral gliomas and its accumulation correlates with the de- gree of malignancy ( I6). Glioma cells in V&X> have also

been observed to manifest high rates of glucose usage

and glycolysis (60). Investigations on a cell line derived from a human cerebral glioma showed that energy linked inhibition of DNA repair and modulation of cell prolifera-

tion due to the presence of 2DG, could lead to an increase

in the radiation-induced micronuclei formation ( 18, 19).

Studies on organ cultures using explants derived from

human cerebral gliomas showed that the presence of 2DG

for a few hours after irradiation could increase the fre-

quency of micronuclei formation in most cases ( 17 ), Therefore, it may be expected that combining 2DG with radiation would significantly enhance the efficacy of ra-

diotherapy of cerebral gliomas.

In the present studies, irradiation with large dose frac-

tions was considered necessary to achieve significant and

effective 2DG-induced inhibition of PLD repair in tumor

cells, repair ratio being proportional to absorbed dose in

this range (25). The treatment regimen was designed, for

the sake of convenience and safety, to combine 2DG with weekly fractionation of 5 Gy because the use of conven-

tional radiotherapy would entail daily administration and

monitoring of 2DG. Furthermore, this altered treatment regimen would also ~ninimize the 2DG requirement and

reduce the machine time required for delivery of radiation

dose. The major objectives of the present investigations were to examine the feasibility of administering oral 2DG

with high dose per fraction (5 Gy) of ““Co gamma radia- tion and to evaluate the tolerance and toxicity of this

combined therapy in a population of supratentorial high grade gliomas. Preliminary results of this work have been presented (44).

METHODS AND MATERIALS

Authorization The present studies were conducted after clearance

from the ethics committees of KMIO, Bangalore and AIIMS, New Delhi. Approval of the Drug Controller, Ministry of Health and Family Welfare, in India was also

obtained.

P&eni.s Twenty patients ( 15 males, 5 females), in the age

group of 2 l-64 years with supratentorial malignant glio- mas (Kamofsky performance status score > 70) were included in the present study after informed consent. They

were treated between October 1988 and June 1992 at KM10 ( 10 patients) and at Institute Rotary Cancer Hospi- tal, AIIMS ( 10 patients). Routine pretreatment investiga- tions included complete hemogram, renal and liver func- tion tests, and contrast enhanced CT scan of the brain besides neurological examination. Diagnosis and grading of the tumor were con~rmed on the basis of histopatho- logical investigations according to the WHO criteria (66). Surgery was carried out to achieve adequate tumor exci- sion (decompression in 14 and near total excision in 6 patients). Tumor volume was also measured with the help of CT scan (38 ) before and after surgery in the 10 patients

Improving cancer radiotherapy with 2-deoxy-w&core 0 B. K. MOHANTI et ul. 105

Table 1. Grade 3 gliomas: Patients, tumor characteristics, treatment and survival (12 = 4)

Tumor vol (ml)* Survival

S1. No. Age/Sex Site Surgery date Pre-Rx Post-Rx’ (months) Remarks

I. KI’ 2X/M Lt. Frontal NTE 9/X)/88 44 0 >63 Recurrence at 38 months (lost to follow-up)

2. K2 59/M Lt. Temporal Decomp. 1 l/18/88 61 78 5 3. K6 4WM Lt. Frontal NTE 615190 37 20 >43 Alive. Disease free 3. K8 36/M Lt. Front0 parietal Decomp. 9i 1919 I 63 22 >27 Alive, with disease

Lt. = Left; NTE = near total excision; Decomp. = decompression of tumor. * Volume assessed from CT scans.

Measurements made 2 to 3 weeks after the fourth fraction of 2-DC + RT. i Institute-wise serial no. of the patients. K = KMIO, Bangalore.

treated at KM10 Bangalore (Tables 1 and 2). Two weeks ment. Complete hemogram and bfood urea levels were

after surgery. radiotherapy (RT) was started. monitored weekly during the treatment.

After overnight fasting, aqueous solution ( 100 ml) of

2DG was adIninistered orally. at a dose of 200 mglkg

body weight. Thirty minutes after oral 2DG, whole brain “‘Co gamma radiation ’ was delivered to a midplane dose

of 5 Gy, by two parallel opposing lateral portals. This schedule of 2DG + RT was given once weekly over days 1, 8, IS, and 22. The total radiation dose was 20 Gy in

four fractions over 21 days. The biolo~icaIly isoeffect

equivalent radiation dose was 4 1 Gy (4, 53) calculated from the modified Ellis formula, NSD (neurets) = D x

T-“-” X N -“J (905.3 neurets). as suggested by Sheline

(53). Two weeks after the fourth fraction, CT scan of the brain was carried out and the residual tumor volume was calculated. Supplement small field RT (focal irradia- tion) was delivered to the target volume comprising the

residual tumor plus a 3 cm margin to a dose of 14 Gy in seven fractions at five fractions per week. Hence, the total

radiation dose delivered to the whole brain was equivalent to 41 Gy in conventional 2 Gy schedule (4), and the further boost of 14 Gy delivered a total dose of 55 Gy

(equivalent) to the tumor site.

All patients were evaluated periodically (every 3-6 months) with clinical assessment. CT scan, and MR im-

aging. These patients were followed until September 1994

or death.

MR imaging Thirteen patients underwent one or more MR examina-

tions from 2-60 months after radiotherapy. Noncontrast MRI of the brain was carried out using a whole-body

superconducting tomograph” with the help of a standard

head coil. Using Tl (TR 700 ms/TE 17-22 ms) and T2 (TR 1.X s/TE 90 ms) spin echo sequences in an axial plane, 5 mm slices with 50% interslice gap were acquired

(matrix size 256 X 256). Additional multiecho (eight ethos) sequences were taken for calculating relaxation time T2 with the help of standard software. Occasionally,

coronal plane images were also taken to clearly define the extent of tumor.

RESULTS

Blood samples were collected hourly up to 6 h follow- ing 2DG administration and at 24 h to estimate 2DG and

glucose levels. Glucose was estimated by the reducing sugar method (55) and 2DG using the diaminoben~~~ic acid (DABA) assay (7).

Immediate tolerance to treatment was assessed by the measurements of vital parameters such as pulse rate, blood pressure, respiration, and body temperature, which were monitored hourly on treatment days. Symptonls such as headache, nausea, and vomiting were recorded besides complete neurological examination during the entire treat-

A brief summary of the clinical and survival data for all the 20 patients (4 with Grade 3 and I6 with Grade 4 tumors) is presented in Tables 1 and 2. Though the proto- col was designed for accrual of the patients with malig-

nant gliomas, four of the treated patients had Grade 3 lesions. The patholo&ic grades in all the 20 patients were reviewed by one of the coauthors (SD.). In the KM10

series, the postsurgical tumor volumes evaluated before administering the treatment varied from 15 to 167 ml (Tables 1 and 2. Kl-KIO).

Response to treatment Acute t$kts. No significant change in any of the vital

parameters was noticed either on the day of treatment or on subsequent days (Table 3). However, general weak-

’ Theratron 780-C, AECL, Canada. ’ Mngnetom, GBS I, Siemens, Germany.

106 I. J. Radiation Oncology 0 Biology l Physics Volume 3.5, Number 1, 1996

Table 2. Grade 4 gliomas: Patients, tumor characteristics, treatment and survival (n = 16)

Tumor Vol. (ml)* Survival

Sl. No. Age/Sex Site Surgery date Pre-Rx Post-Rx+ (months) Remarks

1. K3’ 43/M Rt. temporoparietal Decomp. 2/l 8/89 127 65 9 2. K4 62/M Rt. temporal NTE 4130190 70” 28 10 3. K.5 34/M Rt. temporal Decomp. 6/5/90 1.5 26 10 4. K7 26/F Rt. parietal Decomp. 8/3/90 20 13 5 Unnatural death 5. K9 36/M Lt. temporal NTE l/2/92 34 23 9 6. KlO 53/M Rt. frontal Decomp. l/8/92 167 132 5 7. Al 55/M Rt. temporoparietal Decomp. l/10/91 >18 8. A2 55/F

Lost to follow-up Rt. frontal NTE l/31/91 12

9. A3 21/F Rt. frontal Decomp. 3/28/91 4 10. A4 32/F Rt. frontal Decomp. 4/4/9 1 13 II. A5 40/M Rt. temporal Decomp. 5/l/91 21 12. A6 64/M Lt. parietal NTE 4/4/91 12 13. A7 55/M Lt. temporoparietal Decomp. 9/9/9 1 >19 14. A8 64/F

Lost to follow-up Lt. frontoparietal Decomp. 12/4/9 1 21

15. A9 48/M Lt. frontoparietal Decomp. 12/5/9 1 36 Recurrence at 19 months

16. A10 35/M Lt. frontal Decomp. l/8/92 28 Disease free

Lt. = Left; Rt. = right; NTE = near total excision; Decomp. = decompression of tumor. * Volume assessed from CT scans. ’ Measurements made 2 to 3 weeks after the fourth fraction of 2-DG + RT. ’ Institution-wise serial number of the patients; K = KMIO, Bangalore; A = AIIMS, New Delhi. ’ Presurgical volume.

ness and lethargy was prominent in all patients on the day of administering the combined (2DG + RT) treatment. Nausea and vomiting were absent in 10, mild in 3, and

moderate in 7 patients, and lasted for nearly 18-24 h after 2DG administration. All patients were treated with i.v. fluids, metochlopropamide, and antiedema measures like mannitol and lasix. Steroids were used in only two

patients. Sweating was observed in nine patients. How-

ever, the peripheral pulse rate and the blood pressure

remained stable in all 20 patients. Appetite was poor on treatment days, but it was normal during the rest of the

therapy. Headache was not reported by any of the patients during the course of the treatment. Hemogram and blood urea levels measured weekly were within normal limits in all of the patients.

In all 20 patients, blood 2DG levels showed a maxi- mum at 1 h after administration and thereafter decreased

exponentially with an average half life of 89 ?z 17 min.

Table 3. Acute effects observed in patients treated with the combined (2-DG + RT) protocol

Pt. No.* Gen. cond. Nausea vomiting Sweating B.P./pulse

Kl Stable Moderate I episode Stable K2 Stable Mild Nil Stable K3 Low Moderate Nil Stable K4 Stable Nil Nil Stable K5 Low Nil Nil Stable K6 Low Moderate Nil Stable K7 Stable Moderate Nil Stable K8 Stable Moderate Nil Stable K9 Stable Nil Nil Stable KlO Stable Nil Nil Stable Al Stable Nil Nil Stable A2 Stable Nil Once Stable A3 Stable Moderate Nil Stable A4 Stable Nil Once Stable A5 Low Nil Once Stable A6 Low Nil Severe Stable A7 Stable Nil Severe Stable A8 Stable Moderate >2 times Stable A9 Stable Mild >2 times Stable A10 Stable Nil Once Stable

* Institution-wise serial no. of the patients; K: KMIO, Bangalore; A: AIIMS, New Delhi.

Mental state

Drowsy Alert Alert Alert Alert Alert Alert Alert Alert Drowsy & Giddiness Giddy Drowsy Stable Seizure once Stable Drowsy Drowsy Disorientation Stable Drowsy

Improving cancer radiotherapy with

The levels of glucose, 2DG. and the molar concentration

ratio (2DG/G) observed in a typical case are presented

in Fig. I. By 24 h, detectable amounts of 2DG were

not found in the blood. Blood glucose levels gradually

increased following 2DG administration. reaching a maxi- mum value (three to four times the basal level of 5.0 -C 0.8 mM) at about 3 h after administration. The levels

subsequently decreased and reached the basal value by

24 h. The ratio of 2DG to glucose in the blood was found to be the highest (0.6- I .O) I h after 2DG administration

and decreased rapidly reaching an insignificant value (< 0.02) by 6 h.

None of the patients developed any new neurological

deficit during the entire period of therapy. In five patients.

the general condition and the neurological status showed

significant improvement at the end of therapy. At the completion of the planned protocol, in the KM10 series,

the tumor volume decreased in eight patients, while an

increase was observed in the remaining two patients.

The median survival in this study was 13 months and

7 patients (35%) were alive at 63, 43. 36. 28, 27, 19, and 18 months of follow-up (Tables 1 and 2 ). Three of these

seven patients were lost to follow-up at 63, 19. and IX months. The median survival was 32 months in the four patients with Grade 3 tumors. whereas it was observed

to be 13 months in the 16 patients with Grade 4 gliomas. However, the number of patients with Grade 3 lesions is

too small (four patients) for any meaningful inference. Five patients had recurrence at the primary site and

three of these were subjected to salvage therapy (one underwent surgical decompression and the other two re-

ceived four courses of oral nitrosourea). These three sal- vaged patients were alive at 63. 36, and 28 months. The

remaining two patients succumbed to the disease at IO and 1 I months.

The MR imaging was carried out to evaluate the late radiation effects in seven patients between 12 and 60 months after the therapy. Representative MR images of

a 4%year-old patient investigated at 6 and 18 months of follow-up are given in Fig. 2. Periventricular hyperinten-

sity patterns were graded, as described by Constine et rrl.,

based on Zimmerman’s classification ( 1 I. 65 ). Of the seven patients, four did not show any white matter changes indicating the absence of late radiation damage (Table 4), while in three others. Constine’s Grade 1 to 3 changes were observed.

None of the living patients showed any clinical features

of late radiation encephalopathy till their last fc)llow-up evaluation. None of the living patients had any higher motor function impairment.

DISCUSSION

Although the role of external radiation therapy in mod- estly prolonging survival following primary surgery has been clearly demonstrated ( 23), the current practice of

deoxy-r)-glucose 0 B. K. MOHANTI et a/

b-

c 0.8 -

0.6 -

0.4 -

0.2 -

0 I I I I I I 1 2 3 4 5 6

POST - TREATMENT TIME ( Hours I

FIG. I. Levels of blood glucose (a), 2-DG (b) and the values of the ratio 2-DG/G (c) observed in a 4%year-old male patient following oral administration of 2-DG (200 mg/kg body weight ).

conventional fractionation or hyperfractionation has not provided any significant overall benefit in the manage-

ment of gliomas ( 13, 15,25 ). The radioresistance of these tumors (primarily responsible for the failure of radiother- apy ) could be due to efficient defense, the repair and repopulation mechanisms in the glioma cells, or to radio- protection afforded by the microenvironment. Results of

if7 rlitro studies have shown that glioma cells are proficient

in the repair of potentially lethal damage ( 13, 15). The SF2 values (0.4-0.73) reported for many of the glioma cell lines and primary cultures (2, 58) also point to the radioresistant nature of glioma cells requiring high radia- tion dose ( > 2 Gy) to overcome the shoulder (21). To achieve significant cell kill and to improve the therapeutic outcome, a few promihing attempts to use large fraction irradiation ha\;t; been made (24, 59).

The need to develop strategies based on biology of the

I. J. Radiation Oncology 0 Biology l Physics Volume 35, Number I, 1996

tumor cells that enhance cell kill, while reducing radiation damage to the normal brain, is being increasingly realized.

The present approach, which is based on energy-linked modifications of repair and fixation processes through the

combination of 2DG with low LET radiations, is an at-

tempt in this direction (3 I, 32). The present study demon-

strates that the combination of 2DG (200 mg/kg body

weight) with large doses of gamma-irradiation (4 X 5 Gy/fraction/week) is feasible and causes no serious side

effects.

2DG is transported across the blood-brain barrier by mechanisms similar to those for glucose, and phosphory-

lated by hexokinase to 2-deoxy-D-glucose-6-phosphate

(2DG-6-P), which accumulates in the tumor and blocks

the glycolytic pathway (3). In the peripheral blood, maxi-

mum values of 2DG/G ratios (0.6 to 1.0) were observed

1 h after oral administration of 2DG. If our hypothesis suggesting 2DG-induced differential inhibition of DNA

repair in tumor cells is valid, high levels of 2DG in the

tumor would be required only for short intervals of time following irradiation (the time constant of DNA repair

processes in human cells being less than I h). It is ex-

pected that 2DG-6-P in adequate amounts would be pres- ent in tumor cells under these conditions. In the present

studies, estimates of 2DG or 2DG-6-P levels in the tumors

could not be made; however, measurements of 2DG-6-P using magnetic resonance (MR) spectroscopy or PET are

planned in subsequent studies. The major concern in the present studies has been about

the acute physiological changes induced by the adminis- tration of 2DG. Perturbations are caused by the inhibition

of glucose usage (cellular glucopenia), particularly in the functioning of neuroendocrinal system in the presence of

2DG. The observed hyperglycemic state may be caused partly by the increased secretion of noradrenalin from the

hypothalamus leading to the release of glucagon from the

Table 4. Late radiation effects in patients treated with the combined protocol evaluated from white matter changes

(Constine’s grading of periventricular hyperintensity) investigated using MRI

Pt. No.* Age/sex

Follow-up time

(months)

Periventricular hyperintensity

(Constine’s grading)

Kl 28/M 6 53

K6 40/M 25 A3 21/F 3

12 A6 64/M 5

I1 A7 55/M 6

12 A9 48/M 24

36 A10 35/M 4

6

0 0 0 0 1 0 0 1 2 0 0 1 3

Fig. 2. T2 weighted MR images of a 4%year-old patient at 6(a) and 20 (b) months after radiotherapy.

* Institution-wise serial no. of patients; K: KMIO, Bangalore; A: AIIMS, New Delhi.

Improving cancer radiotherapy with 2-deoxy-o-glucose 0 B. K. MOIIANT-I cr trl. IO’)

pancreas, mobilization of fatty acids, breakdown of liver

glycogen and gluconeogenesis (39). This may, possibly,

cause nausea and vomiting as observed earlier (45). In

this study, 9 out of 20 patients experienced a mild to

moderate degree of nausea and vomiting (Table 3 ). How-

ever, these symptoms did not call for interruption of treat-

ment, and the patient compliance was satisfactory. Eight

patients showed features of drowsiness or stated giddi-

ness, that lasted for a period of 4-5 h, on the days of

combined treatment. Only one patient suffered from sei-

zure on I of the 4 days of treatment (Table 3 )

Clinical signs and symptoms of increased neurological

deficits were not observed in any of the patients, and considerable improvement was noticed in 25% of the

cases during the course of therapy. Headache has been

reported as a common symptom after irradiation with

higher dose fractions (57 ) This problem was not encoun-

tered in the present study.

Brain is a classic late-responding tissue to radiation.

For the development of radiation myelitis, besides the

cytokinetic organization, other important factors are the

total radiation dose, dose per fraction, the repair kinetics, and repair capacities of the tissues. The currently avail-

able information on these parameters in normal brain and

gliomas is insufficient to suggest optimal radiotherapy

regimens. Although, the safe daily fraction size in the

treatment of brain tumors is recommended to be 1.8- 1.9

Gy (47 ). no neural tissue damage (clinical or histologi-

cal) has been observed with a dose of 4.33 Gy and misoni-

dazole (8 ). On the other hand, a few studies with large

dose fraction radiotherapy using 4-5 Gy/fraction have indicated some benefit with this schedule in the case of

patients with glioblastoma multiforme (24, 59). The role

of large fraction radiotherapy in the treatment of brain

tumors. therefore, needs to be examined further.

It is interesting to note that in the seven living patients of the present series, clinical features of late radiation

neuropathy were not observed, inspite of a high dose per

fraction of 5 Gy and a total observed dose equivalent to

the conventional total RT dose of 55 Gy (4. 53). The

development of late radiation damage in brain, often lead-

ing to radiation necrosis, shows a steep dose response

from essentially no effect to full effect beyond a critical

threshold dose (22). Further. Sheline ( 53) observed that

brain necrosis occurred in patients who received doses

corresponding to a range of 1700 to 1800 ret and neuret doses of 1000 to 1100. There has been some apprehension

that a high dose per fraction could lead to greater late effects in the central nervous system ( 14), mainly in the form of demyelinating lesions with focal or diffuse areas of white matter necrosis (9). Magnetic resonance imaging

has been shown to identify these lesions with greater sensitivity due to alterations in water content accompa- nying these lesions ( 1 1. 12). Five periventricular patterns or grades of increasing extent and intensity have been

identified. and higher grade lesions were associated with radiation to large volumes and high dose ( 1 I, 65). MRI

evaluation in seven of our patients during the follow-up revealed Constine’s Grade 0- 1 changes in 4 and Grade l-3 changes in three patients. Present observations could be either due to lower whole brain radiation of 20 Gy in 4 fractions (equivalent to conventional schedule of 41 Gy; 905 neurets) and/or a possible protective effect of

2DG on the glial cells of white matter and endothelial cells of the vasculature. the two important targets of late radiation damage (4, 12. 41, 42 ). These possibilities are

of significance for the study of damage to brain paren- chyma vis-a-vis large fractionated therapy, and they need to be investigated in detail using more advanced and sen- sitive techniques.

In conclusion. present studies show that all the patients could well tolerate the combined treatment of 2DG with large dose per fraction (5 Gy). Although, the objectives of this study were to evaluate the tolerance. toxicity, and feasibility of this experimental protocol. the median sur- vival of 13 months observed in the 20 patients compares well with the published values ( 13. 24. 5 1 ). Therefore, further clinical trials to determine the optimal dose of both 2DG and radiation in escalating dose schedules and to evaluate the efficacy of this treatment are warranted. Although at this stage, it is understood that the presence of 2DG enhances the effects of irradiation in the glioma cells ( 17 ). future human studies should also be designed to observe the separate effects of large dose per fraction of radiotherapy and the oral intake of 2DG.

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