Cancer - November December 1961 - Schwartz - A Biomathematical Approach To Clinical Tumor Growth

A BIOMATHEMATICAL APPROACH T O CLINICAL
TUMOR GROWTH
MORDECAI M.D. *
SCHWARTZ,
D IRECT DATA relating to the natural growth

history of human neoplastic disease are
intrinsically limited by the clinical availability
study of Wilms’s tumor in children. Their
results lend significant support to the exist-
ence of exponential tumor growth and to the
of lesions for observation, study, and measure- applicability and power of the relevant con-
ment. For a number of reasons, such a clinical cepts in explaining many obscure and often
observation span often covers but a small frac- paradoxical aspects of human neoplastic dis-
tion of a tumor’s total period of existence. ease. The following report presents a further
Time limitations are imposed not only by the amplification of the biomathematical basis for
occurrence of various gaps in patient aware- such studies, an analysis of various derivative
ness and co-operation, clinical acumen, or concepts, their clinical significance and their
accessibility of measurable lesions but more bearing on the methodology employed, and a
fundamentally, as we shall see, by the very detailed growth rate study of measurable
nature of neoplastic growth. Under such cir- primary and secondary human pulmonary
cumstances, conclusions concerning preclini- neoplasms. Because the fundamental bio-
cal tumor growth characteristics and predic- mathematics is so basic to the concepts and
tions of future course are, at best, hazardous clinical methodology and analysis that follow,
and tentative. Any approach, therefore, offer- it will be presented as an integral part of the
ing to extend longitudinally our knowledge discussion.
of tumor growth deserves careful study.
A priori, the simplest growth pattern would BASIS FOR EVALUATION
MATHEMATICAL OF
be one marked by regularly recurring cell di- EXPONENTIAL
TUMOR GROWTH
vision at fixed intervals. One cell gives rise to
2, 2 to 4, 4 to 8, indefinitely, with the inter- In the following analysis of exponential tu-
mitotic “resting” phase remaining constant. mor growth, the existence of geometric in-
When various limiting nutritive or environ- crease is postulated and the relevant mathe-
mental factors do not supervene, this pattern matical concepts are then applied. The clini-
of growth is to be found in numerous biological applicability of an exponential growth
cal systems and physical processes. Bacterial analysis, however, must first be determined
growth and, in a reverse direction, isotopic empirically for the particular tumor by dem-
radioactive decay are but 2 typical instances. onstration of a constant doubling time during
How adequately such a logically and con- the period of observable growth. When the
ceptually simple geometric growth schema re- equations themselves are properly interpreted,
flects the realities of human neoplastic disease they lead logically and directly to the various
will be the subject of this paper. clinicomathematical methods of evaluating
Pioneering work in this direction has al- tumor growth data. We may define the follow-
ready been done-most notably by Collins, ing terms:
Loeffler, and TiveyG in their study of growth t,, equals the time of the initial measure-
rates of radiographically measurable meta- ment of the tumor size (usually taken as 0);
static pulmonary disease in adults and in their t equals the time of the final or second meas-
urement of the tumor size, which represents
the time lapse between the 2 measurements if
From the Department of Medicine, Kingsbridge Vet-
erans Administration Hospital, New York, N.Y. we take to to equal 0; tD equals the doubling
Three case analyses (those for patients L.H., J.S., 11, time, representing the time for 1 cell (or for
and A.R.) are based upon radiological and clinical the tumor as a whole if each cell has the same
data from the files of Dr. Daniel Stone and Dr. Robert
Green, Pulmonary Division, Kingsbridge Veterans Ad- t,,) to double in volume, and it is equivalent
ministration Hospital, New York, N.Y. to the interval between successive mitoses; V,,
*Present address: 65-65 Wetherole St., Rego Park, equals the tumor volume at time to of the
New York, N.Y.
Received for publication Jan. 3, 1961. initial measurement; V, equals the tumor vol-
1272
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No. 6 BIOMATHEMATICAL
APPROACH TUMOR
TO CLINICAL GROWTH - Schwartz 1273
ume at time t of the second measurement;

Do equals the initial diameter of the tumor;
D, equals the tumor diameter a t time t; do
equals the diameter of a single tumor cell T h e basic nonrestricted growth rate form-
(approximately 10 p); k, equals the number ula with passage to limit (logarithmic base e)
of cells derived from 1 cell by time t; and nt is:
equals the number of doubling times (num-
ber of mitoses) by time t.
From these concepts of time, tumor size, 8
and cell number, we may derive several major
equations.
T h e underlying proportionality between Derivative T u m o r Growth Concepts. T h e
final and initial tumor volumes regardless of foregoing mathematical analysis of exponen-
elapsed time is expressed by: tial tumor growth makes many valuable
points of contact with clinical tumor study.
V, = V,k, 1 When the empirical data demonstrate uni-
form geometric growth within an extended
T h e basic exponential relation of tumor period of direct clinical observation, extrapola-
volume to time when growth is geometric is tion backward into the preclinical past or
expressed by: forward into the future may be justified. Com-
bined mathematicoclinical analysis can then
indicate many correlations between tumor size
and clinical stage and can give more exact
T h e prediction formula for tumor diameter meaning to such hitherto vague concepts as
at any time t is the basis for forward or back- silent interval, avoidable and unavoidable
ward extrapolation of tumor size beyond the diagnostic gap, apparent and actual survival
period of direct clinical observation: time, 5-year cure rate, and postsurgical period
at risk.
D, = D, .2 t / 3 t ~ 3 T u m o r Size Correlations. Other than multi-
cellular metastatic emboli or the generally
By the doubling time formula (any logarith- remote possibility of simultaneous multicen-
mic base), if, after tD has been determined, we tric origin of a single neoplastic focus, {.he
solve for t, we can state when the tumor was earliest tumor implant would be assumed to
or will be any given diameter: be unicellular and would correspond mathe-
matically to n, equals 0 (no mitotic divisions).
t log 2
t D --_____ Tumor diameter here coincides with cell
4
Dt diameter and on the average may be taken as
3 log /Do
Do equals do equals 10 p. Assuming that the
T h e doubling time formula in terms of vol- earliest macroscopic lesion has a volume of 1
umes rather than diameter (any logarithmic cu. mm., 20 doublings would be necessary for
base) is: the original 10-p diameter cell to yield a
tumor this size. T h a t nt equals 20 when D,
t D --_-t log 2 equals 1 mm., is evident when we observe that
5
log “pV, 1,000,000 10-p diameter cells (cubes) fit into
1 cu. mm. and that 220-1,000,000. When 10
T h e approximation formula for doubling additional mi totic divisions occur, tumor vol-
time, accurate to within one-third of I%, that ume becomes 1 cc. since 1 cc. equals 1,000 cu.
is the basis of practical graphic methods using mm. and 21°- 1,000. After 30 doublings, then,
semilogarithmic paper, is: the initial single tumor cell has become a
- - ~ - ~
tD - t
6
I-cm. diameter lesion (n, equals 30 and D,
equals 1 cm.). A I-cm. nodule may be taken
as a measure of earliest radiographic detecta-
10 log,, Dt/D.
bility.
T h e Y=mx+b form, showing the linearity Such a pulmonary “radiographic” density
of a time-log diameter curve (the true theo- should ordinarily be picked up, while any-
retical basis for semilog plots) is: thing smaller, unless ideally situated and very
1274 CANCER November-December 1961 Vol. 14
sharply circumscribed, would probably be subsequent clinical observation; death would
missed. have occurred before, a t most, 15 additional
An exponentially growing tumor, thus, doublings.
originates 20tD before any macroscopic lesion Such preclinical “iceberg” growth obviously
appears and 30tD before a significant radio- has great bearing upon the significance of
graphic density becomes visible. Barring mul- “early diagnosis” and upon the validity of
ticellular tumor emboli (which, however, is “5-year cures.” Should a n “early” I-cm. lesion
a likely possibility) a primary extrapulmonary be diagnosed, 30 of a maximum of about 45
neoplasm is already inoperable 30tD before de- tumor doublings have already elapsed; two-
tectable pulmonary metastases appear. Fur- thirds of the tumor’s total course and of its
ther, unless the preclinical growth rate ex- possibilities for metastasis have passed!
ceeds the observed clinical growth rate, 30t, If we assume a maximum silent interval of
is a minimal time estimate, since a dormancy 5 years, as is implicitly done in obtaining
state may exist during which the initial tumor 5-year cure rate statistics, we may readily eval-
cell remains latent before the successive mi- uate the corresponding maximum tumor
totic divisions are triggered. doubling time. T h e 30tD spread over a 5-year
When n, equals 40, extensive disease is period yields a tD equal to 2 months. For tu-
present since 40 doubling times result in I-kg. mors with doubling times shorter than 2
of tissue; 220 or 1,000,000 I-cu. mm. nodules months, a 5-year remission should constitute
comprise 1,000 cc. or 1 kg. of tissue, so that as a cure, assuming there is no recurrence at a
many doublings and as much time elapses in poor detectability site. On the other hand, a
going from a single cell to a I-mm. nodule as tumor with a doubling time appreciably
from a I-mm. nodule to a I-kg. mass. After greater than 2 months might well become
another few doublings, death usually ensues. clinically evident after a 5-year remission.
These size-time correlations may be sum- However, even a tumor with a tD of more
marized on the following linear scale: than 2 months might readily recur before 5
I I 1
0 I I I > TIME
No. cells 1,000 1,000,000 1,000,000,000 1,000,000,000,000
Silent Znteruals. T h e term “silent interval” years if any remotely macroscopic disease per-
is often employed in clinical medicine as be- sists after therapy. A barely visible I-mm. nod-
ing synonymous with the preclinical or asymp- ule already has a head start of 20 doublings of
tomatic phase of tumor growth. However, our the 30 required to reach detectability.
ordinary inability to specify accurately the Similar considerations apply in evaluation
time of origin of the tumor, coupled with the of the postsurgical period at risk for which
often haphazard onset of or awareness of the true silent interval or time necessary for
symptomatology, serve to blur this concept a t residual tumor cells to reach clinical detecta-
both ends of the time spectrum. A more bility is again a direct measure. The TSI would
meaningful “true silent interval” (TSI) when have been previously determined by a pre-
applicable would be the time between initial therapy tumor growth analysis with backward
tumor implant and earliest radiographic de- extrapolation. T h e interval may be consider-
tectability. During this period, no present ably shortened if macroscopic tumor remains
diagnostic measures at our disposal-with the behind after surgery. Equally likely, however,
possible exception of routine exfoliative cytol- is an apparent lengthening of the silent inter-
ogy-would demonstrate the tumor clinically. val if the tumor recurs at a site in which a
I n all instances, this interval, which as we lesion larger than 1 cm. in diameter is neces-
have seen requires 30 doublings, would exceed sary for detection. I n other words, the TSI will
by at least a factor of 2 the total duration of be too long a measure of period at risk if
No. 6 UIOMATHEMATICAL APPROACH TUMOR
actual nodules rather than isolated cells re- T r u e diagnostic gap (TDG).This is the inter-
main after therapy and too short a measure val between the initial detectability and the
if recurrence is in a n area in which early de- initial manifestation (tl,Dto tsx). This interval
tection is not feasible. represents the time elapsing between the point
One final possibility in an analysis of post- when a lesion might have been detected if
surgical tumor recurrence is worthy of men- looked for (despite the apparent absence of
tion. Postsurgical pulmonary metastases or signs or symptoms) and the time when i t ac-
other measurable disease might reveal that the tually was detected or a t least manifested
initial metastatic implant occurred a t the time itself. I t is a diagnostic delay generally reduci-
of excision of the primary lesion. This might ble only by intensive routine periodic screen-
provide indirect presumptive evidence for ing of well patients in such places as cancer
surgical dissemination of disease. detection clinics as contrasted to the ADG,
Diagnostic and Surviual Intervals. Survival which is reducible by prompt, appropriate,
time and diagnostic delay are additional con- and complete diagnostic study once clinical
cepts amenable to a more exact treatment suspicion has been aroused.
based upon a mathematical analysis of geo- For example, if a I-cm. diameter lesion that
metric tumor growth. T h e following defini- proved 1 month later to be neoplastic was
tions may be summarized. They assume that detected on a routine chest roentgenogram,
the doubling time tD, and from it the time of TDG would equal 0 and ADG would equal 1
initial detectability tl,D. (Dt equaling 1 cm.) month. O n the other hand, assume in another
and the time of initial implant tl,l, (Dt equal- patient that 3 months after symptoms appear,
ing 10 p) have been calculated from a n ex- chest roentgenograms are taken and show a
ponential tumor growth curve. A knowledge pulmonary nodule of 2-cc. volume. Two
of when the first clinical manifestation- months later, a diagnosis of bronchogenic car-
whether sign or symptom-appeared (ts,), cinoma is made. ADGis, therefore, 5 months.
when the diagnosis was established (tnx), and Assume further that the lesion has metas-
the date of death are also needed. T h e “silent tasized, that no specific treatment directed at
interval” definitions may likewise also be re- the primary lesion is indicated or available,
framed in terms of 5 critical time points. and that careful observation and measure-
T r u e silent interval (TSI).This is the inter- ment of subsequent tumor growth demon-
val between the initial implant and earliest strates a doubling time of 4 months. T h e tu-
detectability (tl,l, to t1.D.). I t may be con- mor, then, was 1 cc. in volume 4 months
sidered a minimal or irreducible silent inter- before the first roentgenograms and, therefore,
val, since only in a rare very strategically lo- 1 month before the first symptom. We then
cated tumor would a lesion smaller than 1 cm. have TDG equal to 1 month.
in diameter be likely to manifest itself clini- Total diagnostic gap. This is the interval
cally. Some of the implications of this concept between initial detectability and exact diag-
have already been explored. nosis (tl,D, to tDx), which is equal to TDG plus
Total silent interval. This is the interval ADG since (tl D. to tDx) equals (tl.D. to tSx)plus
between the initial implant and the first clini- (tsx to tDx).This interval clearly represents the
cal manifestation (tl,l. to tSx). This “actual” total time elapsing from the point when a n
silent interval is a more empirical measure of asymptomatic lesion might have been detected
preclinical tumor growth since it expresses the to the point when an actual diagnosis was
total duration of the tumor before it revealed made.
any signs or symptoms to the patient or the Apparent survival time (AST). This is the
clinician. Only if the first clinical evidence of interval between the initial clinical manifesta-
tumor growth appears when the lesion attains tion tsx and death. This definition corre-
a I-cm. diameter do the true and total silent sponds to our usual practice of dating 5-year
intervals coincide. cures and other rates of survival from the on-
Apparent diagnostic gap (ADG).This is the set of symptoms.
work-up time or interval between the initial T r u e or total survival time (TST).This is the
manifestation and the exact diagnosis (tSx to interval between the initial implant t, and
tDx). This definition corresponds to our com- death. This interval spans the total duration
mon sense notion of a diagnostic gap as the of the tumor from the single-cell stage to the
time elapsing from the first clinical evidence time of death. As we shall see, total survival
of illness to the time of exact diagnosis. may often exceed a decade, even when the
1276 CANCER
November-December 1961 Vol. 14
patient dies shortly after the onset of illness- raw clinical data required as well as methods
that is, AsT is often but a small fraction of TST. for its algebraic and graphic analysis. T h e
necessity for first demonstrating empirically
TOTAL
f-DIACNOSTIC+ the existence of a constant tumor-doubling
WIP time has been stressed. T h e empirical growth
I TE 1 An; I curve for a given tumor must be known before
TRUB S I L m
I 1 I I attempting an analysis of its preclinical char-
DMTR
acteristics or a prediction of its future be-
c TOTAL SILENT INTF.RVAL--+cAPPARFNT SURVIVAL TIME-
* havior.
TOTAL SURVIVAL T M E *
T h e methodology, then, involves the selec-
tion of patients with quantitatively measur-
T h e interrelationships of the terms defined
able neoplastic disease and the evaluation of
may be shown on a linear scale containing the
the growth curve of tumor volume increase
5 critical time points-keeping in mind that
with time. Selection of cases has been based
several of these points in individual instances upon a criterion of measurability sufficient to
may be blurred, or may coincide, or may even calculate an accurate doubling time from
alter in sequence. T h e use and implication of measurable permanently recorded (via radio-
these concepts will be further illustrated logical evidence) disease of lung. Patients with
through detailed case studies. clearly measurable pulmonary radiographic
Two additional derivative concepts are nodules of pathology proved primary or sec-
often of value in analyzing tumor growth ondary neoplasms provide the raw material
data. T h e AST to TST survival ratio is a meas- for this study. I n principle, however, the
ure of the actual clinical time fraction of a methods are equally applicable to lytic lesions
tumor’s total existence: like the proverbial of bone, breast nodules, circumscribed periph-
iceberg, relatively little will be open to direct eral nodes, and other measurable lesions. All
observation. If in place of AST, we use the in- that is required is the date and the magnitude
terval between tl,D, and the time of death, the of measurable disease on serial determina-
corresponding ratio: tions.
t , , t o death Twenty-one patients with pulmonary neo-
TST
plasias satisfying these measurability require-
ments were studied. I n no instance was a case
indicates the maximum fraction of the tu- excluded because of failure to demonstrate a
mor’s existence available for clinical observa- tumor volume increase over a several month
tion. These ratios will be symbolized by CIA observation span. Actually only 1 patient-
and C1, respectively. If nt is the total number with metastatic malignant melanoma-failed
of doublings from tumor inception until to demonstrate progressive tumor growth.
death, then: However 8 cases were excluded from the study
because initially measurable pulmonary infil-
trative disease became nonmeasurable on sub-
sequent radiographs (5 cases of bronchogenic
since 30 doublings are required to reach t1.D. cancer and 3 of metastatic cancer).
from the single-cell stage. T h e discrepancy Several methods are available for the de-
between C1, and CIA is a measure of lost termination of tumor volume from 2-dimen-
observation time (diagnostic gaps); in particu- sional roentgenographic data. T h e most exact
lar, the ratio of CIA to c1M represents the frac- methods involve multiple linear measure-
tion oi theoretic clinical observation potential ments in the posterior-anterior, lateral, and
actually employed. oblique views and would appear essential for
irregularly shaped nodules. When the lesion
METHODOLOGICAL CONSIDERATIONS is roughly spherical, but the 2-dimensional
roentgenographic projection is not completely
This study represents an attempt to obtain circular-that is, has vertical, horizontal, or
reliable data on the natural history of human oblique diameters differing somewhat from
tumor growth beyond the limited period of one another-an average diameter may be
direct clinical observation. T h e biomathemat- used for calculation of volume. More accu-
ical basis for such a n undertaking has been rately, the area may be determined by tracing
detailed and has indicated the nature of the the lesion on squared graph paper and count-
APPROACH TUMOR
ing the squares. T h e volume is then found uniform volume distortion, any reproducible
from the formula: tumor diameter may be used in calculating
the doubling time.
v=- ~ 3 / 2
T h e calculation of initial radiodetectabili ty
3 di is also independent of the distortion, since we
the formula relating the volume of a sphere require not so much the time when the lesion
to its greatest cross sectional area. I t is readily actually is 1 cm. in diameter as we do the time
derived by solving both V = g d and A=m2 when the “distorted” 1 -cm. roentgenographic
for r6 and equating the results. lesion could have first been observed.
This latter is the method employed by However, error does arise when the time of
Ingleby et a1.I2 in their study of 6 radiologi- the initial tumor implantation is calculated-
cally measurable breast neoplasms. They em- for we cannot extrapolate to a true 10-p
ployed the simpler and sufficiently accurate (I-cell) diameter from a sequence of distorted
approximation formula: V=$A3I2. From se- measurements. T h e degree of distortion for a
rial volume determinations, they then calcu- given radiological technique may be deter-
lated a coefficient of monthly volume expansion, mined via mensuration of a projected centi-
which, of course, is operationally equiv- meter rule, and the appropriate correction
alent to obtaining the doubling time. I t factor may then be applied to the measured
should be noted that area might also be de- diameters. This procedure, though, is rarely
termined by tracing or projecting the lesion necessary, for the 10% (average) radiographic
onto paper or other sheeting of uniform distortion yields a far smaller initial implant
weight per unit area. After cutting out the error. If the true diameter is 1 cm. and the
tracing, it can be weighed, and the result can measured diameter is 1.1 cm., the correspond-
be converted to units of area. ing volume ratio is
When a lesion is approximately spherical,
measurement of particular diameters repro-
ducible on serial single-view roentgenograms l3
can yield as reliable results as the more com-
plex methods, and this is the method we em- or 1.33. Thus, the volume correction is consid-
ployed. Our exponential growth formulas and erably less than 1 doubling (for which the
graphic methods then allow direct calculation volume ratio would be 2) of the 30 doublings
of the doubling time, the time of the initial needed to yield a 1-cm. diameter lesion from
implant, and other parameters without prior a single tumor cell. Even this small error pro-
explicit calculation of the tumor volume. portionately diminishes as the tumor size and
Some further justification for the use of the number of doublings increase.
specific roentgenographic diameters as meas- Obviously, if the lesion is not spherical, a
ures of tumor volume must be given. An in- similar error in the initial implant time occurs
herent source of error is roentgenographic from the arbitrariness of the diameter se-
distortion, which, on a good 6-foot posterior- lected. Unless the tumor is markedly elon-
anterior roentgenogram of the chest will still gated, this error too may be neglected for ex-
be about 10%. For several reasons, this error actly analogous reasons. If required, an
is of little concern. Uniform volume distortion interpolative “average diameter” method
of lesions will, on serial study, have no effect would further minimize extrapolative devia-
upon the calculation of the doubling time tions.
(tD). This results from the very principle that Various interpretive problems must be an-
underlies the derivation of exponential growth ticipated in applying exponential growth
formulas: the rate of change of volume is pro- curve methods if valid conclusions on the
portional to the initial volume. T h e constant natural history of tumor growth are to be
of proportionality (k, in the mathematical de- obtained. Four classes of patients with meas-
rivations), however, is independent of the urable neoplastic disease must be clearly dif-
initial volume but is rather dependent upon ferentiated.
time only. Thus, whether we employ a true Class 1. I n this class, multiple serial meas-
or “distorted” initial volume, if subsequent urements empirically document the applicabil-
volume distortion remains constant, the same ity of an exponential growth curve throughout
k, and doubling time t, are obtained. Fur- the period of measurability. Any extrapola-
ther, since uniform linear distortion implies tive conclusions fall outside this time interval.
1278 November-December 1961
CANCER Vol. 14
Class 2. In this class, data are adequate to creasing in size, we may yet be able to say that
apply or impose an exponential growth curve its rate of growth has lessened.
but inadequate to evaluate the validity of this Whether we may attribute a decreased
procedure. In effect, meager data force large growth rate to a given chemotherapeutic drug
scale extrapolations within the period of meas- is a matter for careful individual and statisti-
urabili ty. cal consideration. However, our technique
Class 3. I n this class, data empirically docu- will at least tell us more accurately in what
ment the inapplicability of an exponential direction and to what extent growth has al-
curve-and perhaps demonstrate the occur- tered. It should be noted that a significant
rence of other types of growth curve. incidence of unexplained spontaneous growth
Class 4. In this class, an exponential growth rate change would lessen the reliability of de-
curve fully satisfies the data for some interval ducing a therapeutic drug effect, even though
within the period of measurability; subse- the timing of apparent regression may coin-
quent measurements deviate from the extrapo- cide well with the administration of therapy.
lated curve-either spontaneously or after
therapy. RESULTS
Basic information relating to the natural
history of tumor growth must come from Primary Pulmonary Neoplasms. The follow-
classes 1, 3, and 4, in which empirical data ing data and analyses are derived from an
are adequate to yield reliable growth curves. in depth longitudinal study of 12 male pa-
Existence of a significant number of class 3 tients with 13 bronchogenic neoplasms radio-
patients would obviously offer immediate graphically measurable over an average radio-
grounds for questioning the general applica- logical observation span of 13.5 months. The
bility of exponential growth curve methods 1 patient (L.H.) with 2 separate measurable
and of extrapolative inferences from class 1 lesions-each with its own clearly delineated
data. doubling time-may represent an instance of
T h e relative number of class 1 and class 2 unrelated bronchogenic primaries.
3 patients is similarly a measure of the valid- T h e ages of these patients are relatively
ity of superimposing an exponential curve advanced-58. years being the lowest age and
upon unstructured class 2 data. In other 65.7 the average age of the individuals upon
words, inferences from the assumption rather the appearance of overt symptomatology or
than from the demonstration of geometric the detection of the lesion. All diagnoses are
growth can be reliable only if it can first be pathologically confirmed epidermoid carci-
shown that geometric growth is the rule. On nomas (11) or adenocarcinomas (2) of lung.
the other hand, good agreement between class For the most part, the tumors behaved clini-
1 and class 2 conclusions-for example, simi- cally as more or less gradually enlarging
lar doubling times for similar types of tumors “peripheral” lesions, failing to cause broncho-
-is indirect evidence for the applicability of occlusive pathological involvement until later
exponential growth curves to unstructured in the course of the disease (if at all). This
data. fact is a natural consequence of the selection
Class 3 data, besides giving us a measure of criterion-accurate measurability over an ex-
the limitations of an exponential growth tended period of time during which a clear-
curve method, would also open up the possi- cut volume change occurs. It may, perhaps,
bility of other growth curves that might later also have some correlation with the relatively
be found to have theoretical and practical advanced age of the patient group, for the
significance. more silent peripheral lesion allows a greater
Class 4 is of particular value in evaluating true diagnostic gap from the time of initial
spontaneous and post-therapeutic growth rate radiodetectability to the first clinical mani-
change. An empirically well fitted tumor festation.
growth curve extrapolated into the future can T w o of the patients (L.G. and L.C.) were
be a good measure of drug effect. If the em- seen at the Francis Delafield Hospital, New
pirical curve coincides with a theoretical ex- York, N.Y., and the remainder were seen at
ponential growth curve, we may have a great the Kingsbridge Veterans Administration Hos-
deal of confidence in attributing clinical sig- pital, New York, N.Y. All of the patients fall
nificance to subsequent deviations. For exam- into class 1 or class &that is, demonstrate a
ple, even though a measurable lesion is in- clear-cut exponential growth curve, permit-
APPROACH
TO CLINICAL
TUMOR
GROWTH * Schwartz 1279
ting calculation of a reliable tumor-doubling with the surprisingly long doubling time of
time while in several instances, for reasons to 250 days. Clinically, the infiltrate is felt to be
be considered, subsequent growth rate altera- a malignant bronchogenic neoplasm; however,
tions are noted. the patient has refused thoracotomy, and a
T h e observation data and theoretical con- histological diagnosis has not been established.
clusions are summarized in Table 1. Age, race, I n several instances, despite continued regu-
sex, diagnosis, and location of the neoplasm lar geometric growth with maintenance of a
are indicated for each patient. Listing, except constant doubling time, a clinical illusion of
that for patient L.H., who demonstrated 2 slow initial growth followed by a rapid spurt
distinct lesions, is in order of increasing dou- of growth is given. This impression is most
bling time. For convenience, the doubling striking in those patients whose disease was de-
time is recorded in days; the various diagnos- tected in the 1.- to 1.5-cm. diameter stage and
tic gaps in months; survival time, silent inter- then followed to a tenfold diameter increase
vals, initial implant time, and initial radio- of 10. to 15. cm. and beyond (representing a
detectability in years; and the observation thousandfold volume increase). When a lesion
ratios in percentages. T h e total number of is small, a given fractional volume increment
tumor doublings, n,, from tumor origin to the is not nearly as impressive on roentgenogram
time of death is also entered. Excluding fre- as when the lesion has attained a greater size.
quent duplications for purposes of validating For the larger lesion, the net volume incre-
the reproducibility of the measurements, a n ment is considerably greater although over
average of 9.5 distinct measurable radio- equal time intervals an equal percentage in-
graphic observations of each lesion was made. crease in tumor volume takes place. T h e illu-
Multiple views for clarifying location and sion of more rapid later growth stems from
sphericity are also excluded. I n several in- subjectively equating volume increment with
stances, a choice of reproducible tumor diam- rate of growth and vanishes when exact meas-
eter was available and led to the same urement and analysis are substituted for vague
exponential curve. T h e mean radiological clinical “impression.”
observation span of 13.5 months proved quite From 2 sources comes striking confirmation
adequate for purposes of demonstrating for of the constancy of tumor-doubling times in
each lesion a progressive geometric volume in- well fitted exponential growth curves and of
crease and associated doubling time. Separate the validity of forward and backward extrapo-
tables, giving the raw measurement data for lation in time beyond the period of direct
each patient, are included for the purpose of clinical observation. These sources are the
allowing verification of the accuracy of fit detection of missed radiological lesions with
of superimposed exponential growth curves calculated diameters and the early prediction
(Table 2). of postradiotherapeutic regression while the
A more than tenfold range of tumor-dou- tumor is still increasing in size.
bling times for these bronchogenic neoplasms Three posterior-anterior chest radiographs
exists. T h e most rapid rate of growth was of patient A.R. were initially available to me.
shown by 1 of the 2 adenocarcinomas, which These revealed a sharply delineated left upper
doubled in volume every 17 days. T h e other lobe infiltrate (anaplastic epidermoid carci-
adenocarcinoma had a relatively slow dou- noma) with a vertical diameter of 6.3 cm., 10.9
bling time of 126 days; this was exceeded by cm., and 15.1 cm. at O., 19., and 30.5 weeks
only 1 other lesion-an anaplastic epidermoid respectively. On a semilogarithmic plot of time
carcinoma with a tD equal to 200 d. T h e 11 versus tumor diameter, these points lay on a
epidermoid neoplasms demonstrated a dou- single straight line corresponding to a n ex-
bling time range of between 48 and 200 days, ponential growth curve of t, equal to 56 days.
with no tendency for the more undifferenti- Four additional radiographs, preceding these
ated tumors to grow more rapidly. Similarly first 3, were subsequently located. I n 3 of the
i n this small series, neither the exact site of 4, the lesion had been noted by the radiologist.
the primary nor its metastatic behavior (not T h e corresponding tumor diameters and times
shown in Table 1) correlated with the rate of were 5.7, 5.0, and 3.0 cm. at -3., -lo., and -28.
growth. T h e mean tumor-doubling time is 78 weeks. These 3 points fall upon the backward
days, and the median value is 70 days. One extension of the original straight line, repre-
patient currently being followed (M.I.) has a senting exponential growth with a volume
very gradually enlarging pulmonary lesion doubling every 56 days. I n the fourth radio-
1280 CANCER
TABLE1
LONGITUDINAL STUDY OF 12 MALE PATIENTS
Case Pt. TDG Tot. TSI
no. age, __ diag. ____
Pt. yr. t Diag. & tD, tl. 1. I tl.D., ADG, gap, Tot. sil.
init. Race site days yr. Y r. mo. mo. int., mo. TST
1 76 Adenocarc. 2 1.4
L.G. W RUL 17 1.7 0.25 3 __ 1.83
1 1.6
2 58 Epiderm. 0 2.3
M.M. N carc. RUL 27 2.6 0.36 6 _- 3.6
6. 2.3
3 72 Epiderm. 12. 6.0
N __ 8.9
L.H. carc. Gd. I 73 7.0 1.0 _12_
RLL 0. 7.0
Epiderm. 0. 4.0
a r c . Gd. I 48 4.0 0. __ 0 _- 5.9
RUL 0. 4.0
4 60 Epiderm. 9. 4.6
A.R. w arc.-anapl. 56 5.3 0.7 14 ~
6.6
LUL 5. 5.4
5 64 Epiderm. 6. 4.8
M.N. W circ.-anapI. 58 5.2 1.8 __ __ 5.5
LLL 2.
6 69 Epiderm. 19.
A.C. W carc. RML 62 6.9 1.8 7.2
2
7 63 Epiderm. 7 5.5
R.P. N carc. RUL 70 6.0 0.56 7 -_ 8.3
0.
8 64 Epiderm. 1.
J.S.,I N carc. Gd. I11 70 7.1 1.3 7.7
LLL 14.
9 63 Epiderm. 19. 8.2
H.J. N a r c . LUL 100 10.1 1.9 23 __ 10.4
4. 9.8
10 64 Epiderm. 30. 8.9
M.B. W arc.-anapl. 108 11.9 3.0 37 ~
12.2
RUL 7. 11.4
11 73 Adenocarc. 34. 10.4
N.C. w poorly diff. 126 13.4 3.0 36 -- 14.7
RLL 2. 13.2
12 63 Epiderm. -3. 16.3
J.S.,I I b’ arc.-anapl. 2 00 16.0 -0.3 48 __ 20.3
RLL 51. 16.
11.5
AV. .. 78 7.5 1.1 8.7
3.5$
*The patients are listed in order of increasing tD.See the text for a n explanation of the symbols used for column
headings. RUL indicates right upper lobe, RLL indicates right lower lobe, LUL indicates left upper lobe, LLL
indicates left lower lobe, and RML indicates right middle lobe.
graph at time -50 weeks-the earliest radio- institutions also demonstrated missed lesions
graph of the series-no infiltrate had been de- having the predicted diameters. Patient J.S., I.,
tected by the radiologist. However, on retro- had a left lower lobe epidermoid carcinoma.
spective evaluation of this radiograph, a faint At the Kingsbridge Veterans Hospital, 5 pos-
but clearly demarcated 1.4-cm. diameter left terior-anterior radiographs of the chest taken
upper lobe coin lesion was evident. This is over a 2-month period demonstrated a gradual
exactly the diameter predicted for the lesion increase in volume. Measurements of a par-
at -50 weeks by the exponential growth ticular vertical-oblique tumor diameter fell
formulas or by direct backward extrapolation along a n exact exponential growth curve, with
graphically! I n sum, then, a very exact expo- a doubling time of 70 days. When 2 earlier
nential growth curve plotted for the 3 initially radiographs from the Veterans Administration
available radiographs extrapolates back well Hospital, Castle Point, N.Y., were made avail-
to 4 further radiographs, including 1 of a able, they too fell upon the backward extrapo-
missed lesion at the predicted size. lation of the original curve. A similar situation
I n 2 other patients, radiographs from other also holds for patient J.S., 11.
APPROACH TUMOR
TO CLINICAL GROWTH * Schwartz 1281
TABLE
1
WITH PROVED BRONCHOGENIC CARCINOMA* -
CIA No. meas. X rays
-
NO. doub- C11\.r, CIA P ClM, X-ray observ.
AST lings nt % % % span, mo. Remarks1
3.
0.17 39.2 23. 9.3 40
2.
14. Regress. postradiother.
1.5 48. 42. 37.5 89 __ predicted
6.
9. Poss. double prim.; R.LL
1.9 42. 29. 21. 72 lesion appeared 1st; both
21. later cavitated & growth
7. tapered
1.9 44. 32. 32. 100 __
21.
7. “Missed” lesion exists
1.3 43.2 30. 20. 67 with predicted diam.
22.
9. No object. resp. to JdN2
0.38 35.5 15.5 7. 45 or radiat.
3.5
6. Autop. & X-ray meas.
0.5 42.3 29. 7. 24 coincided
3.5
22. RUL lesion appeared
1.7 39.4 24. 20.5 85 after It. pneumonect.;
26. no HN2 resp.
8. Outside X rays showed
1.6 40.2 25. 21. 84 missed lesion with pre-
7. dicted diam.; no resp. to
DON
11. No object. resp. to DON
0.6 38. 21. 5.8 28
2.
10. No object. resp. to
0.9 43. 30. 7.4 25 mustards
4.5
7. “Satellite” nod. later
1.4 42.3 29. 9.5 33 -- devel.; slt. growth rate
14.5 tapering bef. death
9. Patholog. diag. made a t
4.3 37.2 19. 21. 100 autop.; “outside” X rays
42. fit curve
-
9.5 ...
1.4 41. 27. 17. 62
13.5
tThe average age for this group of patients was 65.7 years.
SHN2 indicates nitrogen mustard, and DON indicates 6-diazo-5-oxo-~-norleucine.
§Excluding patient J .S.,I I.
Early prediction of post-therapeutic tumor short of the predicted diameter for day 148-
regression as a validator of doubling time con- 11.5 cm. Gross inspection of its semilogarith-
stancy and of forward extrapolation from a mic plot in comparison with the previous 9
close-fitting exponential growth curve is well close-fitting values showed the deviation to be
exemplified by patient M.M. A right upper a significant one. Subsequent radiographs
lobe epidermoid carcinoma was found to have taken on days 168, 182, 185, and 189 demon-
a doubling time of 27 days, as calculated from strated an absolute decrease in tumor size from
9 preradiotherapy diameter measurements fall- preradiation levels-to 8.2, 7.7, 7.5, and 7.5
ing between 3.1 un. at day 0 and 9.4 cm. at cm. respectively. I n other words, the earliest
day 127. Then, 5,090 r was administered to the evidence of a post-therapeutic regression con-
tumor during a 51-day period (day 133 to day sisted of detection of a decreasing rate of vol-
184). A radiograph was taken on day 148, and ume increase in the initial stages of radio-
the tumor diameter was then 10.3 cm. Al- therapy, before any actual absolute decrease
though this represented an increase over the in size was observed.
previous measurement, it nevertheless fell It is worthwhile to note that radiosensitiv-
1282 CANCER
TABLE
2
INDIVIDUAL MEASUREMENTS FOR 12 MALE PATIENTS W I T H PROVED
Post.-ant. Post.-ant.
Date Time diam., cm.t Date Time diam., cm.?
Pt. L.G.-R UL adenocarc.1: 2/23/54 0. wk. 6.3
3/3/58 0. days 3.4 7/6/54 19.wk. 10.9
3/26/58 23.days 4.9 9/27/54 30.5 wk. 15.1
3/28/58 25.days 4.9 Pt. J4.N.-LLL anaplastic epidermoid carc.**
4/18/58 46.days 6.5 8/26/57 0. davs 2.3
4/23/58 51.davs 6.9 8/27/57 1: da;s 2.3
P f : ilk.M.--RUL epidermoid carc.8 9/12/57 17.days 2.6
8/12/58 0. days 3.1 10/1/57 36.days 2.7
8/14/58 2.days 3.2 11/4/57 70. davs 2.9
9/16/58 35. days 4.6 1ij6js7 72.days 2.9
9/19/58 38.days 4.8 11/13/57 79.days 3.0
9/24/58 43.days 4.9 11 /19/57 85.. davs
~ 3.2
1o/ 1/58 50.days 5.0 12)6/k7 102.da& 3.4
11/5/58 85. days 6.8 Pt. A.C.-RML epidermoid cam.$
12/16/58 126.days 9.5 11/19/58 0. days 11.4
12I17I58 127.davs 9.4 12/30/58 41.davs 13.4
1 j7/59 148.da$s 10.3 1/12'/59 54.davs 14.5
1/27/59 168.days 8.2 1/14)59 56. da$s 14.5
2/10/59 182. days 7.7 1/30/59 72. days 15.0
2/13/59 185.days 7.5 2/12/59 85.days 15.7
2/17/59 189. days 7.5 Pt. R.P.-R UL epidermoid cam.$***
Pt. L.H.-RLL epidermoid carc.11 6/24/57 0. wk. 1.8
1/14/53 0. wk. 2.9 7115157 3.wk. 1.8
1)2Q)53 1.wk. 3.0 8/21/57 8.3 wk. 2.2
1/28/53 2.wk. 3.2 8127j57 91-Wk-- 2.2
3/2/53 7. wk. 3.5 12/29/57 26.5 wk. 3.3
5/1/53 16.wk. 4.2 1/18/58 29.3 wk. 3.5
8/24/53 32.wk. 5.3 2/5/58 31.6 wk. 3.9
9/10/53 35.wk. 5.2 3/20/58 38.wk. 4.4
9/28/ 5 3 37.wk. 5.2 3)28)58 39.3 wk. 4.5
i)iijsi 53: wk. 7.2 4/9/58 41.wk. 4.7
8/31/54 85. wk. NM(>10) 6)23/58 51.5wk. 5.4
Pt. L.H.-R UL efiidermoid carc. 7/1/58 52.8 wk. 5.9
1/14/53 0. wk. NM 7/17/58 55. wk. 6.1
1/20/53 1.wk. 1.1 7/22/58 55.7 wk. 6.1
1 /28/53 2.wk. 1.1 8/1/58 57. wk. 6.1
3)2/S3 7. wk. 1.4 8/4/58 57.5 wk. 6.2
5/1/53 16.wk. Blurred
~ .-- sisis8 58.wk. 6.3
8/24/53 32.wk. 3.0 8j19/58 59.5 wk. 6.5
9/10/53 35.wk. 3.2 8/30/58 61.wk. 6.9
9128153 37.wk. 3.5 9/5/58 62.wk. 7.4
1/17/54 53. wk. 6.3 10/23/58 69.wk. 8.9
8j31j54 85.wk. NM(>lO) 12/10/58 76.wk. 9.7
Pt. A,R.-L UL anaplastic epidermoid carc.7 Pt. J.S., I.-LLL epidermoid cam.****
3/7/53 -50. wk. 1.4 2/20/56 -50. wk. 1.5
8/11/53 -28. wk. 3.0 2/7/57 0. wk. 4.8
12/16/53 -10. Wk. 5.0 3/5/57 4.wk. 5.4
1,I2,I54 -3. wk. 5.7 4/22/57 11. wk. 6.5
*In this table, RUL indicates right upper lobe, LUL indicates left upper lobe, LLL indicates left lower lobe,
right lower lobe.
t N M indicates nonmeasurable.
$The diameter used for measurement was the posterior-anterior vertical one.
$The average posterior-anterior diameter was used. For this patient, radiotherapy was started on day 133 and
l1In this patient, cavitation first appeared in the right lower lobe mass at week 32. In the same patient, cavita-
is detailed next, a t week 85.
VOn March 7, 1953,the lesion was missed. The last 3 determinations are from initially available radiographs.
**The diameter used for measurement was the posterior-anterior vertical one. I n this case, nitrogen mustard
in 1 week) beginning on day 85.
***Nitrogen mustard was administered at week 55.
****The diameter used for measurement was the greater posterior-anterior oblique one. On Feb. 20, 1956,the
cine (DON) therapy was started and was continued for 4 weeks.
*****DONtherapy was started on day 16 and was continued for 29 days.
******The diameter used for measurement was the greatest vertical-oblique or posterior-anterior one. Nitrogen
ity could reasonably be anticipated in such a therapy (with nitrogen mustard or 6-diazo-5-
rapidly growing tumor with a doubling time 0x0-L-norleucine (DON)) either singly or in com-
or intermitotic interval of 27 days. Of 5 other bination, none demonstrated any objective
patients receiving radiotherapy or chemo- growth rate alteration. The most rapid doub-
APPROACH TUMOR
may drug (or radiation) effect be detected at
BRONCHOGENIC CARCINOMAS* an early stage but the intermitotic interval it-
self might have some predictive value even
Post.-ant. prior to initiation of therapy.
Date Time diam., cm.?
Despite the over-all doubling time constancy
4/23/57 11. wk. 6.4 over long periods of clinical observation, sev-
5/21 /s7 1.5. wk. 7.1
6/4/51 17. wk. 7.5 eral spontaneous deviations from the original
611 1/57 18. wk. 7.6 exponential curves were noted. I n each in-
6/21/57 19. wk. 7.7
Pt. H.J.-L UL ebidermoid carc. t***** stance, definite nutritive factors appear to
7/16/57 0. days 5. 0 have been responsible.
7/18/57 2. days 5.1 Patient N.C. had a right lower lobe adeno-
7/30/57 14. days 5.3
8/8/57 22. days 5.4 carcinoma that gradually enlarged to huge
8/15/57 29. days 5.4 proportions. Pretenninally, the tumor diame-
8/22 157 36. days 5.5
8)29)57 43. days 5.6 ter exceeded 15. cm., and the mass occupied
9/3/57 48. days 5.6 more than half of the right hemithorax.
9/5/57 50. days 5.6 However, only when the tumor diameter did
9/13/57 58. days 5.7
9/18/57 63. days 5.9 exceed 15. cm. did the rate of growth show any
Pt. M.B.-R U L anaidastic efiidermoid caw.****** signs of tapering off-and then only to a slight
4/4/57 0. day; 14.8
4/16/57
A
12. days 15.3 extent. T h e initial diameter measurements

4/17/57 13. days 15.2 were 7.6, 7.7, 8.7, 9.4, and 18.6 cm. at 0, 2, 9,
4/26/57 22. days 15.6 16, and 27 weeks, and they fell along an exact
5/14/57 40. days 15.8
5/22/57 48. days 16.1 exponential growth curve with tD equal to 126
5/29/57 55. days 16.3 days. T h e preterminal measurements were 15.5
6/5/57 61. days 17.2
6/17/57 73. days 17.6 cm. and 15.6 cm. during weeks 61 and 63,
6/27/57 83. days 17.7 which is I cm. less than the predicted diameter.
8/14/57 130. days NM T h e patient died during week 64.
Pt. N . C.--RLL adenocarc.1
11/15/56 0. wk. 7.6 What is surprising is not that there may
11/28/56 2. wk. 7.7 have been damping factors, such as external
1/18/57 9. wk. 8.7 pressure, partial outgrowing of the blood sup-
3/8/57 16. wk. 9.4
5/24/57 27. wk. 10.6 ply, or similar nutritive alterations, but that
1/21/58 61. wk. 15.5 these should have manifested themselves so
2/7/58 63. wk. 15.6
Pt. J.S., II-RLL anaplastic epidermoid carc. late in the course of the disease and to so minor
11/1/51 0. mo. 0.9 a degree. Three other patients with broncho-
12/23/52 14. mo. 1.4 genic primary tumors (patients M.B., A.C.,
1/26/53 15. mo. 1.5
3/6/53 16.5 mo. 1.6 and A.R.) also developed huge tumors with
3/27/53 17. mo. 1.6 diameters in excess of 15. cm. without any
4/21/53 18. mo. 1.7
8/6/54 33.5 mo. 2.7 demonstrable growth rate change.
10/7/54 35.5 mo. 3.1 Spontaneous growth rate change of another
1/26/55 39.5 mo. 3.5 kind is exemplified by patient L.H. I n view
4/13/55
, , 42. mo. NM
of their differing rates of growth, as evidenced
RML indicates right middle lobe, and RLL indicates by a 50% difference in doubling time, L.H.’s
2 clear-cut lesions possibly represent 2 distinct
primary bronchogenic carcinomas. T h e right
stopped on day 184, after 5,090 r had been given. lower lobe infiltrate had a n intermitotic in-
tion first appeared in the right upper lobe mass, which
terval of 73 days, and the right upper lobe
infiltrate had one of 48 days. Extrapolation
was administered on day 36. Radiation was given (750 r
back to the single-cell, or initial implant, stage
reveals that the right lower lobe tumor pre-
lesion was missed. At week 15, 6-diazo-5-oxo-~-norleu- ceded the right upper lobe tumor by 3 years,
if we exclude the possibility that 1 originated
mustard was administered on day 26. as a multicellular emboIus from the other.
However, since the cells of the later right up-
ling time in this group was 58 days. When per lobe tumor replicated more rapidly, this
applicable by reason of measurability, this lesion was first detected radiographically when
technique, then, can provide information use- the right lower lobe mass was but 3. cm. in
ful in cancer drugxreening studies. Not only diameter. For the remaining radiological ob-
1284 Nouem ber-December 1961
CANCER Vol. 14
servation span, subsequent growth of both the first measurable radiograph, generally
lesions could be followed simultaneously. paralleling fairly closely the time the patient
When the diameter of the right lower lobe first comes under medical observation, has
mass exceeded 5. cm., cavitation occurred, with been taken as a base line. The mean initial im-
an accompanying marked decrease in the rate plant time of 7.5 years in this series indicates
of growth. Some 7 months later, when the di- the surprisingly long tumor duration prior to
ameter of the right upper lobe mass exceeded initial detection on radiographs. For the slow-
6 . cm., it too began to cavitate-with a similar est growing lesion, extrapolation back to the
tapering in its rate of volume increase. For postulated single-celled stage yields an initial
both lesions, then, accurate geometric growth implant time of 16 years, and indeed, 4 of the
curves were followed u p to the time the le- 13 tumors were in existence a decade before
sions began to cavitate. Beyond this point, the they were first picked u p on a chest radio-
actual tumor diameters fall short of the pre- graph. Only the most rapidly proliferating
dicted values. Possibly the vascular or other neoplasm of the group, the adenocarcinoma
nutritive defect resulting in cavitation also with a t e ual to 17 days, revealed an initial
D. q
interfered with the tumor’s growth potential. implant time of less than 2 years, and only 1
Another possibility, however, is that the actual other had a tl.l, of less than 4 years.
intermitotic intervals remained unchanged, The bearing these results have upon the con-
but sloughing of the lesions sharply diminished cept of an early tumor is all too obvious. To
the tumor volumes and therefore led artifacti- call a neoplasm “early” merely because it ap-
tiously to a lower tD. Against this latter ex- pears small when initially detected, or because
planation is the observation that significant it is detected accidentally in an asymptomatic
doubling time drops were already evident patient, is to ignore the extensive substratum
when the cavitation volume was minimal. of prior preclinical proliferation. The silent
Whether this similar clinical behavior of the interval calculations further point up the ex-
2 lesions is indicative of a host factor common tent of this “iceberg” growth. The average
to 2 distinct primary tumors or whether the true silent interval was 6.4 years (30 tD); and
2 masses were metastatically related is difficult during these years before a 1.-cm. diameter was
to say. attained, no present clinical weapons at our
For a mean doubling time of 2 months, 5 command-with the possible exception of rou-
years and 30 doublings are required for a tine screening of well patients by exfoliative
single tumor cell to give rise to a lesion 1 cm. cytology-would ordinarily have detected the
in diameter. Accordingly, as we have noted, presence of neoplastic disease. Indeed, even
5-year remissions are likely to represent cures after the tumors exceeded 1.-cm. in diameter
in tumors with a tD of less than 2 months-if another year elapsed, as indicated by the aver-
recurrences at poor detectability sites are ex- age tl.D, of 1.1 years, before they were actually
cluded. Clinical recurrences in tumors with observed clinically (radiographically).
doubling times greater than 2 months can be- This approximate year’s delay between the
come evident more than 5 years after apparently time the lesion was actually seen on a chest
successful treatment and remission. Metastases radiograph and the time it could have been
can also, as we have observed, recur in less detected radiographically represents one area
than 5 years in such slow-growing tumors if in which emphasis upon early asymptomatic
the metastatic lesion originates from a multi- detection in susceptible subgroups seems war-
cellular embolus or residuum. For tD equal to ranted. The striking observation of several
78 days-the average doubling time of our missed radiographic lesions within the period
thirteen cases of malignant bronchogenic neo- of initial detectability contrasts strongly with
plasms-we should speak of 6.4-year cure rates. the diagnostically intractable true silent in-
Similar figures for our least and greatest terval.
doubling times ( t D equal to 17 days and t D If we measure the time interval from the
equal to 200 days) would be 1.4-year and 16.3- 1.-cm. diameter stage to the first clinical sign
year remissions, beyond which time a further or symptom, we have the true diagnostic gap
absence of clinical recurrence could be labeled (TDG),which, in this series, averaged 11.5
a “cure.” Larger statistical samples would be months. This is a more exact measure of the
quite helpful in constructing valid n-year cure failure to detect an asymptomatic but presum-
rate expectancies for specific tumors. ably diagnosable lesion than is the tl,D, of
For calculation of tl,l. and tl,D,, the date of 1.1 years. This is so because, although the first
No. 6 APPROACH
BIOMATHEMATICAL TUMOR
clinical manifestation was in some cases the instance previously cited, despite careful re-
actual radiographic detection of the lesion, in view of all available early radiographs, could
most instances some symptomatology preceded any lesion smaller than 1. cm. in diameter
the initial radiology by about 2 months (the be detected (and even in the 1 instance, the
difference between t1.D. and TDG). By adding difference was not significant). This value,
the 11.5-month TDG to the true or basal silent then, would seem to be a good boundary
interval, we obtain a mean total silent interval choice for initial detectability.
of 7.3 years. This period represents the total T h e survival data offer a striking contrast
duration of the tumor before some clinical between the common sense clinical concept
manifestation either appeared spontaneously of total duration of life after the onset of
or was elicited. symptomatology or detection of disease (ap-
Calculation of the apparent diagnostic gap parent survival time), and the true or total
or “work-up time” between the first mani- survival time dating from the initial tumor
festation and the clinical diagnosis presented implant. T h e mean AST was only 1.4 years,
some difficulties. I n some instances, when the and only 1 patient (J.S., 11) survived more
diagnosis was obvious or reasonably certain than 2 years after the first clinical manifesta-
clinically, the time of the first symptom or the tion of neoplastic disease. Total survival time,
first radiograph was taken as the time of diag- on the other hand, averaged 8.7 years, with
nosis. I n such cases, a work-up time or ADG of several patients living well into a second dec-
0 is recorded. This convention is justifiable ade. These figures, of course, are directly de-
when adequate clinical information is avail- pendent upon the long silent preclinical phase
able for well founded therapeutic decisions, of tumor growth. T h e wide tenfold range of
and, indeed, it seems essential when the diag- doubling times in these bronchogenic neo-
nosis is clinically certain but can be established plasms is reflected in total survivals ranging
pathologically only by postmortem study. from less than 2 years to more than 2 decades.
I n patient J.S., 11, the right lower lobe le- From the survival statistics, several useful
sion was, for all practical purposes, detected at measures of a tumor’s clinical observability
the 1.-cm. diameter stage. T h e actual initial may be derived. Obviously, the AST to TST
measurement was 0.9 cm., and a negative ratio represents the actual clinical time frac-
value, -0.3 years, is therefore recorded for tion of a tumor’s total existence. This ratio,
t1.D.. T h e tumor remained completely asymp- which we have labeled Cl,, was 0.17 or 1701,.
tomatic throughout the patient’s lifetime, and O n the average, then, less than one-fifth of the
death was due to a n unrelated myocardial in- tumor’s total growth was evident clinically.
farction. T h e lesion enlarged very slowly For 6 of the thirteen neoplasms, this observa-
( t D equal to 200 days) during a 51-month pe- tion fraction was less than one-tenth.
riod of clinical observation, during which I n Table 1 are included values of n,--the
time severe cardiopulmonary disease contra- total number of tumor doublings. This index
indicated thoracotomy. T h e diagnosis of epi- represents the number of mitotic divisions
dermoid bronchogenic carcinoma was finally spanning the tumor’s total existence assum-
established at autopsy. Thus, since a patho- ing that exponential growth (that is, a constant
logical diagnosis was not made until 51 months intermitotic interval or doubling time) is valid
after detection of the tumor, an ADG of 51 throughout. T h e mean n, of 41. corresponds
months has been entered in Table 1 . T o avoid to 2 kg. of tumor tissue present at the time of
gross distortion, this atypical value has been death. However, in those instances in which
excluded from the average ADG. cavitation, necrosis, and sloughing occurred,
Keeping these restrictions in mind, the mean n, must be interpreted simply as the nurnber
ADG was 3.5 months-a figure that primarily of tumor doublings and is not convertible into
reflects patient delay in seeking medical care the weight of viable tumor tissue at death.
after the onset of symptomatology rather than Since the total tumor duration is the nurnber
any significant physician delay in instituting of mitoses multiplied by the intermitotic in-
appropriate diagnostic measures. T h e total terval, TST, n,, and tD are directly related by
diagnostic gap, then, is 15 months (TDG plus the equation: TST=tD’nt, so that nt is readily
ADG)-ahOSt 1 year of which (TDG) could be determined from the total survival time and
reduced only by periodic screening of well the doubling time.
Datients. From the total number of tumor doublinps. 0-,
A point worth noting is that only in the 1 we may obtain a measure of the maximal clini-
1286 CANCER
TABLE3 carcinoma originating in the bladder-had a
TUMOR GROWTH RATES I N 8 MALE volume-doubling time of 217 days-slower
PATIENTS WITH METASTATIC than that for the slowest-growing broncho-
CANCER OF T H E LUNG
genic neoplasm. This short series, therefore,
Age, demonstrates an even wider tumor growth
Pt. Y‘.
init. Race Prim. tum. tn. davs rate range than the tenfold span of the bron-
J.R. 60 Hepatoma (anaplastic) 15*
chogenic group.
W Indeed, the patient with malignant mela-
G.J. 32 Embryonal testicular noma showed no change in the size of the
W arc. 18*
C.Y. 40 Hypernephroma metastatic pulmonary mass during a radio-
Ct (anaplastic) 19* graphic observation span of 25 months, and a
L.R. 65 Lymphosarc. stomach 35 doubling time of “infinity” is entered in Ta-
..
W
J.L. 66 Epidermoid carc. ble 3. Death supervened from widespread
W larynx Gd. I11 44 metastatic disease elsewhere. The pulmonary
L.V. 64 Adenocarc. colon Gd. I1 84
coin lesion was detected 1.3 years after exci-
W
W.R. 67 Papillary carc. sion of an enlarging malignant mole from the
W bladder Gd. I 217 back of the neck. We can only speculate as to
G.R. 29 Malig. melanoma m
W what the actual (if constant) growth rate was
during the 1.5-year survival period after ex-
*Average of several lesions.
tThis patient was Chinese. cision of the primary, and whether all of the
metastases had the same rate of growth. Ex-
cal time fraction of a tumor’s total existence. trapolation from the very long tumor-dou-
Since the maximum observability is from the bling time hinted at by a mass unchanged in
1.-cm. diameter stage (when n, is equal to 30) size for 2.5 months strongly suggests that
to death, our desired ratio is: metastasis had already occurred many years
before the primary lesion was excised. Yet the
n,-30 very fact that the lung metastasis showed no
nt growth potential even though the patient
which we have called Cl,. I n this series, the eventually died from metastatic disease else-
average GI, was 27.%, so that even if all neo- where shows how cautious we must be in
plasms could have been detected clinically at drawing general conclusions in relation to
the earliest possible asymptomatic stage, al- tumor growth. Our generalizations should be
most three-fourths of their total growth and not only tumor specific but site specific as well.
duration would have already elapsed unob- Study of multiple metastatic pulmonary
served. Relatively small as is the maximum lesions affords additional confirmation for the
clinical observation potential, the C1, to GI, constancy of the doubling time for a particu-
ratio, which yields a measure of that fraction lar tumor. Patients J.R., G.J., and C.Y., the
of the clinical observation potential actually 3 patients with the most rapidly growing
used, is smaller still-62.% in this series. tumors, all had multiple pulmonary coin le-
Secondary Pulmonary Neoplasms. Tumor sions with a fairly constant tumor-doubling
growth rates of a second group of intensively time-that is, not only did serial measure-
studied patients with measurable neoplastic ments of any particular radiological mass fall
disease metastatic to the lung are indicated in along a well fitting exponential growth curve
Table 3. Direct measurement data are re- but also all other masses in the same patient
corded in tabular form for each patient (Ta- had approximately the same tD, as shown by
bles 4 to 6). While no statistical conclusions closely parallel straight lines obtained on the
are warranted, it is evident that 3 of the 8
patients demonstrated a tumor-doubling time
TABLE4
shorter than that for the most rapidly growing
bronchogenic carcinoma of the previous series. DATA FOR PATIENT J.R., WHO HAD
AN ANAPLASTIC HEPATOMA
Further, the more anaplastic tumors do seem ~~
Post.-ant. diam. vert. xhoriz. view, cm.

to have the more rapidly enlarging metastases
in contrast to the primary bronchogenic le- Date Day Lesion 1 Lesion 2
sions (for which such a relationship could not 12/24/58 0 1.5 x1.5 2 . 2 x1.9
be demonstrated). The slowest-growing meta- 1/8/59 15 1.9 x1.9 2.8 x2.8
static pulmonary mass-a Grade I papillary 1/14/59 21 2 . 1 x2.1 3.0 x3.0
No. 6 BIOMATHEMATICAL APPROACH TO CLINICAL TUMOR GROWTH Schwartz - 1287
TABLE 5 apparent and then only to a minor extent.
DATA FOR EMBRYONAL TESTICULAR Finally, as radiological overlapping of adja-
CARCINOMA AND ANAPLASTIC cent masses progressed still further, the indi-
HYPERNEPHROMA*
vidual lesions became nonmeasurable. Again
Diam. lesion, cm.t we see how extreme must be the degree of
Day L1 L2 L3 L4 R1 R2 R3 external pressure or the presence of nutritive
or metabolic factors before any alteration oE a
Pt. G.J.-embryonal testicular carcinoma
0 1.35 1.15 1.4 1 . 1 1.25 1.25 1 . 3 previously established growth pattern becomes
4 1.5 1.2 1 . 6 1 . 2 1 . 5 1 . 4 1.35 evident.
14 1.7 1.35 1 . 7 1.5 1.65 1.55 1 . 6 Patient G.J. might also have shown a simi-
20 1.75 1.55 1.9 1 . 6 1.8 1.7 1.8
Pt. C. Y.-anaplastic hypernephroma lar spontaneous growth rate tapering, since
0 3.2 2.15 2.35 1.95 1.85 1.6 he had multiple rapidly growing (t, equal to
4 3.3 2.25 2.45 2 . 0 1.95 1.65
17 4 . 1 2.65 2 . 6 2.45 2.25 1.95 18 days) bilateral pulmonary metastases from
21 4.4 2.9 2.7 2.6 2.4 2.0
27 4.7 3. 2.95 2.7 2.65 2.15
35 5.4 3.6 NM NM NM NM TABLE6
42 5.85 3.75 3.4 3.05 NM 2.3 DATA FOR PATIENTS WITH METASTATIC
49 6.0 4.05 3.6 NM NM NM CANCER OF T H E LUNG
60 NM NM NM NM NM NM
Date Day Diam., cm.
*In this table, NM indicates nonmeasurable (be- -
cause of interference from overlapping). Pt. L.R.-lymphosarcomu of stomach (left hilum)*
t I n this case, the average posterior-anterior diameter 8/15/56 -284 days Neg.
was used. 9/14/56 -255 days Suggest. “smudge”
11/6/56 -203 days 1.7
5/29/57 0 days 6.0
semilogarithmic plots of tumor diameter 6/6/57 7 days 6.4
against time. Patient J.R. had 2 measurable 6/12/57 13 days 6.5
6/13/57 14 days 6.6
masses, with an average t, equal to 15 days; 6/19/57 26 davs 7.0
patient G.J. had 7 masses, with tD’s of 14, 14, 6)26)57 27 da;s 7.2
15, 17, 20, 21, and 28 days; and patient C.Y. 7/1/57 32 days 7.4
7/8/57 39 days 8.1
had 6 masses, with t,’s of 15, 16, 16, 17, 21, 7/15/57 46 days 8.3
and 28 days. 7/22/57 53 davs 8.9
816/57 68 d a k 9. . 7.
I n addition, for all patients I-mm. repro- 8)23/57
~
85 da& 10.4
ducibility was generally obtainable in these Pt. J.L.-RLL epidermoid carcinoma of larynx?
very clearly circumscribed coin lesions, and 4/23/57f -27 wk. 1.7
6/26/57P - 18 wk. 2.3
the closely fitting exponential growth curves 7/8/57$’ -16 wk. 2.5
are correspondingly significant even when the 11/3/57 0 wk. 4.5
11/8/57 1 wk.
- ... 4 6
lesions are quite small. Finally, the high de- Pt: L. V.-L UL adenocarcinoma of coiont
gree of sphericity of these metastatic masses 8/21/57 0 wk. 1.0
makes t, determinations even more meaning- 8/28/57 1 wk. 1. o
10/10/57 7 wk. 1.1
ful. 10/17/57 8 wk. 1.2
T h e phenomenon of spontaneous terminal 12/27/57 18 wk. 1.4
5/28/58 40 wk. 2 1
tapering of the rate of growth shown by sev- Pt: W.R:--LLL papillary-carcinomu-of bladder 5
eral patients with bronchogenic carcinoma 8/7/56 -39 wk. 2.2
was also evidenced by patient C.Y. This 11/23/56 -24 wk. 2.4
5/9/57 0 wk. 2.8
young Chinese man had a rapidly fatal ana- 5/24/57 2 wk. 2.9
plastic carcinoma (hypernephroma), with an 10/20/57 23 wk. 3.5
extremely rapid average doubling time of 19 Pt. G.R.-RLL malignant melanoma
11/9/56 0 days 2.5
days. As indicated, separate growth curves 11/14/56 5 days 2.5
plotted for the multiple pulmonary metastases 11/19/56 10 days 2.5
1/2 1/57 72 days 2.5
showed closely parallel rates of growth. Dur-
ing a 1.- to 1.5-month period-long enough *In this case, the greatest posterior-anterior vertical-
oblique diameter was used. On Sept. 14, 1956, and on
for 2 doublings or a quadrupling of tumor Nov. 6 , 1956, the lesion was missed. Radiotherapy was
volume-repeated diameter measurements of started on day 88, with 1,350 r being given over a n
the individual lesions fell on the straight line 18-day period. By day 99, the lesion had disappeared.
t I n this case, the posterior-anterior vertical diameter
semilogarithmic curve extrapolated from the was used.
initial 2 measurements. Only when almost the $On these dates, the lesion was missed.
entire lung volume seemed infiltrated with $0,Aug. 7, 1956, and on Nov. 23, 1956, the lesion
was missed. On Oct. 20, 1957, “satellite” nodules
tumor did any growth rate tapering become appeared.
1288 Nouem ber-Decem ber 1961
CANCER VOI. 14
a n embryonal testicular carcinoma. However, Since the primary bladder tumor was diag-
roentgen therapy was initiated, the pulmonary nosed by excision biopsy almost 7 years before
masses proved highly radiosensitive, and con- that radiograph and had manifested itself,
siderable regression in size was noted on this with hematuria, ly2 years before biopsy, a
basis. H e was discharged and, unfortunately, valid tl.l. of 20 years would mean that the
was lost to follow-up evaluation; i t might have papillary carcinoma was in existence and had
been quite instructive to observe whether and already mestastasized more than a decade
at what rate measurable growth would re- before there was any overt clinical symptoma-
sume. tology. T h e growth data would, therefore, in-
T h e most striking radiotherapeutic effect dicate that the pulmonary lesion was present,
was shown by patient L.R., an elderly man and the primary tumor therefore inoperable,
with a lymphosarcoma of the stomach meta- long before there was any clinical evidence of
static to the left hilum. This lesion, too, grew disease.
rapidly-doubling in volume every 35 days. While such relationships do occur, as evi-
Twelve separate measurements during a pe- denced i n several of the slowly growing bron-
riod of 2.5 months all fell along a n exact geo- chogenic carcinomas (and indeed the average
metric growth curve as the tumor diameter tl.l. for the bronchogenic neoplasms was 7.5
increased from 6.0 to 10.4 cm. During this years), i n this instance it is at least equally
period of time he had been placed on DON likely that a more recent multicellular tumor
chemotherapy with no measurable response. nodule had metastasized from the bladder
Radiotherapy was then instituted, and he re- carcinoma. However, there is no reason to
ceived 1,350 r to the left hilar mass during an suppose that the metastatic pulmonary mass
18-day interval. By the tenth day, however, was of recent origin by virtue of having first
the mass had completely regressed. grown rapidly and, then, during the period
Unfortunately, for metastatic lesions the of clinical observation, grown more slowly. No
calculated initial implant time cannot be di- deviation from a constant slow exponential
rectly equated with the time of origin of the growth pattern was detected during the 62-
tumor, for we do not know whether a particu- week radiological observation span.
lar metastatic tumor embolus was unicellular At the rate of growth shown by this tumor
or multicellular. As has been pointed out, during the period of clinical observation, it
even a small 1-cu. mm. nodule has already may be calculated that the metastasis was
gone through 20 mitotic divisions-about half about 0.1 mm. in diameter at the time that
the total number that will occur before death the primary lesion was excised-which is cer-
results. For bronchogenic neoplasms this prob- tainly a reasonable size for a tumor embolus.
lem does not arise, since a primary focus in- This diameter is a maximum figure, since the
volving a single “mutant” cell can generally size of the embolus was smaller if metastasis
be assumed. preceded excision by any appreciable length
T h e very slowly growing papillary carci- of time. This line of extrapolative reasoning
noma of the bladder (for example, that of pa- might in the future provide useful informa-
tient W.R. in Table 3) had a doubling time of tion concerning the frequency and the prob-
217 days. Since the metastatic left lower lobe able size of metastases induced by the trauma
pulmonary mass was 2.2 cm. in diameter on of surgical excision.
the first positive chest radiograph, initial de- I n passing, we may remark that patient
tectability on extrapolation to the one 1.-cm. W.R. (as is true also for patient L.R.) dem-
diameter stage is: onstrated the phenomenon of the missed
radiological lesion. I n both patients, a meta-
static coin lesion was missed on early radio-
g r a p h . Subsequent review revealed that the
when tD equals 217 days and D, equals 2.2 cm. infiltrates were present and had the predicted
Then, tl.D, is 2.0 years. Adding this 2-year in- size. For patient L.R., the timing of this
terval between the 1.-cm. and 2.2-cm. stages missed radiological lesion is truly striking and
to 30 tn, the true silent interval from the has direct bearing upon the choice of 1. cm.
single-celled stage to the 1.-cm. stage, gives us as the boundary value for initial detectability
tl,l,. Since 30 tD is 18 years, we would have the -a choice that we have previously justified in
surprisingly long initial implant time of 20 other ways. T h e doubling time of 35 days and
years before the first positive chest radiograph. the tumor diameter of 6.0 cm. on the first
APPROACH TUMOR
“nonmissed’ radiograph (time 0) together and remained so as the lesion gradually en-
yield a n initial detectability of 270 days, a larged, a graph of the tumor diameter against
reliable figure in view of the extremely close- time has been a straight line when plotted on
fitting exponential growth curve obtained semilogarithmic paper. As this corresponds to
from many serial measurements. So, 270 days geometric growth increase, it is equivalent to
before “time 0 ’ the lesion should first have the demonstration of a constant doubling
been visible as a I.-cm. diameter infiltrate. time for the tumor. T h e only significant devi-
Two hundred and ten days before time 0, a ations from maintenance of a constant dou-
definite retrospectively evident coin lesion bling time have been noted either in radiolog-
with a n actual diameter of 1.7 cm. and a cal- ically responsive neoplasms or in cavitating
culated diameter of 1.6 cm. had been missed. lesions, huge terminal masses, and multiple
Equally remarkable, 284 days before time 0, metastatic infiltrates in which little pulmonary
a t a time when the pulmonary infiltrate was parenchyma remains and/or nutritive meta-
less than 1. cm. in diameter and should not bolic factors supervene. Indeed, the huge ,size
have been visualized as a discrete lesion, a that a tumor may often attain (up to 15. to 20.
completely negative chest radiograph was cm. in diameter) without deviating from a
seen. preset exponential growth pattern is striking.
All serial determinations during the period These considerations do not contravert the
of measurability preceding the dramatic re- results of various studies that apparently dem-
sponse to radiotherapy already discussed are onstrate occasional true cancer cell dormancy.
listed in Table 6. Measurements represent the Certainly there seems to be incontestable evi-
greatest vertical oblique diameters of a very dence in the literature detailing remarkably
clearly defined, posteriorly located mass over- long latency in tervals-occasionally exceeding
lying the left hilurn. From these raw data, a 3 decades-in which clinically silent periods
semilogarithmic plot confirms the very close of apparent mitotic arrest are sandwiched be-
exponential growth curve followed by this tu- tween periods of rapid clinical proliferation.10
mor, and graphic approximations or more T h e results of this present study, however,
exact exponential scale (log to log) slide rule would suggest that such periods of true la-
calculations readily yield the extrapolative re- tency are quite uncommon once growth has
sults given. begun. What ordinarily masquerades as dor-
mancy is simply extended preclinical prolif-
DISCUSSION eration a t a rate identical to that of later clini-
cal growth. Further, what often appears to be
T h e most significant concept developed in a sudden change in clinical growth rate is
the foregoing presentation has been the gen- merely an illusion created by improper appre-
eral validity and wide applicability of the ciation of the biomathematical characteristics
constant tumor growth rate pattern. This of constant geometric increase.
growth pattern is reflected in a fixed doubling Preclinical neoplastic growth not infre-
time and a close-fitting exponential growth quently exceeding a decade may be demon-
curve during a major segment if not during strated by careful longitudinal study of meas-
the entire life of a tumor. Both direct measurable tumors coupled with backward ex-
urement and analysis during the period of trapolation from a well confirmed exponential
clinical growth and various extrapolative con- growth curve. Successful backward extrapola-
siderations support this conclusion. T h e bio- tion to an early clinical period, such as the
mathematical apparatus and techniques for time of a missed lesion, lends confidence to
handling exponential tumor growth are par- further retrograde analysis-ultimately ex-
ticularly tractable. More important, many use- tending back to the time of origin of the
ful derivative concepts may be developed, and tumor. However, the most convincing evi-
from these much valuable information may be dence for exponential growth as a general
deduced concerning the natural history of property of neoplastic proliferation remains
neoplastic growth. Likewise, tools can be the very great accuracy of fit over wide vol-
fashioned to help evaluate the therapeutic ume and time ranges obtainable upon serial
effectiveness of the various anticancer modali- measurement. As noted, the few spontaneous
ties. variations from a n exponential growth pat-
Thus far, in almost every instance in which tern are, generally, readily explainable.
the tumor diameter was accurately measurable Comparison of our findings with the results
CANCER Vol. 14
of Collins et al.’s6 pioneer study of exponen- -assuming a constant tumor-doubling time-
tial tumor growth in man is informative. No before clinical recurrence would be evident.
analysis of primary bronchogenic neoplasms Obviously, earlier recurrence would be the
was made, but an evaluation of 24 patients rule, because the estimated inception time of
with measurable pulmonary metastatic can- age plus 9 months is a maximum for a num-
cer showed a tumor-doubling time range of ber of reasons: the looked-for recurrence may
between 11 days and 164 days. Growth was be detected when at a smaller size than that of
considered rapid if the doubling time was less the original lesion; the metastasis may already
than 25 days, intermediate if between 25 and have occurred before the primary tumor was
75 days, and slow if in excess of 75 days. This detected, or the recurrence may have origi-
division agrees well with the t, spectrum ob- nated from a multicellular post-therapeutic
tained in both the primary and secondary residuum. These expectations were fully con-
pulmonary neoplasms reported in the present firmed. All recurrences fell within the pre-
study. I n all but 1 of Collins et al.’s6 patients, dicted time, and every 1 of the 49 tumor-free
the time of inception of the metastases pre- “survivals” beyond the estimated maximum
ceded any sign or symptom of the primary period at risk demonstrated no subsequent
tumor. This generalization also holds for each recurrence! This indirect confirmation of g e e
of the secondary neoplasms reported in this metric tumor growth by a simple, almost non-
paper, but, as I have emphasized, caution is quantitative, statistical method is indeed strik-
necessary in such backward extrapolation being.
cause the initial metastatic implant may well That clinical diagnosis is a late event in the
have been multicellular. natural history of neoplastic growth, and that
Initial implant calculations for primary earlier diagnosis cannot extend the total tu-
bronchogenic neoplasms, on the other hand, mor observation potential very much, have
are not open to this objection, since the uni- already been amply emphasized and quanti-
centric, unicellular origin of an isolated pri- tated. The apparent diagnostic gap from first
mary neoplasm-while still unproved-is a clinical manifestation to the time of diagnosis
fairly reasonable assumption. Consequently, is hardly even a measure of the total diagnos-
analysis of the growth behavior of primary tic delay (most of which is comprised by the
bronchogenic neoplasms would be far more TDG interval from the initial detectability to
relevant to a confirmation of the concept of the first clinical manifestation) much less a
tumor inception and prolonged growth prior measure of the total tumor duration before
to clinical evidence of disease. In each of the diagnosis. The long silent intervals and small
primary “peripheral” bronchogenic carcino- AST to TST ratios attest to these conclusions. It
mas reported in this paper, the initial implant is hardly surprising, then, that there is often
time far preceded the first clinical manifesta- little correlation in reported statistics between
tion-the mean tl.l, being 7.5 years before the early diagnosis in the ADG sense and cure rates.
first positive chest radiograph. Indeed the reverse is sometimes true. “Early”
Most remarkable is Collins’6 study of 206 diagnosis soon after onset of clinical illness
children with Wilms’s tumor. Without the can be indicative of a highly malignant, rap-
quantitative measurements and the detailed idly proliferating tumor and, thus, can be
longitudinal study of individual patients associated with a lower cure rate. Collins5 sug-
through which my own confirmation of the gested this as the source of Haagensen and
validity of exponential tumor growth was at- Stout’s9 failure to observe a decreased breast
tained, Collins,5 by the simplest of techniques cancer cure rate with increasing duration of
and the barest minimum of data, reached the disease and of Macdonald and Kotin’s asso-
same conclusion. The only essential informa- ciation of shorter pretherapeutic gastric can-
tion needed was the child’s age at the time of cer symptomatology with lower resectability
diagnosis and at the time of post-therapeutic and survival rates.
recurrence, if any. I n our discussion of methodology, we briefly
Since the tumor must have originated some referred to Ingleby et al.’s12 growth rate study
time after conception, the child’s age at diag- of 6 cases of early breast cancer. The signifi-
nosis plus 9 months represents the maximum cance of roentgenographically seen calcifica-
time required for the tumor to grow from the tion as an indication of neoplastic breast dis-
single-celled stage to its size at diagnosis. At ease was not initially appreciated, so that
most, an equal length of time should elapse these small, nonpalpable, gradually enlarging
APPROACH TUMOR
TO CLINICAL GROWTH * Schwartz 1291
calcifying breast lesions were followed roent- than 250 days for the slowest-growing bron-
genographically for 4 to 16 months prior to chogenic carcinomas that enlarge gradually,
surgery. One ductal carcinoma in situ re- as seen o n radiographs, for years. No upper
mained unchanged in size; 4 carcinomas (1 limit can be set, as is evident from Inglcby
papillary, 1 medullary, and 2 ductal) demon- et al.’sI2 reported cases of breast carcinoma
strated a monthly volume growth factor of with tD’s of 15 months and from the case of
1.05 or 5%; and 1 schirrous carcinoma had a patient G.R. with “stationary” malignant
growth factor of 1.29 (equivalent to a Z9yo melanoma (as reported previously in this pa-
monthly volume increase). Using the exponen- Per).
tial growth formulas, these growth rates are As noted, differentiation between slow
found to correspond to doubling times of 15. growth and true latency can be quite difficult
months and 2.7 months respectively. Collins5 and, further, raises the vexing question of the
had also noted a slow and a fast growth pat- status of carcinoma i n situ-an extensive sub-
tern for the 2 patients with pulmonary breast ject for study in itself. Experimental tumor
metastases in his series of 24 patients with research in animals would seem to show189 29*30
measurable secondary pulmonary disease. that the incidence of lung metastases at any
However, comparison with his metastatic tu- given time is proportional to the size of the
mor-doubling times of 28 days and 84 days primary tumor and, therefore, presumably
shows the “rapidly” proliferating primary le- also proportional to the total duration of the
sion and the slowly proliferating secondary tumor. However, these studies also demon-
lesion had about the same rate of growth. strate that more rapidly growing tumors me-
What is most significant in Ingleby et al.’s12 tastasize earlier. Their metastatic potential
study is not the specific growth rates obtained, per unit of duration is, therefore, higher.
as they can hardly be assumed to be statisti- Roughly then, the metastatic rate in these
cally representative of all breast cancers; the experimental tumors is directly proportional
significant finding is that fixed monthly vol- to the tumor duration and inversely propor-
ume growth factors, equivalent mathemati- tional to the doubling time. How useful such
cally to fixed tumor-doubling times, were di- a “metastatic index” such as
rectly demonstrable. Furthermore, these lesions
were followed for fairly extended periods of t,
- 1.
time while they remained nonpalpable-proof tD
that a small palpable breast mass may really might be in evaluating the malignant poten-
be a late lesion that is well into the clinical tialities of human tumors has yet to be de-
phase and considerably past the t1.D. stage, termined.
not to mention the long preclinical silent in- T h e other end of the tumor growth spec-
terval. Of note, too, is the initial detectability trum is likewise undetermined, for extraordi-
modification necessary for small calcifying narily high experimental growth potential has
breast neoplasms, since several of the lesions been reported. For example, a study of 3 types
were detected while only a few millimeters in of transplantable human tumors2’ had dem-
diameter. Even if we take 1 mm. as our bor- onstrated more than hundredfold-volume in-
derline t1.D. diameter for these tumors-a creases 2 weeks after implantation in X-irradi-
value that would certainly be the exception ated or cortisone-treated rats or hamsters. Such
rather than the rule in any extended series- growth means that 6.7-volume doublings have
the time for 20 doublings or about half of the taken place in 14 days and would therefore
total expected tumor life would still have require a doubling time of 2 days!
elapsed. Assuming constant exponential Returning to the problem of biological pre-
growth, the very slowly growing breast pri- determinism in human cancer growth, the
mary tumors with a tD of 15 months would, observed tenfold range of bronchogenic tu-
even with an initial detectability at the 1 mm. mor-doubling times-and corresponding vari-
diameter, have had their inception 25 years ability for silent intervals, survival times, ini-
earlier. tial implant and detectability, diagnostic gaps,
T h e range of tumor-doubling times re- and other measurable or calculable parame-
ported in this paper extends from as often as ters-has been stressed. Radiomeasurable bron-
every 10 to 20 days for some rapidly proliferat- chogenic neoplasms evidently lend themselves
ing testicular teratocarcinomas, hypernephro- well to such study, and a number of investi-
mas, and undifferentiated carcinomas, to more gators have emphasized their inherently varia-
CANCER Vol. 14
ble proliferative potential and the clinical average about 1 year even when the bron-
significance of their preclinical growth pat- chogenic neoplasm was detected radiographi-
tern. cally in an “early” asymptomatic phase. The
Rigler,23 in a roentgenographic analysis of apparent diagnostic gap from first clinical
the evolution of bronchogenic carcinoma, ob- manifestation to the time of diagnosis is gen-
served the long latent periods that often exist erally a small fraction of the TDG and is most
and the marked variability of the first symp- inadequate as a criterion for an early lesion.
toms in relation to the total tumor duration. Indeed, as already noted, a small ADG may
He carried out a long term radiographic eval- actually indicate a rapidly proliferating, late,
uation of the natural history of bronchogenic incurable tumor.
neoplasms in patients refusing treatment but Most important, however, even a long TDG
permitting radiographic follow-ups and in pa- is nowhere near an adequate criterion of the
itents with “missed” or misinterpreted lung total tumor duration. The long silent interval
lesions on retrospective analysis. He found before initial radiodetectability-before the
that 50% of the cases selected by these criteria TDG even begins-must always be considered
had had pulmonary lesions more than 2 years and often points to total tumor durations of
before the first symptom appeared. As in my more than a decade. Use of a true sur-
own series, many of his patients had periph- vival time (TST) from the time of the initial
eral lesions that became symptomatic only tumor implant until death is a far more exact
after late bronchogenic invasion. Occasionally measure of total tumor existence than is the
the first clinical manifestation-other than the apparent survival time (AST) from the initial
initial radiographic lesion itself-was a sign clinical manifestation. In other words, survival
such as segmental atelectasis or segmental ob- from the time of diagnosis may be brief, from
structive emphysema rather than a symptom. the first symptom somewhat greater, from the
Cavitation was occasionally noted. These pe- first asymptomatic phase-positive chest radio-
ripheral lesions often gave clinical evidence graph still greater, from the time of initial
of metastasis quite late in the course of the radiodetectability greater still, from the time
disease. of initial implantation quite long, and, per-
One typical patient had only a 10-month haps, from a carcinoma in situ stage very long
survival from the time of the first symptom indeed.
but a 3-year survival from the time of the first However, while a carcinoma in situ stage for
positive chest radiograph. Another, a 60-year- bronchogenic carcinoma has been demon-
old woman, had a radiographic lesion for 6 strated,l a carcinoma in situ may not neces-
years before any clinical symptoms appeared. sarily indicate a stage predating the initial
I n 1951, 1952, and 1953, the lesion was present implant. That is, rather than having a dor-
and enlarging; in 1954, it was 2. cm.in diame- mant “preneoplastic” cell that later begins to
ter; and in 1957, it was 5. cm.in diameter. The multiply, the in situ stage may be proliferative
latter 2 measurements allow for calculation from its inception. There would, then, be a
of a tumor-doubling time of roughly 270 days dissociation between growth and invasiveness,
-longer than any tD reported in my series. with invasiveness biologically or locally de-
The diagnosis was bronchiolar carcinoma. A termined after a certain period of growth. If
third patient of Rigler’s,23 a 50-year-old man, this possibility holds, the situation would be
had a normal chest radiograph in 1942, a I.-cm. that of tumor growth at a constant rate from
lesion in 1947 that overlay a rib and was ini- an initial “unicellular tumor,” with an in situ
tially overlooked, and a 5.-cm. mass in 1951. stage included within this period of constant
A thoracotomy diagnosis of adenocarcinoma exponential growth. As indicated, in most
was eventually established. The tumor-dou- instances a long silent interval or long inter-
bling time based upon the 2 measurements 4 recurrence interval is readily explainable as a
years apart is 210 days. property of exponential growth itself without
From these and similar observations, Rig- postulating true dormancy.
lerB stressed the need for a criterion of sur- Several patients reported by Overholt and
vival independent of onset of symptoms. Such Schmidt22 bear out the significance of biologi-
a criterion would correspond to what I have cal predeterminism and, in particular, the
labeled the true diagnostic gap (TDG), from the compatibility-indeed, often the association-
initial 1.-cm. radiodetectable lesion to the ini- of a long clinical duration and resectability
tial clinical manifestation, and have found to and cure. One patient was found to have a
No. 6 BIOMATHEMATICAL APPROACH TO CLINICAL TUMOR -
GROWTH Schwartz 1293
persistent abnormal pulmonary density pres- studied. I n 109 cases of carcinoma of the
ent during a 9-year period. Upon exploratory colon, the patients with the larger local neo-
thoracotomy, a resectable bronchogenic car- plasms had the better 5-year cure rate, and in
cinoma was found, and the patient was alive 1,000 patients with gastric carcinoma a n in-
and well 6 years later. Another patient had a verse relation between prognosis and symptom
silent pulmonary density that was followed for duration was found (as reported in studies of
7 years; exploratory surgery finally revealed a Brindley3 and LaDue et al.15 respectively). A
localized resectable cancer. As the authors similar paradoxical relation was found to hold
pointed out, however,22 exploratory opera- for bone sarcoma and, to a lesser extent, for
tions for clinically silent lesions can also re- breast tumors. Again the final conclusion is
veal extensive metastases. Periodic radiologi- that by the time the phase of “early” clinical
cal screening of well patients for detection of detection has been reached, the growth pat-
TDG phase silent neoplasms, then, may meet tern has been long established.
with outstanding success or with depressing
failure regardless of how early we may feel SuMMARY
the tumor has been detected. Such individual
biological factors as rate of growth (tumor- T h e major conclusions of this study may be
doubling time), the time available for metas- briefly summarized as follows.
tasis (total tumor duration), and other more 1. Constant exponential tumor growth, as
subtle and, perhaps, predetermined specific reflected in a fixed tumor-doubling time, is
metabolic factors are probably decisive. After a basic pattern of neoplastic proliferation
noting that early diagnosis may yield better throughout a tumor’s clinical course and in-
cure rates in rectal, cervical, or thyroid neo- ferentially during much if not all of its pre-
plasms but usually not in tumors involving clinical existence.
stomach, lung, breast, or pancreas, Crile’ em- 2. I n depth, longitudinal biomathemat ical
phasized: “By the time these tumors are de- study of individual patients with measurable
tectable by our present clinical methods, their neoplastic disease is feasible and provides a
biologic characteristics have sealed the pa- wealth of material relating to the natural
tient’s fate.” history of neoplastic growth.
I n another study, by Overholt and Bougas,21 3. T h e biomathematics of exponential tu-
of 51 cases of 5-year survival in patients with mor growth is readily adaptable in some pa-
lung cancer, 7 of the tumors had been dis- tients to the detection of early response to
covered on survey chest roentgenograms while cancer chemotherapy or radiotherapy, even
44 of the patients had manifested symptoms at while the lesion is increasing in size. Study of
the time the first roentgenogram was taken. postsurgical recurrence is similarly facilitated,
T h e authors further noted an ADG difference and t, may help predict response to medical
between these 51 patients and the nonsur- treatment even before its initiation.
vivors in their series. T h e average delay from 4. Spontaneous deviations from a n estab-
initial manifestation to diagnosis was 6.8 lished exponential growth pattern are rare,
months in the 51 survivors and 10.3 months even when a tumor has attained huge propor-
in the nonsurvivors. T h a t many of the 5-year tions. Apparent spontaneous variability of
survivors had residual disease is indicative of tumor growth rate is often a n illusion created
the arbitrary nature of 5 years as a cutoff by the very nature of geometric increase.
point. T h e significance of 5-year cure rate 5. Prediction of the size of missed radio-
statistics in relation to tumor-doubling time graphic lesions provides a striking confirma-
has already been discussed. tion of the validity of extrapolations from
Macdonaldle found it necessary to state, well fitting exponential growth curves.
“. . . to no small extent the doctrine of syn- 6. Separate primary tumors are, in princi-
onomy of ‘early’ treatment and curability ple, distinguishable from multiple metastases
should be recognized for the shibboleth which or from satellite lesions by the equivalence or
it is.” Carcinoma of the cervix is the only neo- nonequivalence of the corresponding dou-
plasm for which he found a relationship be- bling times.
tween size and curability. Even here, however, 7. Study of primary and secondary pulmon-
a tenfold-plus delay (12 months versus 1 ary neoplasms reveals a more than tenfold
month) was accompanied by only a 1701, variability i n tumor-doubling times, appar-
greater risk of incurability in the 225 patients ently as a n intrinsic predetermined biological
1294 CANCER
hTovember-December 1961 Vol. 14
property of the individual tumor. Experi- an “early” lesion. A paradoxical inverse rela-
mental tumors display a n even greater range tionship is often noted between resectability
of variability. and tumor size or symptom duration. Clinical
8. From a detailed analysis of the properties dormancy may, in most cases, be equivalent
of exponential tumor growth, the useful de- to extended preclinical proliferation.
rivative concepts of true and total silent inter- 10. T h e direct relationship of n-year sur-
val, true and apparent diagnostic gap, true vival to the tumor-doubling time provides a
and apparent survival time, initial implant more rational approach to the concept of
time and initial detectability, and several 5-year cure rates. Similarly, a tumor-specific
parameters of clinical observation potential and site-specific “metastatic index” based
may be derived. upon the intcrmitotic interval, total tumor
9. The long preclinical “iceberg” phase of duration, and similar growth parameters
tunior growth radically alters our concept of might be constructible.
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Cancer - November December 1961 - Schwartz - A Biomathematical Approach To Clinical Tumor Growth

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A BIOMATHEMATICAL APPROACH T O CLINICAL

D IRECT DATA relating to the natural growth

ume at time t of the second measurement;

No. cells 1,000 1,000,000 1,000,000,000 1,000,000,000,000

12. days 15.3 extent. T h e initial diameter measurements

Post.-ant. diam. vert. xhoriz. view, cm.

time while they remained nonpalpable-proof tD

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