THE CARBOHYDRATE TOLERANCE IN CANCER PATIENTS, AND T H E EFFECT UPON I T OF ROENTGEN

RAY RADIATION

F. H. L. TAYLOR, PH.D., AND HENRY JACKSON, JR., M.D.

(Front tlae Pondville Hospital and the Thorndike Memorial Laboratory, the Second and Bourth

of Medicine, Harvard Medical School) Medical Services (Harvard) of the Boston City Hospital, and the Departmmt

There has been much investigation of the carbohydrate metabolism in malignant disease since Warburg’s (1) first publication on this subject. This author showed, and his work has since been confirmed, that a considerable increase in the utilization of glucose occurs in malignant tissue. Cori and Cori (2) have also shown by studies of lactic acid production an abnormal carbohydrate metabolism. Because of Warburg’s findings, it has been expected that in malignant disease the organism as a whole might show an abnormal carbohydrate metabo- lism. Investigations by various authors have brought forward some- what contradictory evidence.

Basing their conclusions on the return of the blood sugar content to a normal value in ninety minutes after the ingestion of 50 gm. of glucose, Slosse and Reding (3) stated that cancer patients have a diminished tolerance for carbohydrate, and Beregoff (4) arrives at the same conclusion. The presence of such diminished carbohydrate tol- erance, when occurring simultaneausly with an alkalosis, the latter author considers of diagnostic significance. Studies conducted simul- taneously on the ionized calcium and the sugar tolerance show, in the opinion of this author, an interrelationship between the level of the calcium ion and the carbohydrate metabolism.

Enocksson ( 5 ) found abnormal prolongation and elevation of the sugar curve following glucose administration in advanced cases of gastric cancer. He ascribed some diagnostic importance to this find- ing, but pointed out that equally marked disturbances may be found in other diseases resulting in cachexia.

Benso (6) found that in patients suffering from malignant disease hyperglycemia reached a higher level more quickly and decreased more slowly than in normal individuals. Following extirpation of the tumor, this author claims, the tolerance curves approach a more normal value. He also states that a return to normal tolerance for carbohydrates follows radium treatment, but he did not observe such an effect after roentgen therapy.

Romanin (7) found the rising part of the sugar tolerance curve to be normal in patients with cancer, while there existed a marked prolon- gation of the curve. This finding he interpreted as of diagnostic importance, although similar curves are obtained from patients suffer-

1 The expenses of this investigation were defrayed, in part, by a @ft to the Harvard Medical School from the Smith, Kline and French Laboratories, Philadelphia.

536

T H E CARBOHYDRATE TOLERANCE IN CANCER PATIENTS 537

ing from other diseases. Hueper, Woodward and F r y (8) found a hyperglycemia in the majority of their cases of malignant disease.

In contradistinction to these findings, DeNiord (9) and his co- workers present data showing a lowered sugar tolerance in only about one-third of their cancer cases. The altered carbohydrate metabolism is of no diagnostic significance in the opinion of these investigators. No significant changes in the carbohydrate metabolism were observed by these authors during or after roentgen ray therapy. Moreover, Pena (10) in a study of 258 cancer patients found a sugar tolerance curve similar to that encountered in normal human subjects. He did not find that the site of the tumor or its histological type bore any rela- tionship to the sugar tolerance of cancer patients. He did observe. however, a lowering of the carbohydrate tolerance as the disease pro- gressed towards the terminal stage.

The present investigation was undertaken to determine further the incidence of a lowered carbohydrate metabolism in cancer and to study the relationship, if any, of the blood calcium to the carbohydrate tolerance in cancer patients.

EXPERIMENTAL

Thirty-five patients suffering from various forms of carcinoma were studied. In each case the diagnosis was confirmed by biopsy or the malignant condition had developed to such an extent that no reasonable doubt of its nature was possible. Each patient was treated with a known dosage of roentgen-rays, a full suberythema dose being admin- istered. The voltage used was 220 kv. Sugar tolerance curves were obtained in the usual way, usiiig the improved Folin (11) micro pro- cedure. One hundred grams of glucose was used as the test meal. While the general consensus of opinion is that this amount of glucose is too great, it was, nevertheless, necessary to use this amount if results were to be compared satisfactorily with those of other investigators, the great majority of whom have used this amount of glucose. Of the original 35 patients, 27 were studied before and after x-ray treatment, and in 16 cases the study was completed by a third curve one to three months later. Distance from the clinic or death accounted for failure to obtain second and third curves on all the patients studied,

Blood calcium determinations were made simultaneously with the sugar tolerance curves on 15 patients. The blood calcium was deter- mined according to an unpublished method of Dr. Cyrus H. Fiske (12).

A complete rQsum6 of the studies on 27 patients is given in Table I. Eight patients on whom only one curve was obtained were not included in this table, but were used in determining the incidence for lowered carbohydrate tolerance in cancer patients.

Contrary t o the findings of many authors, but in agreement with DeNiord, a decreased tolerance for glucose was found in only one-third of the entire group of 35 patients prior to roentgen radiation. It is of interest that, with the exception of one patient with carcinoma of the

-

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(Tab

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0)

THE CARBOHYDRATE TOLERANCE IN CANCER PATIENTS 539

cervix of two years ' standing (No. 1926), all of the patients who showed a lowered sugar tolerance prior to radiation had either lost a consid- erable amount of weight or had malignant disease of the gastro-intes- tinal tract or oral cavity. It will also be noted that with three excep- tions the patients showing a lowered tolerance were above fifty-five years of age.

The data were analyzed in an attempt to discover the bearing of a lowered carbohydrate tolerance on the final outcome of the disease. The effect, if any, of roentgen radiation on both the lowered and the normal sugar tolerance in cancer patients was studied and so fa r as possible the cause of the lowered carbohydrate tolerance occurring in some patients was investigated.

There appeared to be no consistent effect of roentgen radiation on the tolerance of a cancer patient for glucose. Sixteen patients had a

' 0 1 2 3

TIME I N HOUR8

FIG. 1. COMPOSITE CURVE OF NINE C A N C F ~ PATIENTS WITH NORMAL SUGAR TOLERANCE ORIQINALLT

0- 0 Control period 0 - - - - - 0 Immediately after roentgen therapy 0-0 One to three months later

normal tolerance for glucose before x-ray treatment (Period I). Nine or 56 per cent of these maintained a normal curve after x-ray treatment (Period 11), while in 7 or 44 per cent a slightly lowered tolerance developed. I n 9 of the 16 patients having a normal tolerance to glucose before radiation, a third curve (Period 111) was obtained one to three months later. A composite graph derived from the averages of the sugar content of the blood for the three periods of study in these nine individuals is given in Fig. 1. It will be observed, from this figure, that roentgen radiation had no marked effect on the sugar tolerance in cancer patients when the tolerance curve was normal before the institution of therapy.

Eleven of the patients included in Table I had before roentgen radiation a lowered carbohydrate tolerance. Of these, 63 per cent showed a noticeable increase in tolerance for glucose after treatment by roentgen rays. Seven of the 11 patients were studied one to three months after radiation. Fig. 2 is a composite graph based on averages

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Inte

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THE CARBOHYDRATE TOLERANCE IN CANCER PATIENTS 54 1

of the values obtained in these 7 patients. On the whole, the suc- cessive curves show a tendency towards an increased tolerance for carbohydrate.

Seven of the 10 patients not studied a third time were dead six months after the initial investigation. Five of these 7 patients had previously a normal carbohydrate tolerance. Of the patients who lived long enough for the final tolerance curve to be obtained, none showed an improvement in tolerance for carbohydrate when a lowered tolerance for glucose was originally present. It would seem impos- sible, from a consideration of the carbohydrate tolerance in period one, to determine how long the patient would survive. A progressive de- crease of tolerance for carbohydrate would be a distinctly unfavorable sign, but thc presence or absence of a lowered tolerance for glucose before or after treatment does not offer an aid to prognosis.

I 2 3

TIME IN HOURS

FIG. 2. CONPOSITE CURVE OF SEVEN CANCER PATIENTS WITH A DECREASED SUGAR TOLERANCE ORIQINALLY

0- 0 Control period 0 - - - - - 0 .----. Immcdiately after roeiitgeii therapy

One to three months later

From a study of the data obtained from sugar tolerance curves one to three months after treatment by x-ray, some interesting facts emerge. More than 75 per cent of those patients presenting a lowered tolerance for glucose at this time had shown the same abnormality prior to roentgen therapy. Clinical improvement following radiation does not appear to change the picture. Of the patients in whom radiation brough about clinical improvement, two-thirds had a normal carbohy- drate tolerance prior to treatment, and the same incidence appears in those patients in whom radiation brought about no clinical improve- ment.

Four typcs of abnormal glucosc tolerance curves were encountered during the investigation. No one type could be considered predomi- nantly characteristic of malignant clisease. These types are shown in Fig. 3.

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185

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125

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200

148

110

110

145

128

165

140

150

200

148

205

197

197

242

125

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114

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2 hr.

123

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163

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118

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170

160

200

130

106

106

127

123

166

125

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155

125

155

177

177

217

115

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105

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145

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175

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102

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113

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100

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Inte

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curv

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T H E CARBOHYDRATE TOLERANCE IN CANCER PATIENTS 543

Six patients had a lowered tolerance for glucose, giving a high maximum in thirty minutes but returning to a normal value within three hours (Fig. 3, Group A). Five patients showed a lowered tol- erance for glucose, giving a high maximum but failing to return to a normal value in three hours (Group B). In 6 patients only a normal elevation of the blood sugar occurred, but the blood sugar level failed to return to normal in three hours (Group C). In 4 patients a plateau appeared (Group D). While it is not particularly safe to ascribe any particular type of sugar tolerance curve to any definite disease, the general consensus of opinion would attribute Groups A and B to con- ditions generally associated with malnutrition and cachexia, while groups C and D are generally considered (13, 14, 15, 16) to occur in

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patients showing a poor absorption of glucose from the gastro-intestinal tract. There is no question, also, that some of the prolongation of the curves found in this series, and by other workers, may be due to the effect (17, 18, 19, 20) of an excessive amount of glucose used in the test meal. Consideration of this fact was given in the interpre- tation of normal and lowered tolerance in this study. It was generally found that when a hyperglycemia was present originally, the sugar values fell, not necessarily to the original value but to a more normal value. A high percentage of such abnormalities as shown by groups A and B is not inconsistent with the loss of body weight and appetite so characteristic of advanced malignant disease. The occurrence of a large number of plateau curves in the period immediately after roentgen treatment may be accounted for by gastro-intestinal dis- turbances due to roentgen-ray sickness in the patients a t this period.

544 F. H. L. TAYLOR AND HENRY JACKSON

It has been previously shown (21) that a hypocalcemia occurs in a certain number of cancer patients and that roentgen radiation had no effect on the level of the blood serum calcium. As has been men- tioned previously, a lowered blood serum calcium has been considered by some authors to be linked in some way to a lowered sugar t,olerance. In an attempt to discover if such a relationship exists, simultaneous calcium and sugar tolerance determinations were made on 15 patients. The serum calcium values taken before, during, and some months after x-ray treatment were averaged. This average figure is given in Table I. In confirmation of a previous report (loc. cit.) one notes that a hypocalcemia occurred in only 34 per cent of the 15 patients.

Examination of the data obtained on those patients in whom a normal sugar tolerance existed shows an average calcium value of 9.3 mg. per 100 ml. of blood serum. The extremes encountered were 7.25 and 10.50 mg. of calcium per 100 ml. of blood serum. In those patients showing a decreased tolerance for glucose the average calcium value was 9.84 mg. per 100 ml. of blood serum, the extremes being 7.78 and 10.50 mg. per 100 ml. Definite hypocalcemia was found to be present in 30 per cent of patients having a normal carbohydrate tolerance and in 28 per cent of those having a decreased tolerance. No direct relationship, therefore, seems to exist between the sugar tolerance in cancer patients and the level of the total serum calcium.

DISCUSSION On the basis of the foregoing experimental evidence there seems to

be no direct relationship between a decreased sugar tolerance and cancer per se. There is some evidence that the decreased tolerance for carbohydrate encountered in about one-third of the patients studied was due in part to the general malnutrition and cachexia commonly found in cancer. Some patients with a lowered sugar tolerance had definite involvement of the gastro-intestinal tract. Even in those patients where a lowered sugar tolerance was found, as determined by the usual criteria, it was not certain that such decreased tolerance curves were not due to delayed utilization of glucose caused by the large amount of this material ingested. It is interesting that, while no one type of tolerance curve was characteristic of the disease, yet most, of the abnormalities found were consistent with the types found following the feeding of carbohydrate in non-diabetic patients suffering from starvation or malnutrition. It is, of course, appreciated that involvement of certain specialized areas such as the pancreas, the para- thyroids, and the hypophysis by malignant disease may alter the tol- erance curve entirely (22). Some of the curves which have been considered normal show some elevation above the base line after three hours. As stated above, we have borne in mind that with an original hypoglycemia the return of the sugar level to a normal value, even if this value is above the original base line, is not indicative of an ab- normal sugar tolerance. We have in the interpretation of curves con-

THE CARBOHYDRATE TOLERANCE IN CANCER PATIENTS 545

sidered the hyperglycemia produced and the duration of this hyper- glycemia above a normal figure. Recognition of the reported effect of age on the glucose tolerance (23) has been made. All except two of the patients were over fifty and most were over sixty years of age. It is believed that in comparative studies of glucose tolerance the individuals sliould be in the same general age group.

In short, it was found that about one-third of the patients studied show a lowered tolerance for glucose, the presence of which was not inconsistent with the malnutrition accompanying the malignant state. This relationship may be further modified when one considers the in- cidence of a lowered glucose tolerance in non-diabetic persons between fifty-five and seventy years of age. It seems rather difficult to account for a lowered carbohydrate tolerance in cancer in terms of Warburg’s theory. The presence of an actively growing malignant tissue having a high rate of carbohydrate utilization would tend to cause a more rapid, and not a less rapid removal of carbohydrate from the blood stream.

The lack of direct relationship between cancer and the sugar toler- ance of individuals was still further shown by a consideration of the effect of roentgen radiation. Radiation by roentgen rays did not pro- duce any marked changes in the carbohydrate metabolism. When the tolerance for glucose was normal a t the outset, over half of the patients studied showed an unchanged sugar tolerance following roentgen ray treatment. Of those patients who did show a change, the same number showed a trend toward normal as showed a further decrease in toler- ance for glucose. There was, however, a tendency among patients originally possessing a lowered tolerance for glucose for the tolerance curves to become more normal. In this connection i t is noteworthy that Lennox (24) has shown that with marked abnormality of sugar tolerance, repeated tests, even after considerable intervals of time, produce tolerance curves which are somewhat flatter and more close to normal.

It was found impossible to predict from an analysis of initial sugar tolerance curves whether the outcome would be favorable or unfavor- able. In patients who originally showed a normal tolerance for car- bohydrate, the development of a progressively decreasing tolerance strongly indicated an unfavorable prognosis.

It has been found impossible to show any relationship between the decreased sugar tolerance found in some cases of cancer and the total serum calcium. That a lowered blood serum calcium is encountered in diabetic malnutrition in some instances and increases in calcium are observed during insulin therapy is well known. It does not follow, however, that in these conditions the rise in the blood sugar, together with the fall in the blood serum calcium, or in the second instance the fall in the blood mgar with a rise in the blood serum calcium, has any causal relationship. In the temporary hypercalcemia following insulin therapy, the changes in the blood serum calcium are probably secondary to the removal of phosphate ion to form hexose phosphate,

546 F. H. L. TAYLOR AND H E N R Y JAUESON

as glucose utilization is accelerated. In the hypocalcemia of diabetes and malnutrition, as in other cachectic states, the lowered serum calcium is probably associated with the lowered serum proteins particularly of the albumen fraction.

CONCLUSIONS I. I n only one-third of 35 cancer patients studied was a decreased

tolerance for glucose found, prior to the institution of roentgen therapy. 11. Consideration must be given to the fact that a lowered tolerance

for glucose is not an uncommon tendency in persons between fifty-five and seventy years of age, particularly if they are suffering from malnutrition.

111. The presence of a lowered carbohydrate tolerance in cancer is not diagnostic nor is it of assistance in prognosis. However, progres- sively increased abnormality of the carbohydrate tolerance may be regarded as an unfavorable sign.

IV. Roentgen radiation has no consistent effect on the sugar toler- ance of cancer patients.

V. No relationship has been found between the decreased sugar tolerance occurring in some cases of cancer and the total serum calcium.

Note: The authors express their appreciation of the co-operation of the S W of the Pondville Hospital during the progress of this investigation. They acknowledge in par- ticular the technical assistance of Miss Eleanor R. Shea, A.B., and Mr. Roderick Dwyer.

BIBLIOGRAPHY 1. WARBURG, 0. : Verbesserte Methode zur Messung der Atmung und Glykolyze, Biochem.

Ztschr. 51: 152, 1924. 2. CORI, C. F., AND Cow, 0. T.: On the carbohydrate metabolism of malignant tumors,

Proc. SOC. Exper. Med. & Biol. 22: 254, 1924. 3. SLOSBE, A., AND REDING, R.: fitude des althrations humhrales dans le cancer et le

prBcancer, Bull. Acad. roy. de mBd. de Belgique 7: 405, 1927. Also in Cancer, Bruxelles 4: 442, 1927.

4. BEREOOPP, PAULINE : Changes in the blood chemistry in malignant disease with special reference to carbohydrate tolerance and alkalosis, J. Cancer Research 14: 559,1930.

5. ENOCKSBON, B.: Carbohydrate metabolism in gastric cancer, Svenska lak. 27: 729, 1930. Abst. in Am. J. Cancer 15: 365, 1931.

6. BENSO, F.: Le xantoprotein, i lipoide, il glucosio nel siero di sangue dei cancerosi, Tumori 4 : 425, 1930.

7. ROMANIN, V. : Apparato glicoregolatore e tono vegetativo nei tumori maligni, Minerva med. 1 : 870, 1931. Abst. in Cancer Review 7 : 151, 1932.

8. HUEPER, W. C., WOODWARD, G. E., AND FRY, E. 0.: Interrelations between histologic structure and blood chemical findings in cancer, Am. J. Cancer 15: 2666, 1931.

9. DE NIORD, R. N., SCHREINER, B. F., AND DE NIORD, H. H. : The effect of roentgen rays on the metabolism of cancer patients, Arch. Int. Med. 25: 32, 1920.

10. PENA, FAUSTINO A.: La glicemia en el cancer, Bol. Inst. de med. exper. para el estud. y trat. del cheer 7 : 1258, 1930. Abst. in Am. J. Cancer 15: 1654, 1931.

11. FOLIN, O., AND SVEDBERQ, A.: Micro methods for the determination of non-protein nitrogen, urea, uric acid, and sugar in unlaked blood, J. Biol. Chem. 88: 85, 1930.

12. FISKE, CYRUS H., AND LOGAN, M. A.: Unpublished calcium method. 13. LEHMANN, W. L. : Het arsenigzuur als geneesmiddel bij diabetes mellitus, Amsterdam,

1873. Abst. in Arch. exper. Path. u. Pharm. 2: 463, 1874.

THE CARBOHmBATE TOLERANCE IN CANCER PATIENTS 547

14. Du VIQNEAUD, V., AND KARR, W. 0.: Carbohydrate utilization. 1. The rate of dis- appearance of d-glucose from the blood, J. Biol. Chem. 66: 281, 1925.

15. LENNOX, W. G., O’CONNOR, M., AND BELLINQER, M.: Chemical changes in the blood during fasting in the human subject, Arch. Int. Med. 38: 553, 1926.

16. MOROULIS, S., AND EDWARDS, A. C. : Chemical changes in the blood during fasting and subsequent refeeding.

17. CORI, C. I?.: The fate of sugar in the animal body. I. The rate of absorption of hexoses and pentoses from the intestinal tract, J. Biol. Chem. 66 : 691, 1925.

18. FADER, K.: Benign glycosuria due to disturbances in the blood sugar regulating mechanism, J. Clin. Investigation 3: 203, 1926.

19. HANSEN, K. M.: Investigations on the blood sugar in man. Conditions of oscilla- tions, rise, and distribution, Arta med. srand. Supplement 4, pp. 1-221, 1923.

20. STAtrB, H. : Untersuchungen iiber den Zuckerstoffwechsel des Menschen, Ztschr. f. klin. Med. 93: 89-140, 1922.

21. JACKSON, HENRY, JR., AND TAYLOR, F. H. L.: The calcium, potassium and inorganic phosphate content of the serum in cancer patients, Am. J. Cancer 19: 379, 1933.

22. WILDER, R. M., ET A L : Carcinoma of the islands of the pancreas: hyperinsulinism and hypoglycemia, J. A. M. A. 89: 348, 1927.

23. SPENCE, J. C.: Some observations on sugar tolerance with special reference to varia- tions found a t different ages, Quart. J . Med. 14: 314, 1921.

24. LENNOX, W. 0.: Stimulation of the sugar regulating mechanism as shown by dupli- cate blood sugar curves, J. Biol. Chem. 73: 237, 1927.

Experiments on dogs, Am. J. Physiol. 68: 477, 1924.