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MARCH, 5974 TOTAL OF BODY CHRONIC IRRADIATION IN THE TREATMENT LYMPHOGENOUS LEUKEMIA* JANEWAY LECTURE, 1973 By JUAN A. DEL REGATO, M.D., COLORADO SPRINGS, COLORADO Sc.D.t I N March 1902, William Allen Pusey, a pioneer American radiotherapist and dermatologist, co-author of one of our earliest books on roentgentherapeutics, re- ceived from Dr. Jacob Frank, of Chicago, a referred patient with a diagnosis of leu- kemia: the year old man had voluminous lymphadenopathies of the neck, axillae and groins (Fig. i), plus enlargement of the spleen and liver; in addition he presented 74,000 white cells per mm.', 8o per cent of which were lymphocytes, in the circulating blood. Roentgen therapy was administered on a daily basis; the lymph nodes regressed notably within the first 2 days, the spleen diminished in size and the white cell count came down to normal limits (Fig. 2), but irradiations were continued for 3 weeks pro- ducing epilation and dry epidermitis.4' One year later, Nicholas Senn, a Chicago sur- geon, reported his experience with roent- gentherapy in a case of leukemia.44 In 1903, Efim S. London, of Berlin, pub- lished the sequence of observed events fol- lowing total body irradiation of lower ani- mals. Also in 1903, H. Heineke, of Leip- zig, produced his masterfully detailed histo- logic studies of the effects of radiations on the tissues of experimental animals.'6"7 Heineke's description of the radiation effects on lymphoid tissue has never been surpassed; he also noted the bone marrow's ability to recover. In 1904, Charles Auber- tin and E. Beaujard, made observations, in Paris, on the effects of irradiations on the blood of leukemics.' In 1906, Alfred S. Warthin, of Ann Arbor, studiously verified and extended Heineke's reported effects of irradiation on the blood forming organs.5#{176} . __.S.(;__ - r _`$1 FIG. I. Patient with cervical and axillary lymph- adenopathies from chronic lymphogenous leu- kemia, irradiated by Dr. William A. Pusey, of Chicago, in March, 19Q.41 Friedrich J. Dessauer, Frankfurt's pio- neer biophysicist, proposed in 1905, the irradiation of the entire human body (Fig. 3) by means of 3 low voltage roentgen-ray sources operating simultaneously.'2 But early enthusiasts of whole body irradiation must have been deterred by poor results and by the untoward effects on the hemo- poietic system. In 1923, Henry Chaoul, of Berlin, reported his early trial of teleroent- gentherapy in Hodgkin's disease.6 In 1925, Werner Teschendorf, of Cologne, initiated his work which was followed by his long sustained advocacy of total body roentgen- therapy for the treatment of polycythemias, * Presented at the Fifty-fifth Annual Meeting From the Penrose Cancer Hospital, Colorado t Professor of Clinical Radiology, University of the American Springs, Colorado. of Colorado. Radium Society, Colorado Springs, Colorado, April 22-26, 1973. 504 VOL. 520, No. 3 Total Body Irradiation of Lymphogenous Leukemia 505 lymphoid tumors and leukemias.47'48 Con- currently, Torleif Dale of Oslo, also applied this approach, with a higher daily dose, for the treatment of leukemias.9 In May, 1931, Arthur C. Heublein, of Connecticut, started work in a specially built unit for the continuous and simultaneous total irradia- tion of patients at the rate of 1.25 r per hour.'8 The Heublein unit, built at the Memorial Hospital of New York under specifications of Gioacchino Failla, pro- vided for continuous irradiation with auto- matic interruptions for visits by physicians, nurses and attendants (Fig. ; and 5); the patients received about 350 r in 12 days and sometimes more. Heublein died prema- turely in the course of this experiment; posthumously, his colleagues reported on its results on a variety of cases which in- cluded 27 patients with lymphogenous leu- kemia.8 At the same time Traian Leu- cutia of Detroit, made a serious analysis and defense of the relative advantages of regional radiotherapy. In the 1930S the work of Teschendorf motivated a wave of enthusiasm for sub- .N__ w.. -S- -. -t.i- Fic. 2. Same patient following regression of lymphadenopathies the axilla and chest.4' irradiation showing and epilation of total and total body irradiation in various countries of Europe: Auguste Devois" and Lucien C. M. Mallet29 in France, Max Fic. ,. Scheme for total body roentgen by Friedrich J. Dessauer therapy with 3 sources of Frankfurt, in 1905.12 as suggested 506 Juan A. del Regato MARCH, 5974 Li___ ,, , , / , / , / / I `I 1111 I / LEAD LEAD \ LEAD-h .. " III II `1 Fic. 4. Sketch total body neously.8 of the Heublein unit for continuous irradiation of 2 patients simulta- Sgalitzer45 in Austria, Felix Sluys46 in Bel- gium and many others,4#{176} variously tried and reported their results in cases of gen- eralized carcinomatosis as well as of malig- nant lymphoid tumors J oseph Belot4 in France and leukemias. and H. Fuhs'5 in Germany, treated generalized dermatoses with total body irradiation. Gian Giuseppe Palmieri'8 of Bologna, favored, as Heub- 1cm, the continuous irradiation of confined patients; Pierre Xavier Marques'0 of Tou- louse, utilized simultaneous irradiation from twin tubes for homogeneous distribu- tion throughout the body. P. Jacob19 of Nancy, proposed the irradiation of patients in a moving bed, a method that he called cineroentgent/lerapy. Daniel den Hoed" of Rotterdam, and others became discouraged by the hemopoietic injury resulting from the latent effects of what appeared to be rela- tively small doses. A review of 270 cases of total body irradiation, including 72 cases of chronic lymphogenous leukemia, treated during the decade, was published by Fred- erick G. Medinger and Lloyd F. Craver.'2 In the 1940S the tragic events of Hiro- shima and Nagasaki triggered attention to the consequences of total radiation expo- sure; the survivors of the holocaust offered sad evidence of various degrees of somatic effects of a single massive exposure to radia- tions.25 Experimental researchers, by the hundreds, undertook anew to study the radiation effects of various tissues and organs, repeating, often without gain, the overlooked or forgotten experimental work of the pioneers. Accidental irradiation of atomic scientists added to the recorded evi- dence of the lethality of relatively small amounts of radiations, when received in a short time by the entire body.2#{176} In the 1950s total body irradiation was advocated in the management of acute leu- kemias as a preliminary step to total bone marrow replacement.5"1 The procedure was well founded on experimental evidence of success in lower animals, but it was seldom successful in man; moreover, the increasing effectiveness of chemotherapy in the acute leukemia of children was soon to retire these efforts. Concurrently, Edwind E. Osgood, of Portland, Oregon, persistently emphasized the value of total body Fic. . Floor plan of the Heublein unit designed Dr. Gioacchino Failla for the Memorial Hospital New York City.8 by of VOL. 220, No. 3 Total Body Irradiation of Lymphogenous Leukemia 507 ("spray") roentgen therapy and of radio- active phosphorus administered at regular intervals ("titrated") in the management of chronic leukemias.'6"7 Vincent P. Collins and R. Kenneth Loefller7 investigated again the possibilites of single dose total body irradiation; E. Richard King con- tinued to utilize total body irradiation in the treatment of generalized malignant tumors.2' Cobalt 6o units began to be uti- lized for these purposes and special rooms were designed for the utilization of radio- active cesium i. It is of interest that those who advocate total or subtotal body irradi- ation of generalized malignant tumors,26'48 often invoke an indirect effect to explain the beneficial results of small doses. In the 19605, it was in the expectation of temporary suppression of the lymphoid and reticuloendothelial tissues, for the pur- pose of suppressing the immunologic rejec- tion of transplanted tissues, that total body irradiation was again sought."49 And here again this aid was soon renounced in favor of effective drugs. A contemporary interest in total body irradiation comes under the aegis of Civil Defense.24'42'4' RADIOPATHOPHYSIOLOGY Most of our knowledge of hematologic radiation effects is based on the results of experimental, massive, single dose total body irradiation of lower animals; the usually referred to LD50 is found from such single exposure experiments. Friedrich Ellinger'4 showed that simple fractionation decreased the mortality rate of a given total body dose. A. H. Pontifex and Leon- ard F. Lamerton'9 studied the hematologic response of rats to repeated total body ir- radiations at rates ranging from 15 to 200 r per day; they found a more rapid mortality for the higher doses, and a lesser damage or a greater ability to recover with the lower dose rates. It must be borne in mind that the time sequence may be quite different in lower animals than in man because of the differences in the cell kinetics of the hemo- poietic cell-renewal systems. The victims of the atomic bomb and the accidentally irradiated atomic scientists suffered also from a single massive expo- sure. Patients irradiated in anticipation of bone marrow replacement or organ trans- plants were usually exposed to one or two sublethal doses of radiations. A more or less intense syndrome ("radiation sick- ness") definitely dose related, may be ob- served in man; it consists of nausea, vomit- ing, fatigability, listlessness and diarrhea.2 Lowell S. Miller and associates'4 found these symptoms practically absent below a single exposure of ioo r, but rather impor- tantly disturbing in those receiving 200 r. Although the irradiation may be simul- taneous, the facts observed in the periph- eral blood do not occur simultaneously for they result from the effects on different hematopoietic cell lines with their own dy- namic balance. Half a century ago, George R. Minot and Roy G. Spurling'5 made a collective study of 42 patients with various forms of cancer, regionally irradiated with rather large fields. In patients in whom they observed relative leukopenia they found its extent and the patients recovery directly related to the size of the field of irradiation and to the dose administered. Maurice Tubiana and Claude M. Lalanne49 contrasted the hematologic effects observed in patients who received 400 r or 100 r (Fig. 6) at one sitting: the drop in the numbers of total leukocytes, of lymphocytes and platelets, which occurred in both, was faster for the larger dose; recovery was manifest after the third week, but it was more vigorous in patients receiving the smaller dose. James Adelstein and James B. Dealy, Jr.' studied 6 patients who re- ceived an initial total body dose of 250 r; they found the half-reduction time for lym- phocytes to be days, for granulocytes 6 days, for reticulocytes 10 days and for platelets i6 days. There are no studies available of the effects of fractionated total body irradiation of normal persons over a period of weeks or months. MATERIAL AND METHOD Our experience with total body irradia- 508 Juan A. del Regato MARCH, 1974 platelets I' `S 1% I' `I a U I0 `S 1 I I S / I I "II, I I I I S I' I II a .a! a tine after initial irradiation (days) Fic. 6. Peripheral blood changes observed in a normal individual submitted single total body irradiation of ioo r (from Tubiana and Lalanne'9). to a tion of patients with chronic lymphogenous leukemia is reported here for the first time. We carried out total: body irradiation in the late 1930s, but have lost contact with the patients' records. This report is based on i patients irradiated at the Ellis Fischel Can- cer Hospital of Columbia, Missouri, from 1943 to 1948, and on 46 additional patients treated at the Penrose Cancer Hospital of Colorado Springs from 1949 to 1969. Thirty-seven of these patients were males and 24 females; the youngest was 3 and the oldest 84 years of age; both the median and average age of these patients was 64 years. Patients whose treatments were started in the past 3 years are not included in this report, for some are still under treatment. Patients receiving only regional irradia- tion were excluded. Two patients who died of concurrent metastasizing cancer, one of the bladder and another of the prostate, were not included; i who had had cancer of the breast, but who died of leukemia was retained. Two patients with congestive heart failure who could not stand the treat- ments were eliminated from consideration. Thus, this is a selected series. In the 30 years of this experience we have diagnosed and followed a number of symptomless patients who received no treatment or only occasional regional ir- radiation; they constitute a more favorable group than the one subject of this report. The disease is often insidious, but not al- ways slow in its development. All of the patients had repeated con- firmatory bone marrow biopsies. In 8 of our patients, who had started their clinical course with a peripheral lymphadenopathy, a biopsy had been done and a diagnosis of "malignant lymphoma" (lymphocytic, re- ticulum-cell, histiocytic, lymphoblastic) had been rendered; in 2 patients such diag- nosis had been made on a surgical specimen of the cecum. We have long maintained that a diagnosis of malignant lymphoid tumor in a lymph node should be challenged Voi.. 120, No. 3 Total Body Irradiation of Lymphogenous Leukemia 509 t7 16 144 12 112 0 0 o 96 m 80 E (`Sc" 11222 154$ 32 PC H 52-847 1912 16 S. 8 0 30 60 90 120 150 180 210 240 270 300 330 360 tiMe after initial irradiation (days) lIG. 7. Observed changes in the tota' white blood cell count of 2 patients during the first ear of irradiation. if the clinical character and course of the case are at variance with what one expects from generalized lymphosarcomatosis. Ad- vanced age, preserved general condition in spite of large masses and long course, maintained weight, symmetry of lym- phadenopathies, etc. should bring suspicion that a histopathologic diagnosis of "malig- nant lymphoma" is probably in error. The accommodating theory that malignant lymphomas may "turn into a leukemic phase" simply contributes an often con- venient white-wash for too categorical an initial diagnosis of tumor, where vacillation would have been justified. Equally accom- modating and unproved is the concept that lymphosarcoma and leukemia are but colors of the same rainbow. As a result, clinicians everywhere fail to acquire a clear concept of the differences involved and the confusion distorts our statistics of results. In malignant tumors of the lymphoreticular system, clinicians and pathologists have failed to exploit the modifying light of con- tributory clinical details, as they have in bone tumors; internists seem to expect, and accept without dispute, the morpholo- giSts word as definitive. Yet, it remains a fact that without clinical information to help him the histopathologist may be en- tirely unable to exclude leukemia on a biopsy of a lymph node. When we began our experience, we chose to deliver a short series of daily total body treatments with the intention of repeating it at long intervals; in other cases we gave smaller amounts daily for several weeks. Some of our earlier patients treated at the Ellis Fischel Cancer Hospital received only repeated discontinued series lasting about JO days, but no weekly irradiation. Once we became aware of the relative safety of our doses, we decided to start with a series of 10 daily total body irradiations and to 510 Juan A. del Regato MARCH, 1974 I' 72 It I' 66 `` 2 60 I' g I, t 54 %I% `i 8/ I 1 LV M PHOCYTES i number 2o,, I I $5 , I 5, 5I, I %g t, 5, I $ II,' ` I I `5 I S 8 5, A I' g Ij % I. !36 .0 30 E 3 24 18 PC" 53-758 1953 96 88 90 I I S % I- # I S S I S I S 72 64 56 0 48 `O 36 24 12 6 3 0 30 60 Fic. 8. Although in this patient 90 120 150 180 210 time after initial irradiatIon 240 (days) a,u iou the total number of circulating white blood cells was diminished during the first year of treatments, the peripheral lymphocytosis $2 jju i considerably persisted. follow this by a weekly irradiation. In due course we decided to repeat an annual course of the same order as that of the initial series. In summary, our procedure consists of the following: i. a series of io daily irradiations of 10 r 2. one weekly irradiation of r 3. regional irradiation of spleen or lymph nodes as required 4. an annual "booster" of io daily ir- radiations of 10 r. Our purpose is to maintain all patients under this regimen for their life time. We have found the procedure safe and satisfac- tory. In this series of patients the total dose received varied, of course, with their sur- vival: the maximum was 2,760 r in 7 years; another patient received 1,870 r in 6 years; 2 had nearly I,2oo r in 4 years; 6 others received between 900 and i,ioo r in 3 to 3 years. For a long time our patients were irradi- ated at 2.30 m. target skin distance, with a 250 kv. unit, operating at i#{231}ma. with 2 mm. of copper and i mm. aluminum filtra- tion; patients layed recumbent on the floor with their knees flexed and received oblique irradiations frontolaterally, alter- nating sides for homogeneity. Presently they are irradiated with a cobalt 6o unit, in the sitting position, at 3.10 m. source skin distance. The doses are calculated at the surface of the skin without benefit of back scatter. An integral dose, ideally de- sirable, is difficult to establish; the distri- bution of doses in the trunk of a phantom reveal a coefficient of homogeneity of 0.87. Irradiation of the spleen has often to be done also; it is our feeling that the spleen should be irradiated without waiting for it to become uncomfortably large and sub- ject to infarction. The dose administered to the spleen need not be large, and should not be, to allow for re-irradiation when it be- comes necessary again. Irradiation of cer- vical, axillary, inguinal or abdominal VOL. 120, No. 3 Total Body Irradiation of Lymphogenous Leukemia 51$ 100 PC" 62-854 19*2 H E E S.5 a .0 15 E 3 C 12 ,__... / / / 9 6 3 LYMPHOCYTES 1 number 2 percent / S. , , `I `S. S. 2 S. S. 88 80 72 64 % 56 48 40 32 24 16 8 0 30 60 90 120 150 180 210 240 270 300 330 360 time after initial irradiation (days) Fic. . Total body irradiation of this patient was followed by gradual lymphocytes and in their relative percentage in the peripheral increase in the number blood cell count. of lymph nodes may also have to be done to eliminate discomfort. Regression of these lymphadenopathies takes place rather promptly and the total dose necessary for complete regression may be less than mod- erate. All our patients were kept under close hematologic surveillance, receiving medical treatment as became indicated. Hospitali- zation and antibiotic therapy were readily available to them, since they are often sub- ject to infections. RESU LTS Chronic lymphogenous leukemia is an incurable disease; results of treatments can only be evaluated on a relative basis. An expression of "remission" requires tion of a concept of such remission definiwhich may be thought self-serving. Very few of our cases had periods in their course when their chronic lymphogenous leukemia was not diagnosable. All of the 6i patients sub- ject of this report have died: the longest sur- viva! was 15 years, the shortest 2 months; the average was ,t6 months, and the median 39 months. The 5 year survival was 21 per cent (Fig. 12). There were 39 patients with elevated white blood cell counts at the be- ginning of treatments; their average sur- viva! was 5! months. The 22 other patients had normal or subnormal white blood cell counts in the peripheral blood: their aver- age survival was38 months. In 7 patients in whom the differential white blood cell count never showed a percentage of lym- phocytes above 50 per cent, the average survival was only 26 months. The hemopoietic response, as measured by the peripheral blood cell count revealed a frequent decrease of leukocytes when the original count was high, coming down to normal limits within a few weeks and some- times below normal; but in other instances the leukocyte count remained high or even increased during the course of treatments (Fig. 7). In patients who presented a nor- mal or subnormal initial white blood cell 512 Juan A. del Regato MARCH, 1974 16 (FSCH 14 10561 1948 12 0 0 1C 0 8 6 I / PCN 4 2 S,," HEMOGLOBIN / S./ S. ` `I V 30 60 90 120 150 180 210 240 270 300 330 360 time after initial irradiation (days) Fic. 10. The hemoglobin was not affected by total body irradiation at therapeutic levels. represent variations observed during the first year in 2 different patients. These 2 curves PC" 53-738 1953 0 0 0 9- H E E 2 E PLATELETS Fic. ii. A gradual decrease body irradiation, time after initial irradiation (days) in the number of circulating platelets is often observed sometimes to very low levels, but without bleeding during the course of total consequences. VOL. 120, No. 3 Total Body Irradiation of Lymphogenous Leukemia 99 (I) Iz- LU 84 a. -J 1 50 U- 0 I- z 16 LU (.) LaU. 1 SURVIVAL FROM DIAGNOSIS 61 PATIENTS DEAD WITH DISEASE ELLIS FISCHEL & PENROSE CANCER 1943-1969 HOSPITALS MEAN SURVIVAL 94TH TINE PCTL IS 76N0S IS 45.9 _MOS 30TH PCTL IS 39 16TH CTL IS 11 Mo:g_o 0cP#{176} #{149}_MIN IS 2 NOS GAP 0_..MAX IS 13 YEARS 0 0 0 & o0 0 0 PLOT OlDER OF STATISTICS YEAR SURVIVAL IS 21% HETEROGENEOUS CUMULATIVE DISTRIBUTION OF SURVIVAL TIMES 5,3 TIME Fic. 12. Cumulative distribution State Cancer Hospital (i 10 AFTER INITIAL 100 DIAGNOSIS of duration of survival from date of diagnosis. patients, 1943-48) and Penrose Cancer Hospital (MO S) 1000 Pooled data of Ellis Fischel (46 patients, 1949-69). count normal initial often there was levels or percentage unaffected often a reduction no change at of lymphocytes by irradiations to sub- all. A high was most in spite of an absolute decrease of all leukocytes (Fig. 8). Some patients who had an initial normal percentage of lymphocytes underwent a gradual increase to high levels (Fig. 9). In Fic. 13. Extensive infiltration of kidneys is frequent. Routine mild irradiation of these organs may be as justifiable as the irradiation of the spleen. Fic. 14. Infiltration at autopsy and frequent death of the lung is frequently may be in part responsible through pneumonia. found for the 514 Juan A. del Regato MARCH, 1974 .5.- I' I' 9 `I #{149} 8 Fic. i. Meningeal genous leukemia. mimic a stroke. infiltration by chronic lympho- Intracranial manifestations may Fic. 17. Leukemic infiltration of the small intestine may suggest a primary tumor of that area. The same is true of the cecum. a few cases the normal percentage of lym- phocytes or the lymphopenia persisted or became worse. In very few cases the ini- tially normal hemoglobin or hematocrit came down (Fig. io); some patients necessi- .: V... -. #{149} . . ./4' ?,4I.. 5_- ..`#{149}-`.- . -.- -. - - #{149}_,,#{149} .. ... .... .-.`--..`.#{149} - ....-. -` . - . . .. . : .1 #{149.} ` #{149} ---.: I -- . -.-5r#{149}-. `9---- FIG. i6. Pericardial infiltration leads to effusion and possible tamponade. Fic. 19. Higher magnification of bone marrow in another total body irradiation for of 2,760 r. of autopsy specimen patient who received over 7 years to a total VOL. 120, No. 3 Total Body Irradiation of Lymphogenous Leukemia 99 Cl) Iz- LU I- 84 a. -I -J 50 U- 0 I- 16 (U) 1 SURVIVAL FROM DIAGNOSIS 46 PATIENTS DEAD PENROSE CANCER 1949 -1969 WITH DISEASE HOSPITAL S S 0000 o0 .#{149} S S 4- GAP 0 0 PLOT ORDER OF STATISTICS HI TEROGENEOUS CUMULATIVE OF SURVIVAL DISTRIBUTION TIMES 515 lU 100 100(1 TIME AFTER INITIAL DIAGNOSIS (MOS) FIG. 20. Cumulative distribution of duration of survival Hospital only). If the durations of survival of patients the shape of the cumulative distribution suggests that The relative width of the gap permits the hypothesis rejected with the probability of Type i error of 0.02. from date dying with the corresponding of unimodality of diagnosis (data of Penrose Cancer leukemia are distributed log normally frequency distribution is bimodal. of the frequency distribution to be tated transfusions or steroid therapy. Platelets frequently decreased in numbers, rarely to very low levels (Fig. ii). Although low platelet levels persisted in some pa- tients, there were no bleeding tendencies ap- parently related to it. In only one instance of a patient with initial low platelet count, was there further decrease and some subcu- taneous ecchymoses before death; the au- topsy revealed massive bone marrow leu- kemic replacement. The palliation afforded these patients was often immediately acknowledged. The pa- tients seem to be comfortable until the inevitable terminal complications occur. A large proportion of these cases died of pneu- monia and other infectious complications compounding the pathologic talley of their advanced age; there was one instance of cardiac tamponade due to pericardial effu- sion. In 20 cases an autopsy was done; the postmortem findings varied, but as a rule there was leukemic involvement of various organs in addition to multiple lymph node enlargement and splenomegaly. In most in- stances infiltrates were found in the kidneys (Fig. 13), liver and lungs (Fig. 14), and occasionally also in the meninges (Fig. ii), thyroid, pleura, pericardium (Fig. i6), adrenals, stomach, small and large bowel (Fig. 17), bladder, and prostate. In no in- stance were there signs of radiation effects or injury of the bone marrow or other struc- tures examined; patients who had received total body irradiation for several years had rather healthy appearing bone marrows except for the present leukemic infiltrates (Fig. i8; and 19). 516 1000 Juan A. del Regato ASSOCIATION OF SURVIVAL & INITIAL 47 patients dead with disease PENROSE CANCER HOSPITAL 1949 - 1969 MARCH, 1974 WBC aos contour ellipses (I) 0 E 100 0 (I) (I) 0 C (5 V E 10 0 Group I, GM SURVIVAL: 41, GM.: 27300 MOE MM3 (5 Group 11 GM>1 SURVIVAL: 4.2 MOS GM WBC : 11300 MM3 U) GM. GIOMITIIC NIAN 1 10 INITIAL WBC 100 (N/mm3 x 1000) 1000 Fic. 2!. Bivariate distributions of logio (duration of survival from diagnosis) and loglo (WBC at diagnosis). (Data of Penrose Cancer Hospital only.) The pattern suggests that this bivariate distribution is hetero- geneous. The hypothesis that the point-biserial correlation coefficient for WBC and the 2 survival groups is zero can be rejected with probability of Type I error of 0.05. (The point-biserial correlation coefficient measures the strength of the linear association between a dichotomous and a continuous variate.) PROGNOSIS The data presented result from a retro- spective survey of clinical information gathered over a period of 25 years. The sample of selected patients is relatively small; no random alternatives were used. However exiguous, any experience of this order represents considerable painstaking effort and expense. Therefore, one is ob- ligated to analyze thoroughly the material and to extract any plausible, however tenuous, statistical suggestion which might reveal unsuspected variations and lead to a greater understanding of the problem at hand. If the duration of survival of all of our patients, dead with leukemia, is distributed log normally (Fig. 20), the shapes of the cumulative distribution suggest that the corresponding frequency distributions are bimodal and that the sample is heteroge- neous. There appear to be 2 groups of pa- tients in the sample judging by their re- sponse to total body irradiation and their median survival. Other univariate and bi- variate analyses of the material can be adduced in support of this hypothesis (Fig. 21; and 22). It is natural to seek some em- pirical method of identifying, a priori, members of these 2 hypothetical groups. A decomposition of the bivariate distribution VOL. 120, No. 3 Total Body Irradiation of Lymphogenous Leukemia HYPOTHETICAL SUBGROUPS PROGNOSTIC 41 patients dead with disease Penrose Cancer Hospital 1949-1969 517 1008 `4 (8) E #{149},+ - survival 7 patients 9mos o- survival14mO5 35 patients C) 10 10 100 PLATELETS N/mm 3x1000 FIG. 22. Bivariate distribution of initial values of logio (WBC) and logio (platelet). The arrow I is parallel to the linear discriminant function for the 2 variates. L is the value of this linear form which best discriminates between the 2 response groups. Q, Q' are values of the quadratic form which best discriminates between the 2 response groups. The 2 histograms erected upon the Line represent the marginal distributions of the values of the linear form in the 2 response groups. The hypothesis of homogeneity can be tested by a measure of the overlap of these marginal distributions. `I'he hypothesis is rejected with a probability of a Type i error of 0.05. of initial white blood cell and platelet counts according to survival after total body irradiation is shown in Figure 22; these 2 variates were selected on the basis of the strength of their linear association with the 2 survival groups (point-biserial correlation). Linear and quadratic forms discriminate moderately well between the 2 survival groups, but the size of the sample would not permit a realistic appraisal of the size of the possible error. A decomposition of the distribution of survival times shown in Figure 20 is pre- sented in Figure 23: there seem to be 2 dif- ferent homogeneous groups in reference to survival. The analysis of the survival data suggests the existence of 2 different groups of pa- tients with chronic lymphogenous leu- kemia. Others have found suggestion for subgrouping in serial studies of bone mar- row. Juan A. del Regato MARCH, 1974 99 `4,) I- z 84 SURVIVAL FROM DIAGNOSIS 46 Patients dead with disease Penrose Cancer Hospital 1949-1969 Plot of order statistics Cl 50 50TH 4.2 S 16 7 PATIENTS 50TH PCTL 42 MOS Homogeneous Cumulative Distributions of Survival Times GROUP II 39 PATIENTS 10 CJC' 95% confidence limits on GROUPI cumulative KOLMOGOROV distribution - SM1RNOV) 10 100 1000 TIME AFTER INITIAL DIAGNOSIS (M0S) Fic. 23. Cumulative distributions of duration distribution of Figure 20 has been decomposed of survival from diagnosis into a superimposition for 2 groups. The heterogeneous of 2 homogeneous distributions. EN VOlE Our experience would appear to justify a more aggressive irradiation in the hope of better results. In the past we have found the margin of safety of total body irradia- tion to be rather narrow. Someone with a lifetime ahead might wish to explore the possibilities of larger doses again. Whereas total body irradiation seems useful, primarily because it allows regional it is so irradi- ation at longer intervals and with less than customary intensity. It would appear that irradiation of organs found frequently in- volved at autopsy, before ment has become manifest, their involvemay be well justified in order to allay the advent of complications and to prolong life. Thus, total body irradiation could be system- atically complemented by periodical re- gional irradiation of kidneys, lungs, liver, as well as of spleen and lymphadenopathies; the doses be rather repeated necessary moderate, at intervals. for these permitting purposes their may being CONCLUSIONS i. Total body irradiation is a satisfac- tory procedure in the palliative treatment of chronic lymphogenous leukemia. 2. An initial series of io daily irradia- tions of io r may be safely followed by weekly exposures of r and annual "boost- ers" of ioo r delivered in io days. Patients have been kept on this regimen for periods of to 7 years. 3. In a series of #{244p}aitients so treated the average survival was 46 months, with a maximum of 15 years, a minimum of 2 months, and a year survival of 21 per cent. 4. Autopsies performed in one-third of these patients failed to reveal one instance of untoward radiation effects. VOL. 120, No. 3 Total Body Irradiation of Lymphogenous Leukemia 519 5. Total body irradiation has to be corn- plemented by regional irradiation of spleen and lymphadenopathies. Those organs fre- quently found involved at autopsy such as kidneys, lungs, etc. should perhaps be simi- larly irradiated at very moderate doses. 6. Statistical study of the survival data suggests the presence of 2 different sub- groups in the sample. Clinical Penrose Colorado Radiology Cancer Hospital Springs, Colorado 8oo7 The observations which form the basis of this lecture have been patiently gathered over the years by my faithful associates and by dozens of our residents in training: it is their work that I have presented. For the analysis of the data and the preparation of statistical illustrations and the statistical hypothesis, I am indebted to Don Herbert, Ph.D., and for the photo- micrographs, to Don Dawson, M.D., both of our staff. Richard A. Smith has been most patient and helpful in the drawing and lettering of illustrations. REFERENCES I. ADELSTEIN, S. J., and DEALY, J. B., JR. Hemato- logic responses to human tion. AM. J. ROENTGENOL., whole body irradia- RAD. THERAPY & NUCLEAR MED., 1965, 93, 927-934. 2. ANDREWS, G. A., COMAS, F. V., EDWARDS, C. L., KNISELEY, R. M., LUSHBAUGH, C. C., and VODOPICK, H. 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