Document 375v13KKr5Kag4BoRQYq7xaRa

r 7/ 0 The prognostic value of measuring the gross linea# radial growth of pulmonary metastases and primary pulmonary cancers PLAINTIFFS exhibit The gross rates of growth ofpulmonary cancers and pulmonary metastases may be reduced to clinically useful nomograms and graphs. The constructs are feasible because most neoplasms growing in the lung are observed only during a limited segment of their life history, often being observed loo few times to permit the identification of the growth curve of best fit. Consequently, the parameter that can be calculated most quickly, namely linear radial growth rate in mm.Iday, may be most useful. The linear radial growth rates are plotted against observed survival. The nomograms permit easy approximation of the volume doubling time and the exponential radial growth rate in mm.lmm.lday. The medn of the log normal frequency distributions of doubling times for common primary and metastatic cancers found growing in the lung is plotted on one nomogram to put the information in perspective. The more widespread reporting and tabulation of such data should lead to a highly useful kinetic staging and treatment evaluation system. John S. Sprau, Jr., M.S.P.H., M.D., F.A.C.S., and John Arthur Spratt, B.A.. Columbia, Mo. Thhe one characteristic known to be common to all cancers is growth. Until recently, this characteristic has been described in subjective terms like "fast" or "slow," but the actual rate of growth has been re corded infrequently. A brief summary of the utility val ue of knowing the rates of growth is given in Table I. Growth of any cancer fits into a kinetic model determined by many variables acting simultaneously to effect a net rate of increase or decrease in the total mass of a cancer. The kinetic model is depicted in Fig. 1. Beginning in the early 1960's, we have been able to accumulate considerable data from several roentgen files. Clusters of observed growth curves measured for 22 primary lung cancers of different histologic types and of pulmonary metastases have been previously From the Cancer Research Center and the Ellis Fischcl State Cancer Hospital, Columbia. Mo. This investigation was supported by the Public Health Service Research Grant CA-08023 from the National Cancer institute. Received for publication May 28. 1975. Address for reprints: John S. Spratt. Jr.. M.D.. Cancer Research Center. Business 70 and Garth Ave.. Columbia. Mo. 65201. Director, Cancer Research Center, and Chief Surgeon, Ellis Fischel State Cancer Hospital. published.-8 The dimensions of roentgen shadow: recorded at different times for growing cancels cat it: measured by calipers. Though radiographic geomen factors affect actual size, the rate of change is M significantly affected by these same factors if ruetupa j techniques remain constant. We have now measwif ] hundreds of different cancers growing in the lung, i bones, the breast, the lymph nodes, and the oi*. j Furthermore, numerous review articles on compkaj tions of similar observations are beginning to actus* j late. The more completely and comprehensively w* data are reported, the sooner it will be feasibk * establish a kinetic Classification for benign malignant neoplasms that will explain many behaoua characteristics of cancers not elucidated by aiuliou and morphologic classification systems. ConcUti between kinetics and morphology remains hig*desirable to make maximum use of past chw] experience largely based on gross anatomic microscopic morphology. The gross rates of growth are measurable in oaul segment of the entire period of growth. This segaal exists between the threshold diameter of radiogram] visibility and the prelethal diameter which 274 NOT,\ ti ;;z MAlEP.iAL f.'AY EE PROTECTED BY C-'MI'VlMCHf LAW \;l.LG 17. U. S. CODE) 6113 18097 t grov such i nock ItWfccn the (selected ; becomes : segnw appro *-} *-t <976 V % GY< >wth ofpulmonary metastases andpulmonary cancers 275 Host dettrmmoott of growth Nutrition iinmunn rostromH Chorocteristics of cells of origin Endocnnt facto** 1 INCREASING MASS AT NET GROWTH RATE f --------?---------- --r- GENETIC PREDIS POSITION INDUCED ENVIRON MENTAL DETECTABLE SYMPTOMATIC LETHAL I OR ENDOGENOUS CARCINOGEN t Re. I. Kinetic rrKxlel of an untreated cancer. A solid cancer growing in the lung is a dynamic mass of tissue on jl'il uhich many factors are acting simultaneously. These variable factors produce a net effect on growth which produces grossly measurable grmuh rates characterizing various cancers (and pulmonary metastases) and affecting longevity. V.i-mc obscured by confluent growth of multiple ____ atwases or by secondary events such as pneumonia -n shadows atelectasis in the lung. icers can he jSgt. A'previous report* indicated that the radiologist c geometric Sgi* *riy sees pulmonary metastases at sizes less than 6 ange is not mSI tm (a size obtained by 26.7 net doublings of a 1.000 if roentgen act!!) and never at sizes less than 3 mm. They arc not 'V measured i'jSB arrnlariy visible until they reach 10 mm. in diameter, he lung, the At these metastases grow, the untreated host will not two times, before and affer a span of time adequate for growth, as is the situation in many cases. Thus arguments over whether the growth is logarithmic. Gompertzian, linear, or other are often impossible to resolve in the clinical setting because of the short period of observation relative to the total life history ofthe neoplasm. Furthermore, there are good animal models of solid tumors which suggest that radial growth really is linear during this segment of spherical cancerous growth if continued cell duplication is re stricted only to an advancing margin of active growth while the center becomes dormant and necrotic. In fact, Mayncord4 provides very sound observations that the radial growth of at least some cancers is linear. He. observes that Jensen's rat sarcoma increases linearly with time, not exponentially. He developed a mathematical theory that satisfactorily explains the observed linear growth. The explanation hinges on the observation that active cellular proliferation occurs only in a thin outer shell of a spherical cancer with the central cells being cither dormant or necrotic. With these points in mind, we re-examined data previously reported. Several years ago, the foremost concept was doubling time. We have recalculated the growth in millimeters per day of radial growth and correlated that growth with observed survival from a ECC2742 6113 18098 276 Spratt and Spratt Tho Joutn* a Thoracic and Caroovakuar Fig. 2. This scalier diagram compares the correlation between the linear radial growth rate of the fastest growing pulmonary metastasis with the duration of host survival. The duration of survival has been corrected for the observed rate so that survival is plotted from a common size, a greatest chordal diameterof 10 mm. The scatter diagram defines the limits of lethality based on the linear growth rate. Table 1. Clinical value of knowing the growth rate of pulmonary neoplasms (metastatic and primary) Differential diagnosis Prediction of longevity Evaluating and planning effective detection programs Planning therapy Evaluating therapy Correlation of gross rates of growth with cellular kinetics Improving understanding of the natural history of cancers w ith prevention or suppression of neoplastic growth being litc ultimate objective common poini. The common point is aTadiogruphic density with a diameter of 10 mm. (Fig. 2). To calculate the linear radial growth of a cancer, one need only use a standard rate formula: radial growth rate <nun./day) where the diameter at the first measurement (d,| a. subtracted from the diameter of the second measure ment (dj). The difference is divided by 2 to give u* radial change. This, in turn, is divided by the number , of days elapsing between the first and second observe . tion to give the linear growth rate in mm./day. With exponential or geometric growth, the line* radial rate increases as the sphere e llarges. if the radial rate is expressed as a geometric rate (mm./mm./duo. this apparent increase in growth ate with incrcinaj size remains constant. Several simple nomograms are needed to display the interrelations among tinic. size, tales of growth. *al survival. The first nomogram developed relates radii growth rate in mm./mm./day and doubling times w tumors of different radii to the linear radial growth rue I (mm./day) (Fig. 3). Tliis nomogram will permit the crude but rafl approximation of the exponential growth rate d spherical cancers for which two measurements J diameter or radius are available at two different pints in time. Time intervals must be great enough topers* measurable growth. To use. calculate, the linear radii growth in mm./day. Next, add the diameters measutt* at points a and h and divide by 2 to obtain the miilpux diameter. Divide this diameter by 2 again to obtaintk midpoint radius. Select the point on the nomogr* where a vertical line from the mm./day intersects at line most closely approximating the midpoint radi* Lixtend a line horizontally to intersect the equips exponential growth scales giving the exponential rai* growth of the cancer in mm./mm./day and the *a* giving the doubling time in days. The relation between the number of doubling k survival for pulmonary cancers and metastases it been published previously. A scatter diagram shnJ{ the relation between linear radial growth (mm.ili' and host survival is given in Fig. 2. This diagrams particularly useful for predicting the minimum a. maximum duration of survival of persons haU| pulmonary metastases of known linear growth rate A second nomogram with added data of tlmu value is given in Fig. 4. This nomogram penutbfc direct conversion of the exponential radial grtmlii mm./mm./day) and host survival is given in Fig This diagram is particularly useful for predicting * minimum and maximum duration of survival persons having pulmonary metastases of known i.tu growtlt rate. A second nomogram with added data of de value is given in Fig. 4. This nomogram pernut-t direct conversion of the exponential radial grave 6113 18099 ii`x*C2743- "4 'nifT40 1 * <ri id,) a) casun i ve lumber^ bxerrvJ linear! e radial] i. /day ),"i rcasinf^ 3 . 1976 lifV y, Pi Growth of pulmonary metastases and pulmonary cancers ' 277* ilny I ih. and' v radial/ me* fof| vth i fir it rapid; rate nf| ents cfjj t point* * i permit j r radial! casurrd'! Cl nogram ,-cts the j radiut. n valent fifa ;l radial Zf. le scalej ingx l?1 scs hat i howinf; n./dny) gram it = Jtn and having. rate. clinical ] nits the i iwth in jj,{3 Fig. 2.:.^ ring the , ival of n linear, clinical jhe in ,ci Fig. 3. To use this nomoeram. calculate the linear radial growth rate in mm./day as described in the text. Similarly, determine the length of the radius midpoint between the two measurements of tumor size. TYc slanted lines are the nomograms for the midpoint radii: Protect a vertical extension from the calculated growth rate Imm./day) to intersect the line most closely approximating the midpoint radius. From this intersect, extend a line horizontally to obtain an approximation of the doubling time on the left. By extending the horizontal line to the nght. one can obtain the exponential radial growth in mm./mmjday. J000 5 500 1 Slower hnn this n lung -- usuOlly bntqn 100 50 r'mnry r hon'lrosnrComo* n bon* Primoty ad^nocorcmoma* Metastatic adenocarctnomasfcoioa ond rectum) _E pid^fmoid cancer* of the lung . Vflonnmo* Metostotrc opi-t* Metasiatrc sarcoma* Primary wing s and o*teogentc sarcomas Metastatic Ewmg'j and osteogenic sorcoma* 10 No metostosis or cancer actually observed., to grow foster than this if 'aster thon this, suspect inflammation, effusion or edema statistical motimum growth rote with 99% confidence 10 50 100 500 1000 EXPONENTIAL RADIAL GROWTH (mm/mm/day)*K)*4 10000 Fig. 4. This nomogram relates the lime n->|uiu-d m das s lor a cross ing spherical eanecr to double its volume to the exponential radial growth rate in nun /mm /das My multiplying the exponential radial rate by 3 and moving the decimal place to the right three places, still an additional parameter is obtained--the net gain in cancer cells per thousand existing cancer cells per das. ^ VI BGC2744 6113 18100 278 Spratt and Spratt mm./mm./day to the time required for the volume (o double, but the line of intersection reports the mean rates for various types of cancers and metastuscs that have been observed to grow in the lung.-* As a basis of comparing the linear radial growth rale of cancers to the linear growth of a non-neoplastic epithelial tissue in an adult, we can look at the data on the growth of William Bean's left thumbnail. Secular trends in growth of my thumbnail are reported. Various observations, including slowing on the rate of growth with infections, arc recorded. The slowing of the rate of growth has progressed in somewhat irregular phases. This is a phenomenon that most people observe if they care to introspect themselves as they participate in the aging process. The average daily rate of growth has varied Inmi 0.123 mm. per day when I was 32 to 0.100 mm. when 1 was 61.* Throughout a 30 year period the growth was much faster than that observed for the cancers measured in this study. Cancer tissue may frequently grow more slowly than normal tissues, rather than more rapidly. The difference between cancerous and normal tissue is more a matter of control and organization than of rate. During the period of clinical observation, it might prove useful to be able to quantitate a slowing of growth rate as a parameter of effective therapy. This might be particularly useful with chemotherapy. A slowing of rate might be an indication for continued therapy. An acceleration of rate would certainly merit a consideration of stopping the treatment. In the case of surgical resection of metastases, survival in excess of the maximum survival to be expected for a metastasis with a known growth rate would serve as an index of therapeutic success. The data in this study ail apply to untreated cancers. Short-term betterment of survival in categories of cases of similar size and linear growth rate would be From Bean, W. B.: Arch. Intern. Med. 134: 497. copyright 1**74. American Medical Association. The joutcj 3 ' Thoracic and CardevutJ* - I necessary to show the longevity benefit of ncwtjpmf therapy. When present, many of these benefits are sh, Us i term. For example, 200 days of comfortable life attic end stage of cancer is superior to only 100 days oL`1 progressive dyspnea prtxluccd bv the sustained grua ' j of cancer. However, such short-term evaluation vnsut be facilitated by a kinetic staging1 system based growth rate and mass that is applicable to indivaiud '| I ten rear* cases. /* tp^cur, Khl-FRHNCES 1 Bean. W. B.: Nail Growth: 3*1 Years of Obscruu*.. Mr Wt. Arch, intern. Med. 134: 497. I`*74. 2 Bean. W. B.: Nail Growth: A 1 wcnty-Year Study. AulhJ Intent Mill. Ill: 476. 1963. . j, 3 Kusaina. S.. .Spratt. J. S...Jr.. Doncgun. W. L.. F. R .. and Cunningham. C.:Thc Gross Rates of GnmiH Human Mammary Carcinoma. Cancer 3<h S94. 1972. 4 Mayiicoiil. W. V.: On a Law of Growth of Jensea's&l .1 Sarcoma. Am. J. Cancer 16: 8--I, 1932: "jl ItUgl rpt*>r gt ft 5 Spratt. J. S.. Jr., Ter-Pogossian. M., and Long. R. T l~`j The IX-tcction and Growth of Intrathoraric Neopta* J l ower Limits of Radiographic Distinction,^ the Amina-1 lent Si/e. the Duration, and he Pattern of Gnmtkt Determined by Direct Mensuration of Tumor Diane From Random Thoracic Roentgenograms. Arch. Surf He. 2X3. 1963. 6 Spratt. J. S.. Jr.. Spjut. H.'J.. and Roper. C. L: Ik' Frequency Distribution of the Rates of Growth and tk I.Mounted Duration of Primary Pulmonary Culunucj*. C ancer 16: 687. 1963. 7 Spratt. J. S.. Jr., and Spratt. T. L.: Rates of Grunina Pulmonary Metastases and Host Survival, Ann. Surg 191 j 161.' 1964. 8 Spratt. J. S.. Jr.: The Rates of Growth of SLofla I Sat comas. Cancer 18: 14. 1965. 9 VVi-lm. S.. Yourkcr. J.. and Spratt. J. S.. Jr.: RatorK j Patterns of Growth of 375 Tumors of Large inicsuiwi Ri-cium Observed Serially by Double Contrast tan | Study (Malitin Technique). Ant. J. Roentgenol. R.c-a j Ther. Nml. Med. 90: 673. 1963. Ul C+ aver [faien ILSI puinii igi Ot : buci IMo i In alic ymj in sjneta it Di J969 jWere tines [often r 4*1 BGC745 6113 - ait.. 18101