THE MERICAN
JOURNAL OF CANCER
A Continuation of The Journal of Cancer Research
VOLUME
XXV
DECEMBER,
1935
NUMBER
4
OBSERVATIONS ON T H E ADYINISTRATION O F LARGE
DOSES O F CALCIUM I N METASTATIC
CARCINOMA I N BONE
ALEXANDEK BRUNSCHWIG, M.D.
(Prom the Dcpartnzent of Surgery and Divzsion of Boertgenology, The University of Chicago)
INT ~ ~ U C T I O N
I n the search f o r an efficacious chemotherapeutic agent for the trratment of malignant neoplastic disease, calcium has received its share of
attention. Shear in 1933 reviewed the literature on the effects of calcium on tumor growth as reported f o r laboratory animals and irb viLro
tissue cultures. His conclusions werc : “Many investigators have reported that calcium has an inhibitory influence on tumor growth. I n
tumors that are old or growing slowly, the calcium content is greater
than in young rapidly growing tumors. It is generally agreed that
deposition of calcium phosphate in necrotic areas probably accounts
for the increased calcium in necrotic tumors. . . . Administration of
calcium salts t o animals by various routes, it has frequently been reported, delays the appearance of transplanted tumors and slows down
their subsequent growth. This retarding effect was not obtained by
Shear in an extensive serics of experiments. Treatment of tumor tissue with calcium ‘salts irz v i t r o prior t o inoculation into animals inhibits
tumor growth. Culture of neoplastic tissue i.n vitro is inhibited by
calcium salts in concentrations that do not inhibit growth of normal
tissue. ”
Willy Meycr briefly reviewed the occasional clinical reports on calcium therapy in malignant neoplastic disease especially from the standpoint of its effect on the p H of the blood (acido-therapy), but reached
no final conclusions. Behan, as a result of personal experience, has
reported that calcium therapy is of distinct value in alleviating the pain
accompanying advanced cancer. He found it possible to reduce or even
to discontinue morphine for varying periods in such cases.
721
722
A IJEXANDER BRIJNSCTTWIG
CASESTUDIES
Calcium in relatively large doses was administered to a number of
patients exhibiting advanced malignant neoplastic disease of various
organs. The results liavc viiried considerably. I n some, it was felt
that Behan’s obscrvations were confirmed; in others, no relief from
pain was obtained. The unexpected results in two cases of metastases
to bones from carcinoma of the breast a r e of sufficient interest, however, t o report in some detail.
PIG.1. CASE I (Z. P., UNITNo. GS734) : ROENTGENOGKAM
OF PELVIS
ON ADMISSION,
OCT. 7, 1932
The rocntgcn diagnosis was multiple ostcolytic and ostcoblastic carcinoma metastases.
The former are clearly sccn in thc left anterior superior spinc, about the syniphysis pubis, and
the loft sacro-iliac joint. Ostcoblastic mctastases are present i n the trochanteric region of
both femurs. Arrows indicate points for comparison with Figs. 2 and 3.
I
*
CASEI. Z. 1’. (68754), a white woman of forty-four, was admitted to the University
of Chicago Clinics Oct. 7, 1932, complaining of severe pains in the groins radiating down
the thighs, and pains in the spine and shoulders radiating to the occiput. These symptoms had gradually increased in severity f o r the past year, and f o r three months there
had been anorexia and loss of wcight. Active movements of the extremities were accompanied by a.ggravation of pain. A right radical mastectomy had been performed i n 1930
for carcinoma, followed by one series of x-ray treatments to the operated breast region.
On the examining table the patient complained of generalized discomfort and attempts to rise cuusrd severe pain in the pelvis, thighs, and back. Passive movements of
the lower extremities caused considerable pain ; passive movements of the neck and arms
produced little discomfort. Percussion of the spine caused severe pain in the lumbosiicral region. Thcw was no evidence of local recurrence in the right breast region and
CALCIUM I N METASTATIC CARCINOMA I N BONE
723
no visibIe o r palpable masses were present elsewhere. The reflexes were normal. The
white cell count was 6,900; red cell count 4,400,000; hemoglobin 80 per cent. The Wassermann and Kahn reactions were negative. Urine examination was negative.
Roentgenograms of the pelvis and upper femurs showed multiple osteolytic and
osteoblastic lesions (Fig. 1). Osteolysis was especially marked about the symphysis
pubis, in the left ilium near the left anterior superior spine, and about the left sacroiliac joint. A large intramedullary osteoblastic lesion was seen in the upper portion of
the left femur. Roentgenograms of the chest iwealed no pulmonary metastases.
Diagnosis : Multiple o ~ e o u metastases
s
(osteoblastic and osteolytic) from previously
removed carcinoma of the right breast.
FIG.2. CASE 1 (z. P.) : ROENTGENOGRAM TAKENAPRIL 4, 1933
There is a diffuse sclerosis of the pelvic bones apparently the result of six months calcium
therapy. Increase in density is t o be observed espcc~inllyin the upper right femur, about the
right acetabulum, and in the lower lumbar vertebrae. Areas of osteolysis shown in the previous roentgenogram show extensive “filling in ” by bone, uiz., anterior superior spine, region
about the sacw-iliac joints, especially left, pubic bones, iieck of right femur, left ischial
tuberosity.
During the four weeks following the first visit the patient received three intravenous
injections of 1 0 C.C.of 1 0 per cent calcium gluconate solution each week, and during
this period and for the next five months 9 gm. of calcium lactate daily by mouth. Improvement in the general condition, with considerable rclief from pain, was experienced
the first few weeks after beginning this medication. After three weeks the patient
began to walk, arid by April 1933 her physical activity was almost normal. There was
relatively little pain, anti roentgenograms now showed a general increased density in the
pelvis a r i d u p l ) ~ femora
r
(Fig. 2 ) . Area5 that previously showed bone destruction were
partially or almost rornpletely srlerosed by new hone formation. These areas were
ac*tuiilly denser than the surrounding, apparently uninvolved bone.
Dui-ing the next six months the patient gained 25 pounds in weight and became
quite active physically. She complained of no discomfort except occasional brief “bor-
724
ALEXANDEIt BKLJNSCHWIG
ing pains” in various parts of the body. On her own responsibility she reduecd the
calcium lactate to 2 gm. a day f o r four months of this period and then took 4 gm. a diiy
for the next two months. I n October 1933, roentgenograms of the prlvis showed a
slightly greattlr iricrrase in density of the pelvis and upper femora. The solitary osteohlastic metastasis in the upper end of thr left frmur did not increase in size and nppearrd irss dense tit this time because of the less marked contrast with the surrounding
bone, which had become more sclerotic. From October 1933 to April 1934, 4 gm. of
ciilcium lactate were taken daily, arid the clinical improvement was maintained, the patient indulging in i*athrr strenuous physical activity. Rocntgcnograms taken on the
lattrr date shomeil 110 :rtlditional chungcs. The blood calcium on May 25, 1934, was 9.91
mg. and phosphorus 4.08 mg. per 100 C.C. of blood.
On Nov. 3, 1934, the patient was readmitted to the hospital because of pain for
FIG.
3.
CASE
1
(z. P.):
I~OENTGENOGRAM TAKEN MAY 21, 1935, TWO Y E A RS AND
M O N T H S AFTER INITIAL ADMISSION
SEVEN
Many scattered osteolytic lrsions lruvc progressed since the previous roontgenogram (Fig.
2). Howover, some sclerosis of several of the previously lytic lesioiis, czz., in tho left anterior
superior iliac spine aiid about the symphysis pubis, still persists.
the p s t two months in both groins and tlir spinr, not, however, approaching in severity
thr pain exhibited a t the initial admission. No calcium had been taken during the
prcvious three months. Tliere xvab loss of appetite and weight, although the patient
weighed 7 pounds more than two years prrviously. Roentgenograms of the pelvis still
showed tliffuw iwrrasetl density, especiiilly mnrkrtl in the a i m s of initial hone destruction. ‘t’hrre x w s som(1 rvitlriicia, however, of dec:ilcification in some of the sclerosed
lrsions and in thr left iiifwioi- pubic i’iiiiius one osteolytic focus had increasrd in size.
Tlir blood cdciurri W:I\ 10.5 mg., ant1 phosphorus 4.3 ing. per 100 C.C. of blood.
Fi-oni Kov. 3 to 1-5, l!M, daily intrnvenous in.jeetions of 30 C.C. of 20 prr ernt ~ a l ciuin gluconatr solution wrrr given. The p i i n was relieved during this period, : i d tbe
patient \ V R ~ dischwgctl with instructions to take 12 gm. of enleiurn gluconate a dny by
mouth.
C A L C I U M I N M E T A S T A T I C CARCINOMA IN BONE
725
On Jan. 22, 1935, the patient was seen in the out-patient department. She was free
from pain when a t rest and could perform moderate physical work with little discomfort.
Strenuous physical activity, however, as performed a year and a half earlier, induced
considerable pain in the spine, pelvis, and inferior extremities. The appetite was good,
the weight was 158 pounds, the sanic as on thc first admission two years and four months
previously.
On May 27, 1935, the patient was readmitted to the hospital complaining of aggravation of the '' deep boring " pains in the pelvis and thighs, although it was still possible for her to indulge in inoderate physical activity. There was loss of appetite, and
the weight had fallen to 148 pounds. Physical examination revealed no evidence of local
or visceral metastases. The blood calcium was 10.3 mg. and blood phosphorus 3.96 mg.
per 100 c.c. of blood.
TAKENDsc. 4, 1933, ONE
FIG.4. CASE I1 (A. G., UNIT NUMBER93373): ROENTGENOGRAM
MONTHA F T E R I N T E N S I V E CALCIUM TIIERAPY
The appearance is identical with the roentgenogram taken on admission Nov. 8, showing
osteolytic metastases t o the pelvis and upper femora. Arrows indicate points f o r comparison
with Figs. 5 and 6.
Roentgcnogieriii of the chest 1 evealed no pulmonary riietaitases. Roentgenograms
of the pelvis (Fig. 3 ) showed several largc osteolytic lesions not seen a t the previous
examination and evidence of some geiirralized decalcification. The previously sclerosed
lytic lesions wcrc riot extensively decalcified, although they appcared relatively less dense
than on the previous examin;itioris.
Because of the obvious progreisiori of the multiple carcinomatous lesions in the
skeleton, x-ray therapy was instituted.
CASE 11. A. ( i . (95373), a whitc woman of forty-one, WLS admitted to the University of Chi(2ago Clinics Nov. 7, 1933, complaining of iiiterrnittent deep boring pain, f o r
thc 1)ilst ycai', i i i thcb iippw portioii of the left thigh, gradually iricrcasing i i i 5everity and
for thr last tlirre I\ ec.ks rir( itiitiiig the iisc of crntchcs. There had becri gradual and
several months, a1thc)ugh the patient could not state the
considerable loss in weight
exact number of pounds. Tl'eakness aiid anorexia had been iricreasirigly noticeable.
I n 1931 a left radical mastectomy had been pcrformed for carcinoma.
726
ALEXANDER BILUTNSCHWIG
The patient was pale and eriiaciatetl and appeared chronically ill. Attempts to
walk without crutches produced sevwe paiiis in the left leg. There was no evidence of
recurrence in the left breast region, nor WPIX there visible or palpable masses elsewhrre.
Percussion of the spine cauml little discomfort. Passive movements of the lower extremities were not very painful, but active motions while the patient was sitting o r lying
induced pelvic pain. The reflrxes wrre normal. The red cell count was 2,900,000; the
white cell count 7000; hcmoglobin 65 per ccnt. Uririalysis was negative. The Wassermann and I h h n tests were negative. The blood calciuni was 11 mg. per 100 C.C. of blood
Rocntgrnogi-ams of the pelvis (Fig. 4) ihowed small scattered osteolytic lesions,
especially about the left acctabulum arid in the sublrocharlteric region of the left femur.
Roentgenograms of the chest showed no pulnioiiary metaitases.
MONTHS 08‘
5. CASE 11 ( A . c i . ) : It01 N‘ W hhOGRAhI T A K E N bfARCT1 3, 1931, AFTER FOIJR
INTICNSIPE
CAL(’lI’.U ‘I’IIERAI‘Y A X D TITILICE ~ f o N T H SAF‘I‘EIL PATIIOI,WI(’ J!’IIAC’J’ZJRE
IN Liwr FEI\ITIR
Cliiiically the fracture was firmly united at this tirnc. There is slight diffuse incrcased
deiisity of portions of tlw sltrleton, espcrially about tlic symphysis p h i s , the ac*ct:il)ula, and
hcad and neck and troc.li:tntrric region of tlic right femur.
14’1G.
Diagnosis: Multiple ostecilytic carcirionia riictahta
in the pelvis and upper fcirioi-a
from previously removed carcinoma of the breast.
The i)iitirrit was admitted to the hospital, W I I C ~ Cfor
~ one month she received 10 gin.
of calcium glueonate hy mouth and three iiijectioils of 1 0 C.C. of a 10 per cent glueonate
(Sandoz) solution intriiveiionily a day. After the first werk the pain was ariicliorated
and thcb apptitite itnprovtd. At thc rnd of a month tlir patient was discharged a t her
o w i r q u c s t , m w h irnpivvd a ~ i dable to walk with alnlost no pain, ant1 without the aid
of crutches. Two d n y i later she tripped ant1 suitiiinetl a pathological fracture in the
left suhtrorhaiitc~i~ic~
wgioii and WAY reailrultted to the hospital, where the fracture was
reduced and ii hody ;tilt1 lcg cast api)Iir(l. She iwriaiiird in the hospital from 1I)rr. 11,
!XU, During thct lirst t w c ~ r i t y - t h ~days
~ ~ e of this period calcium was
i l m l nhovta ; f o r th(1 rcuiaiiiing pwiotl thc i~iti~iivt~iioiis
iiijwtioiis
W ~ I - Ptlis(witiiiiicd, hecauw thry iiiducccl iiaiisea.
011March 3, 1934, thr w s t wtis rcmoved ant1 roentgciiograiiis of tlie pelvis (Fig. 5 )
showed a diffuse jncrwsc in dcwsily, c~speciallyabout the acetabula, the sacro-iliac joints,
CALCIUM I N METASTATIC CARCINOMA I N BONE
727
and the symphysis pubis, with filling in by bone of some of the osteolytic lesions. Although there was little roentgenologic evidence of union of the fracture, clinically there
appeared to be firm consolidation. Since leaving the hospital the patient had received
1 0 gm. of calcium gluconate daily by mouth.
During the spi-ing, summeis, and early fall of 1034, the patierit was almost entirely
free from pain. Roentgenograms on scveml occzisions showed little change in the pelvic
bones. Limited physical activity was permitted. I n spite of a large appetite, there was
no gain in weight. Walking with a cane instead of crutches was possible. Though receiving repeated instructions to continue large doses of calcium by mouth, the patient
took only occasional tablets of calcium lactate, stating that larger doses induced constipation and nausea.
FIG.6 .
CASE
11 ( A . G.) : ~ ~ ~ E N T G k : i Y O G l ~TAAMK E N
YEB.
6 , 1935
During the previous six months calciuiii adiiiiiiistration had been discontinued. A widespread progression of osteolytic foci is shomn. Tlie increased density about the symphysis
pubis, acetabula, a i d upper portion of right femur has disappeared. A second recent pathologic fracture is seen beneath the old one, in the left femur.
By January 1935, moderate pains had recurred in the left thigh, and after an attempt to walk rapidly without support, the patient experienced sudden sharp pain in
the upper left thigh at the seat of the old fracture, causing her to remain in bed f o r one
week. A t no time, however, was the pain as severe as on the initial hospital admission
fourtecn months previously. On return to the out-patient clinic, roentgenograms of the
chest and pelvis were made. There was a diffuse osteoporosis, obviously the result of
considerable progression of numerous osteolytic metastases. I n the shaft of the left
femur below the previoui friicture was a recent impacted pathologic fracture ; the lungs
were clear.
Physical examination was essentially negative except f o r pallor and emaciation.
Active and passive movements of the left inferior extremity were quite painful, but there
were no clinical signs of fracture in the left femur. The red cell count was 2,290,000;
the white cell count 18,000; hemoglobin 60 per cent. The anemia was ascribed to extensive osseous metastases. The blood calcium (average of 4 samples) was 12.12 mg.
and phosphorus 2.66 mg. per 100 C.C. of blood.
728
AL1CXANI)Elb RHIJNSCHU'IG
After sistrcn tlilys iri the lioipital, during which time 30 gin. of cdcium glnconatc
w\'cI+cgiven daily hy mouth, aiid two blootl traiiifusioiir wrrc atlriiiiii~tc~rcvl,
the patiriit
mas tlischiirgcd with iiistrurtions to rcmaiii in bet1 for t\velvc weeks. No cast w:is ;ti)1)lied. Ihiring this liiit pc~iotlof hospitalization it w i i \ tlrvitlecl to givc the piticrit t l i ~
I)cncfit of x-ixy thwir1)y to thc pt11vis :iiitl upper fi~in iii>\,siiicr the tlisrii\r tviis t1ppiiiwitly
eritrririg i t i trriiiiiiiil stages, although, :is s t : i t d , thc gciirral cwiiclitiori cwiitiiiiic.tl h i i b
jcetivcly btltter than fourtcrn months piwiouily.
The paticut w:is again wen in the out-patient c h i c on Julie 11, 19335. After twelve
werks iii hrd, shc had brm periiiitttd to sit up iii a wheel-chiiir f o r two weeks arid thrn
walk with the a i d of crutches. She s t a t r d that therr had heen 110 pain in the previous
twelve weeks and that h w apprtitc \vai good. Shr h i d gained 15 pouuds. Twelve
grains of c;~lciuniglucwiiatr mcre tiikeri duily after hrr discharge from thr hospital four
months and a half pi~evioiisly. On physical exaniiiiation the left leg was found to be 2.5
em. shorter thiiri thc right, and their w i i i no evidence of false motion a t the fracture sites
in the upprr left frmiir. Roentgrnogi-amsshowed slightly increased calcification in the
lxllvis arid hr:iIiiig of the morr rccent pithologic fracturr (with ilight deformity.)
DISCUSSI~N
I n view of the unanticipated changes occurring in the skclet ons in
the cases reported above, it becomes necessary to inquire whether or
not they may he clue to some othcr factor than citlcium, especially since
it is generally held that calcium ildmiliistration alone cannot produce
sclerosis in the bones when one is not dciiliiig with osteomalacia in one
form or another. Other possible explanations for these changes, such
a s di fferences in roentgenographic technic, fluorine poisoning, spontaiieous cliange of ostcolytic metastases into ostcoblastic metastases ( a
phenomenon iliat has, as far a s the writer lias been able t o ascertain,
never hecii repor~tod)were taken into consideration, but cannot account
for the changes observed in these cases. Tlie writer has had occasion
to study roentgenograms of the skcletoii of a patient of Dr. Donald C.
Abbott of Chicago, wlio received large doses of calcium powders over
a period of four years in tlie medical management of peptic ulcer.
The pelvis aiid vertebrae exhibited a marked increase in density, there
w a s calcareous ureterolithiasis, and over one of the phalanges of the
limd tliere was limited pcriostcal new bone formation (not pulmonary
osteoarthropatliy). This obsczvation constitutes additional presumptive evideiice that large doses of calcium may, in some patients, cause
iiicreased deiisity of tlic skeleton in the absence of ostcomalacia.
T n five other patients exhibiting osteolytic metastases from carcinomas of the breast, iiit ensive calcium therapy, while affording in
three instances some degree of amelioration of pain, failed after
three, four, aiid six moiiths respectively to produce roentgenologic
evidence of clianges in the normal or involved portions of the skeleton.
The fact tliat oiily two cases in this series of seven responded t o calcium therapy by showing roentgenologic evidence of osteosclerosis in
the lesions and uninvolved bones is unexplained. The various factors that affect calcium balarice were not taken into consideration during tlic periods of observation. Perhaps adjustment of these factors
preliminary to a i d concurrently with intensive calcium therapy would
have altered the incidence of sclerosis of the slteleton.
CALCITJM I N METASTA'L'IC C A R C I N O M A I N B O N E
729
I t must be cmphasizod that these cases arc reported because of their
iniusual coiirsc. No coiiclnsio~ismay be clrawii from sucali limited obsorvatioiis. Tlic iliagiiosis of metastatic carcinoma to bone in these
eiiscs is a 2.oriitgeiiolofiicaltli;~giiosisoiily, h i t in the writer 's opinion 110
ot licr condition uiider tlie cii*cumstnnccscould have caused the chaiiges
seen in tlic iiiitial rociitgeiiograms. No post-mortem studies arc available at this time.
SUMMARY
1. In two cases of metastatic carcinoma to boiic from the breast
(diagiiosed roentgcnologicnlly) intensive calcium therapy was the apparent cause of a temporary sclerosis of tlie skeleton, with partial or
almost complete filliiig iii of many of the osteolytic lesions by bone.
2. The severe paiii accompaiiying these lesions was greatly relieved
f o r long periods. No opiates or other analgesics were administered
during tlie periods of symptomatic improvement. I n one case there
was a return t o normal pliysical activity f o r oiie and one half years.
3. N o x - r a y t h r r a p y was administered t o these patieibts during or
prior. t o t h e periods in which temporary sclerosis of t h e skeleton
occurred.
RIDL~OGRAPHY
BEIIAN,R. J. : Calcium trcJatmerit of pain in cuncrr, Tr. Amrrican Therapeutic Society for
1931, 11. 44.
B m r m , R. J. : Relief of pain in cancer by calcium, Am. J. Surg. 1 9 : 301, 1933.
BEIIAN,R. J. : Ncwer concepts in cancer trciitnient based 011 research, Pennsylvania M. J.
36: 401, 1033.
MEYER,W.: Cancer, Paul C. EIoeber, Inc., Kcw I'ork, 1931.
SIXEAR,
&
JI
. :.Tlir r81c of sodium, potassium, calcium and rnagnesium in cancer. A rc\ irw, Am. J. Cancer 18 : 924, 1933.