Pion radiotherapy at LAMPF

036~3016/X2/122181~650300/0 Copyright 0 1982 Pergamon

??Symposium

V--Clinical

Charged Particles PION RADIOTHERAPY

AT LAMPF

E. BUSH, M.D., ALFRED R. SMITH, PH.D. AND SANDRA ZINK, PH.D.

STEVEN Cancer

Press Ltd

Research and Treatment

Center,

University of New Mexico. and Department New Mexico, School of Medicine

of Radiology.

University

of

Clinical investigatims of pi meson radiotherapy were conducted by the Cancer Research and Treatment Center of the University of New Mexico and the Los Alamos National Laboratory from 1974 until 1982. Two hundred and thirty patients have been treated for a variety of locally advanced primary and metastatic neoplasms. One hundred and ninety-six patients have been followed for a minimum of 18 months. Crude survival data range from 11% for unresectable pancreatic carcinoma to 82 % for Stages C and Dl adenocarcinoma of the prostate. Acute tolerance of normal tissues is approximately 4500 pion rad in 36 fractions over 7 weeks. Severe chronic reactions have appeared with increasing frequency after doses in excess of 4000 pion rad. Pions, Particle

radiotherapy.

INTRODUC’TION The potential mesons

(pions)

were

were

treated

Facility

(LAMPF). 1974 and

neoplasms Clinical dose

suggested

at

between

from

the

a variety

and

treatment

dosimetric

methods,

immobilization, ning.

One

large

volumes

hundred

and deep-seated

curative rad,

intent

and

additional intent

33

with

a combination

pion irradiation of treatment reported

of conedown of a portion

30 patients

tissue

of patient

positioning

and

been

IX

treated

volumes.

Additional

prior

to

19X1

I25

pion An

and

pion

group

and results

have

regarding

been

the

basis

tumor

of this

METHODS LAMPF Pions

casts.

surgery

combined

conventional

MeV of

water-cooled and bending

is a linear proton

accelerator

beam

appropriate graphite magnets

AND MATERIALS at

momenta target

designed

a current by

as described

are

of

to produce

collected

a series

an

1 milliampere. from

of quadrupole

by Paciotti

rr ~1.~ The

These investigations were supported by U.S.P.H.S. Grant NO. 5 PO1 CA 16127 from the National Cancer Institute and by the U.S. Department of Energy.

was 80’S

Supplemental

Table

1 shows

patients

followed

at least

had

known

two

who

tional

from

the

less than

patients

with

have

been

dose

for

dose

in whom

in or

com-

pion

irra-

of

those

I96

Thirty-eight

died

cura-

therapy

planned

distribution

2700

for at least

radiotherapy

analysis,

5 who

of the

of cvaluable

prescribed

follow

IX months.

additional

metastases.

received

not

and

rad.

minimum

of the

in selected did

pion

volumes

conventional

regression

of tumor

radiation

The

1974 Phase

196 patients.

treated

conedown

interval.

diation.

patients

including

during

pion

3

therapy.

rad

I &ho and

without

addi-

potential

curt

therapy.

The a

of

same

was employed

under

followed

with

tumor

treated

regression

has been

known

between

2700

33 patients

volumes

or without

pions

of

than

complctc

observed.

the

of

techniques

a spectrum

additional

wet-c excluded

report.

X00

most

plcte

of an additional

form

treated

were

An

for

pion

with

A population greater

irradiation

followed

rate

of 2 liters.

treatment

with

to elucidate

dose at which was first

2700

curative

treated

reactions. received

minimum disease

months. with

and follow-up

which

intent

Preliminary

data

of

but

intended

tive

irradiation

patient

six patients

with

than

of

All

tissue

and

a fixed,

a dose

in a volume

patients

and

IX months.

treated

and thirty were

1982.

with

described.‘.‘.’

disease

I- I I trials

126

minute

mctastatic

normal

plan-

with

hundred

produces

beam

of the channel

in

and

treatment

patients

have

been

of this

respon:;e

treated

to standardization

of conventional

previously.‘,”

and normal

and

increase

per

been previously

Two

treated

or metastatic

sites and histologics.

in doses greater

have

were

advanced

a minimum

patients

Physics

treatment

divergent

5 rad

have

twenty-live

pions for

approximately Characteristics

neoplasms

with

followed

in

pion radiother-

localiration and

Perkins

used in patient

minimally

Meson

to a gradual

techniques

tumor

vertical,

Alamos

of primary led

pi

and

of 230 patients

have

channel

negative

to receive

Los

A total

with

by Fowler

19X2 fcr locally

observations

pion

‘3f radiotherapy

1974, the first patients

1961.’ In apy

advantages

patient

includes and

neck

and

3

population

3X patients (35 with

with

with

analyzed advanced

T3 and

locally

for

neoplasms

T4 squamous

advanced

minor

cell

of the head carcinomas

salivary

gland

Reprint requests to Steven E. Bush. M.D.. St. .loscph ltohpltal. 400 Walter Avenue, N.E.. Albuquerque. NM X7 102. Accepted for publication 2X .luly 19X7.

2182

Radiation Oncology

Table

0 Biology

0 Physics

December

patients

RESIILTS with

tumors).

Forty-two

including

27 with

grade

astrocytoma.

radiotherapy conedown

125

volumes

additional

patients

patients

miscellaneous nary bladder.

with

had locally (Stage

carcinoma

skin, stomach,

gliomas

other

DI)

treated

tumors

rectum,

including

cervix,

Sixteen

with

additional

clinical

for logistic and

on the

(cx-

other

sites

curves for the two

of 28 patients multiforme)

of IO months and I4 patients

adenocarciand

I8

with

had

a median

indicates

Twenty-three alone

(glioblastoma

i.e., those with gliomas

grade

for

survival

III

and

combination

of the

doses of

3600

of that

received

subgroup

treated

whole brain rads

and

A third

curve

of I7 patients

pion

with

with

a planned

radiotherapy

to

irradiation

01

conedown

volumes in doses of 1250 to I800 pion rad. This

in

treatment

plan was employed

in this

follow-up

is abbreviated

of beam

treated

basis of any

only after August.

compared

with pions alone; the median

to that survival

1979. so

for patients has not yet

been reached. 3 shows similar

curves for patients

treated

-Dead n=36

-Alive (X)

l-l =25 n=23

n=22 I

l(

a Head +

survival

with grade II I astrocytoma

IV astrocytoma to 4600

a median

of 22 months.

of conventional

lung and uricom-

survival

and

with grade IV astrocywith

Survival in 125 patiants with 126 tumors treated to dose >27DDTr

Brain

those

2 shows the survival

of

Figure

“r

and miscellaneous

of patients;

of

of the pelvis

Figures 2 and 3 show crude survival

parameters. 5

thorax

tumors

toma

to scheduling

not selected

for advanced

tumors of the head and neck. Figure

and pion irradiation

reasons related

were

treated

pancreatic

percent

those with advanced

doses less than 2700 pion rad. Patients were treated fashion

and unresectablc Fifty-two

conventional

carcinoma

patients

radiotherapy

carcinomas

respectively.

largest subgroups

pions

esophagus,

I I’P for

and Stage C

and I5 with

advanced

C and

head and neck tumors.

eluding prostate), survived.

pion irradiation

of the pancreas.

were

bined conventional

operation

and DI prostatic

2

for at least IX months.

rates are 2X%. 34’7r. 82% and

advanced

carcinomas,

in doses of 1200 to 1800 pion rad.

of the prostate

unresectable

brain

gliomas,

patients

received

with pions alone in doses grcntcr

than 2700 pion rad and followed

31 5

malignant

rates for 125 patients

crude survival

I26 tumors treated

These survival

33

multiforme

Seventeen

to the whole

Twenty-two noma

had

patients

glioblastoma

I indicates

Figure

196

Patients receiving >2700 pion rad Patients receiving ~2700 pion rad with additional conventional XRT Non-curative patients Known distant metastases Died during therapy Dose ~2700 pion rad without additional therapy

I7

X. Number

I. Patients treated with pions I974- I98 I Total

III

19X?. Volume

Prostate

Pancreas

Other

fl0Ck

Fig. I. Survival of I25 patients with 126 tumors treated to doses of 2700 pion rad and followed for a minimum of I8 months.

for

Pion radiotherapy at LAMPF 0 S. E.

I_

l(4)

c

‘-;

-

-

2183

BUSH ef al.

-II-

--y L_

b-l L

‘7

--,

-L

‘,”Booat I

;

??conv4ntional

1

7

I-

XRl

1

-l

Or

1

Ll UL, L

- -1

----I

---

l

‘c&H

L

0

I

5

15

10

Thm

Fig. 2. Crude survival-Glioma

c4ud8

20

25

30

35

bnonw

patients

strvw-

by histology and treatment

techniques.

t488d + M8ck Patbntr

00

II0

1’0

I10 _ f

c

E

a

_ A’ oropharynr

00

u

All

patients

30

20

10

0

patmntf

(n = 15)

!I0

10

20

30

40

50

Thm hlcum8)

Fig. 3. Crude survival-Head

and neck patients.

80

(n = 38)

21x4

Radiation

Oncology

0 Biology

0 Physics

December

advanced neoplasms of the head and neck. This population of 38 patients includes 35 with squamous cell carcinomas Stage T3 and T4 with or without regional nodal disease and 3 patients with minor salivary gland tumors. Fifteen of these patients had primary tumors in the oropharynx and are analyzed separately. The median survival for the entire population is 12 months with 90% of deaths occurring within 2 years. Eight of I5 patients with oropharyngeal primaries survive at times up to 5 years with no deaths after I8 months. Figure 4 shows local control statistics for the same population of I25 patients treated with pion irradiation in doses in excess of 2700 pion rad previously analyzed with respect to survival. Local tumor status was assessed clinically by means of physical examination, routine CT scanning and other radiological procedures and clinical laboratory studies. Local control was obtained in only 8% of glioma patients when determined by the following criteria: neurological stability, absence of mass effect and contrast enhancement on CT scan, and absence of steroid dependence. The local control statistics for neoplasms of the head and neck, prostate, and pancreas were 50% 73%‘. and 0%. respectively. Local control was determined only upon complete disappearance of mass effect on CT scanning in the cases of pancreatic carcinoma. Twenty-six percent of patients treated for miscellaneous tumors of the skin, lung, esophagus, stomach, cervix, rectum, and bladder had no evidence of local disease at follow-up of 18 to 55 months. Determination of acute and chronic normal tissue 50

19X2. Volume

8. Number

I7

reactions for various tissues has been a major goal of the Phase I-II clinical trials. Acute normal tissue reactions have been qualitatively identical to those associated with conventional radiotherapy and have not necessitated unanticipated interruption of therapy except in four patients (2 with head and neck neoplasms and two with massive pelvic primaries). Acute reactions to pion radiotherapy have been systematically recorded according to a scale of O-4 as follows: O-nil; l-skin erythema, mucosal injection, mild dysuria or diarrhea 54 stools per day, etc.; 2--dry desquamation, patchy mucositis, moderate dysuria, diarrhea with mucus (~5 stools per day), etc.; 3-moist desquamation, confluent mucositis, severe dysuria with bladder spasms, diarrhea with blood, etc.; and 4-acute necrosis. Average sums of acute reactions were obtained by summing severities of all reactions for individual anatomic sites as follows: head and neckmucosa, skin, salivary glands; pelvis-skin, rectum, bladder; thorax-skin, dysphagia; abdomen-nausea, diarrhea; brain-skin. An analysis of acute reactions for the first 91 patients treated with pions alone after biopsy is shown in Table 2, demonstrating a trend to more severe reactions at all sites except pelvis and brain in the higher dose range, although these data ignore such potentially contributory factors as daily fraction size, treatment volume, and hyperfractionation. The average sum of acute reactions for I I patients (10 with carcinomas of the head and neck and one with carcinoma of the stomach) receiving greater than 5000 rad was 6.2. Of greater importance in evaluation of the therapeutic

Local control in 125 patients with 126 tumors treated to dose >2700 fr

iG.l

-local failure

n=30

40

In E Q .L 2 a.

-local control (%I

3c

5 $

n =23

n=22

+ 2

20

18

n=

7//

10

73

/

0 261

0

Fig. 4. Local tumor control minimum of 18 months.

Brain

in 125 patients

Head +

& Prostate

with 126 tumors

-

treated

Pancreas

Other

to doses 2700 pion rad and followed for a

Pion radiotherapy

Table

2.

Acute injury related to pion irradiation >2700 pion rad by site and dose range

Dose range

Site

at LAMPF

in doses

adenocarcinoma

Average sum of acute reactions

13 8 3 6 6

5.1 4.6 2.3 1.8 I.2

area receiving tumor

Head and neck

24

5.8

Pelvis Thorax Abdomen Brain

I2 I 6 I2

4.9 3.0 2.2 I.2

Note: See text for explamtion

chronic

and

Chronic

irreversible

reactions

been recorded

treatment

following

according

of EORTC/RTOG,

with bowel

small

in which

able to radiotherapy.

Grade

while reactions

There

effects

year-old

female had chronic

following

related

morbidity.

fibrosis

have

4300

less than

Eight

of IO patients

pion

rad

had

exceeded

one

liter

provide all

a population

patients

were

techniques.

alone.

0

=

severe

Pion radiotherapy ment of advanced

life-

best suited to this analywith

pions

observations

to increasing treatment

severity

volume

has been employed neoplasms

alone

of other of

late

and especially

??

! I I I I I I 1 I I I I 1 I I I

0

0 looo----------------------

?? ??

---7

IQ I I I

0

0

??

0

?? 3500

4ooo

DOSE

Chronic injury with pion irradiation

I

I

I I I I I

I 4500

4700

(nr)

of rectal carcinomas

-Dose-volume

in

in 230 patients

SCORE

ii s

Fig. 5

or

for prostatic

DISCUSSION

2m-

2ooL

doses

total dose.

carci-

0

to had

to severe

severe

o-1

??

for

rad

whose treatment

treated

treated

However.

the trend increasing

pion

receiving

0=2

500-

late effects recorded

moderate had

late effects. The patients

effects with

lNm?Y

using

only two of nine patients

CHRONtC RECTAL WLJFW WtTH PION IRRADIATION OF PROSTATE CANCER CHRONIC

to

in a group of

4300

and three of those six patients

using similar

4000 pion rad for a large

R’roG/EORrC

Fig-

related

carcinomas

also

sites confirm

developed

prostatic

reactions

sis because

edema and aspira-

A second patient following

treated

volumes carcinoma

A 70

doses

reactions. than

life-threatening

irradiation

laryngeal

rectal injury

to the EORTC/RTOG

less than one liter;

threatening

ranges

5000 pion rad for a T4 squamous

noma of the larynx. pulmonary

to pion

following

intestine.

were no severe late effects

receiving

greater

of grade 3 and above are consid-

chronic

for advanced

prostate developed

expired

of devitalized

and volume

moderate

of

are of moderate

have developed

involvement

dose of pion irradiation

system.

to 5, i.e. death ascrib-

2 reactions

resection

recurrent

Two patients

advanced

and

of chronic

patients

of reaction

nodal

obstruction

are scored according

irradiation

severity

reaction

ered severe. Five patients

tion

related

locally

ure 5 shows an analysis 20 men treated

is the incidence

the pion

rad for

regional

surgical

locally

histologically.

pions alone in doses of 3300 to 4600 pion rad. Late effects

to the late effects scoring system

from 0, i.e. no detectable severity

modality

pion

late

attempted

of scoring system.

of a new treatment

4500

woman

brain necrosis in an

3700 pion rad, although

carcinomas

volumes efhcacy

developed

was also demonstrated

receiving

>4000

of the lung and a 58 year-old

with grade III astrocytoma

Number of patients

Head and neck Pelvis Thorax Abdomen Brain

t4000

2185

0 S. E. BUSH ef al.

considerations.

the manageof whom

196

2186

Radiation Oncology 0 Biology 0 Physics

have been followed

for at least 18 months.

December

1982. Volume

One hundred

volumes

less than

with doses of

acute

and twenty-five

patients

pion irradiation

in excess of 2700 pion rad, a potentially

curative tional

have been treated

dose. Follow-up information

normal

tissue reactions

comprise

of these patients

regarding

disease site, histological treatment

Relatively

small

intervals,

population

numbers

studies

efficacy

of pion

conventional These

may eradicate

be obtained

with

able chronic

reactions

ters including determined,

respect

to

of con-

radiotherapy.

short

observations

on the

and its comparability

with

previous advanced

reports

acute morbidity

dose and volume

considerations

of 4250 pion rad in 33 to 35 fractions

trend toward

treated

rad, particularly diation may

when associated

or subsequent not

following

severe injury

with doses greater

manifest

surgical themselves

in

with large volume until

These

or

2

irraeffects

more

years

therapy.

Clinical

trials

at LAMPF

1982. although

related

the SIN

in Villigen.

facility

that continued

were

clinical

follow-up

of patients

radiotherapy.

to techniques

and accept-

zation,

dosimetry

other forms of particle been collected.

a large

of patient and

is proceeding

treated clinical

at LAMPF of dose

trials of pion

body of information

positioning

treatment

at

It is anticipated

in determination

in future

In addition.

related

in April,

discontinued

research

Switzerland.

in a vari-

over seven weeks to

of

than about 4300 pion

intervention.

considerations

have been

terms

has appeared

patients

and volume

and suggest that doses of pions in the range

in

ever a definite

pion

parame-

acceptable

Late effect dat;i follow-up, how-

may

in most cases. Treatment

are

necessary guidance

up to 4’/2 years. This benefit

tolerable

liter

will provide that

neoplasms

one

and late normal tissue to tolerance. remain incomplete given relatively brief

follow-up

design of these early

techniques.

substantiate

ety of sites for intervals

pion

definitive

irradiation

treatment

data

irradiation

preclude

and

These patients with

of patients,

addi-

control

type and combinations

supplementing

and the non-randomized

clinical

provides

tumor

to pion irradiation.

a heterogeneous

ventional

survival,

I7

8. Number

planning

and conventional

and immobilirelevant

radiotherapy

It may be hoped that this information

to has will

direct future research in particle radiotherapy in general, as well as ongoing clinical trials of pion radiotherapy.

REFERENCES 1. Fowler,

P.H., Perkins, D.H.: The possibility of therapeutic applications of beams of negative x mesons. Nature 189: 524-528, 1961. 2. Hogstrom, K.R.. Smith, A.R.. Kelsey, C.A., Simon, S.L., Somers, J.W., Lane, R.G., Rosen, 1.1.. Von Essen. C.F.. Kligerman. M.M., Berardo, PA., Zink, S.M.: Static pion beam treatment planning of deep seated tumors using computerized tomographic scans at LAMPF. In?. J. Radiar. Oncot. Biol. Phys. 5: 875-886, 1979. 3. Kligerman. M.M.. Bush, S.E.. Kondo, M.. Wilson, SE., Smith, A.: Results of Phase l-11 trials of pion radiotherapy. Proceeding of the Second Annual Rome International SJlrnposium on Biological Bases and Clinical Implications of Tumor Radioresistance ( In press). 4. Kligerman, M.M., Hogstrom, K.R.. Lane, R.G., Somers, J.: Prior immobilization and positioning for more efficient

radiotherapy. Inr. J. Radiat. Oncol. Biol. Phj,s. 2: I 141I 144. 1977a. S. Kligerman. M., Tsujii. H.. Bagshaw. M.. Wilson, S.. Black, W., Mettler. F., Hogstrom. K.: Current observation of pion radiation therapy at LAMPF. In Treatment of Radioresistant Cancers. Abe. M., Sakamoto. K. (Eds.). Amsterdam. Elsevier/North Holland Biomedical Press. 1979. pp. 145 157. 6. Paciotti. M.. Bradbury. J.. Hutson. R.. Knapp, E., Rivera, 0.: Tuning the beam shaping section at the LAMPF biomedical channel. IEEE Trans. Nut. Sri. NS-24: 1058, 1977. 7. Tsujii, H.. Bagshaw, M.. Smith, A., Von Essen, C., Mettler. F., Kligerman. M.: Localization of structures for pion radiotherapy by computerized tomography and orthodiagraphic projection. Int. J. Radial. Oncol. Biol. Phys. 6: 319-325. 1980.