Diagnostic and Therapeutic Implications of Ectopic Hormone Production in Small Cell Carcinoma of the Lung

Thorax: first published as 10.1136/thx.35.2.101 on 1 February 1980. Downloaded from

Thorax, 1980, 35, 101-106

Diagnostic and therapeutic implications of ectopic hormone production in small cell carcinoma of the lung

MOGENS HANSEN, MOGENS HAMMER, AND LOTTE HUMMER From the Department of Chemotherapy R II-R V, Finsen Institute, and Department of Internal Medicine C, Bispebjerg Hospital, and the Departments of Nephrology P and Nuclear Medicine, Rigshospitalet, Copenhagen, Denmark

ABSTRACT In 75 unselected and untreated patients with small cell carcinoma of the lung, plasma ACTH, serum calcitonin, and antidiuretic hormone (ADH) in plasma and urine were related to corresponding clinical symptoms and biochemical findings at the time of diagnosis. The significance of elevated concentrations of these substances in relation to treatment was also investigated. Plasma ACTH concentrations were increased in 22 patients (29%), and 25 patients (33%) were considered to have inappropriate ADH secretion. Only one patient had definite hypokalaemic alkalosis, and one patient pronounced hyponatraemia, with associated clinical

syndromes of ectopic ACTH and ADH secretion. Serum calcitonin concentrations were in- copyright. creased in 48 patients (65%). No related clinical symptoms were disclosed, and all these patients had normal serum calcium concentrations. Thirty-three of 66 patients (50%) had raised levels of free cortisol in a 24-hour urine and these levels were significantly related to plasma ACTH concentrations. The median survival was slightly shorter in patients with increased values of the

three substances, but this was not related to increased plasma ACTH concentrations and was not http://thorax.bmj.com/ statistically significant. Survival rates and results of treatment were independent of the pre- treatment levels of the three substances.

Ectopic production of ACTH and ADH in mal- patients with scc," and Gilby et al,10 using water ignant tumours is well documented, and usually loading, found an overall prevalence in about 40% occurs in relation to small cell carcinoma of the of their sample. Both ACTH12-14 and ADH15 lung (scc).1-3 Recently the production of cal- appear to be produced in almost all cases of scc. citonin in scc has also been documented.4-6 While We have studied ectopic ACTH, ADH, and cal- on September 29, 2021 by guest. Protected no clinical signs related to hypercalcitonaemia citonin production at the time of diagnosis in 75 have been observed, clinical syndromes have been unselected patients with scc. The relationships related to the ectopic production of ACTH and between these three substances, their clinical ADH.2 7 8 features, and the implications for response to In a review of 138 cases with scc Kato et a19 treatment and survival have been investigated. found Cushing's syndrome in 2-8% of the patients. Investigating 41 treated and untreated patients Methods with scc Gilby et alPO found increased concentrations of plasma cortisol before and after dexame- The study included 75 unselected patients with thasone suppression in half of the patients, but sccl6 referred to Medical Department C, Bis- only three were considered to have the ACTH pebjerg Hospital, between May 1975 and March syndrome. The inappropriate ADH syndrome 1976 (46 patients), and to the Finsen Institute (SIADH) is claimed to occur in up to 20% of between May 1976 and February 1977 (29 patients). Fifty-three patients (71%) were men Address for reprint requests: Dr Mogens Hansen, Department of Chemotherapy RII, Finsen Institute, 49 Strandboulevarden, DK-2100 and 22 (29%) were women with a median age of Copenhagen, Denmark. 64 years (range 38-75 years). Sixty-two patients 101 Thorax: first published as 10.1136/thx.35.2.101 on 1 February 1980. Downloaded from

102 Mogens Hansen, Mogens Hammer, and Lotte Hummer below the age of 70 years were treated in ran- The median value of urinary cortisol was 726 domised trials.17 18 nmol/24 hours (range: 468-13 500) in the 18 Before starting chemotherapy or radiotherapy patients with plasma ACTH below 76 ng/l, and or both two 24-hour urine samples were collected, 750 nmol/l (range: 455-10 020) in the 15 patients the second being acidified with 10 ml 0'1 HCl. Be- with plasma ACTH above 76 ng/l. Only nine tween these two collections a fasting blood sample patients (14%) had significantly increased keto- was collected. Blood was taken on ice and centri- genic steroids, and eight of these also had in- fuged at 40C immediately, and plasma and serum creased free cortisol. The patient with increased were kept below -200C until analysis. ketogenic steroids and normal free cortisol had Plasma ACTH19 and serum calcitonin20 were an increased plasma ACTH, while eight patients measured by radioimmunoassay techniques. Two with raised plasma ACTH and free cortisol had samples for analysis of plasma ACTH were ob- normal ketogenic steroid levels. tained with a 10-minute interval, and the lower value was used (in healthy control subjects 76 ng/ ANTIDIURETIC HORMONE l=mean+2 SD). Only one patient was clinically suspected of Arginine-vasopressin (ADH) was measured by SIADH because of lethargy, weakness, and radioimmunoassay in acidified urine21 and in oliguria. This patient had hyponatraemia (Na+: plasma.22 Analyses on urine were attempted in 123 mmol/l), hypotonic plasma with higher urine the first 46 patients, but a sample was not ob- osmolality (plasma: 244 and urine 345 mosmol/kg tained in five patients. If frozen plasma was H20), and inappropriately increased concentra- available, analysis were performed in patients tions of urine ADH (34 mU/l) and plasma ADH with raised urine ADH or decreased plasma os- (3*1 pg/ml). Eleven more patients had plasma molality or both, thereby including 31 patients, sodium between 132 and 135 mmol/l. Altogether, 15 of whom had also urine ADH measured. 32 patients (43%) had hypotonic plasma (osmola- In the first 24-hour urine sample free cortisol,23 lity below 280 mosmol/kg H20). In only two copyright. of ketogenic steroids (KGS),2' creatinine, and os- these patients was the osmolality of urine below molality were measured. Routine plasma analyses that of plasma. Urine ADH was measured in 15 were performed for osmolality, sodium, chloride, potassium, standard bicarbonate, calcium, and

phosphorus. http://thorax.bmj.com/ 12 Results (82.5 Polml)

ACTH None of the patients had the physical signs of Cushing's syndrome and only one was clinically 8 U suspected of ectopic ACTH production because of oedema, polyuria, and thirst. This patient also 0. - on September 29, 2021 by guest. Protected had hypokalaemic alkalosis (K : 2-2 mmol/l, I 6 HCO3-: 34-2 mmol/l) and a plasma ACTH of 199 ng/l. Five other patients had hypokalaemia, the lowest value being 2'8 mmol/l. Serum bi- cL4 carbonate in these five patients ranged from 24-4 to 29*5 mmol/l. Plasma ACTH concentrations 2 were above 76 ng/l in 22 patients (29%-95% con- (Normal fidence limits: 19-41%). The highest value, 199 range) ng/l, was obtained in the above-mentioned 0 _- patient, while the remaining results had values 300 290 280 270 260 250 240 below 157 ng/l. The median value of ACTH in all patients was 64 ng/l, twice the median value P-osmolality (mosm/kg) in healthy control subjects.19 Thirty-three of 66 Figure Corresponding values of plasma ADH and patients (50%) had increased urinary excretion plasma osmolality in 31 patients with small cell of free cortisol, including 18 of 47 patients (36%) carcinoma of the lung. The range of similar values in with plasma ACTH below 76 ng/l, and 15 of 19 healthy control subjects falls between the two solid patients (79%) with plasma ACTH above 76 ng/l. lines. Thorax: first published as 10.1136/thx.35.2.101 on 1 February 1980. Downloaded from

Diagnostic and therapeutic implications of ectopic hormone production 103 of these patients and was increased in 13, from 6 vations of the individual substance is also shown to 6250 mU/I. in table 1. It appears that the frequency of con- The relation between plasma ADH and plasma comitant elevations found was the same as the osmolality in 31 patients is shown in the figure. estimated one. Altogether, 63 patients (84%) had Twenty-two of 31 patients (71%) had inappro- either increased plasma ACTH or serum calcitonin priately increased ADH concentrations, including concentrations or inappropriately increased ADH two with normal plasma osmolality. Taking both values. ADH and osmolality in plasma and urine into account, 25 patients (33%-95% confidence limits: RESPONSE TO TREATMENT 23-45%) had inappropriate ADH secretion. Sixty-one patients with measurable or evaluable disease were treated. Forty-two patients (69%) CALCITONIN responded with a decrease by more than 50% Serum calcitonin concentrations were measured of the product of the longest perpendicular di- in 74 patients and were increased in 48 (65%- ameters of measurable lesions or by more than 95% confidence limits: 53-76%), while serum 75% of evaluable lesions. Minor or no changes calcium concentrations were normal in all patients. or progressive disease were found in 19 patients These data have been presented in detail else- (non-responding). The relation of responding and where.25 non-responding patients to the levels of plasma ACTH and serum calcitonin and the occurrence of RELATIONSHIPS inappropriate ADH secretion is given in table 2. The relationships between increased plasma ACTH No statistically significant differences were found and serum calcitonin and inappropriate ADH for the response rate in patients with one of the secretion are seen in table 1. The estimated fre- substances raised and in patients with normal quency calculated from the occurrence of ele- levels. Nor was any statistically significant differ- ence observed between patients with normal levels copyright. Table 1 Relationship between increased plasma of all three substances and patients with two or ACTH, serum calcitonin (CT) and inappropriate ADH three concomitantly increased substances. secretion (ADH) Increased substance Frequency SURVIVAL

Sixty-two patients were treated in prospective http://thorax.bmj.com/ Estimated* Found (95% clinical trials.17 18 Survival data for these patients confidence limits) with regard to the level of the three substances ACTH+ADH 0.10 0-08 (0-03-017) are given in table 3. The median survival was ACTH+CT 0-18 0-20(0-12-031) ADH+CT 0 21 0-21 (0-13-032) somewhat longer for patients with normal levels ACTH+ADH+CT 0-06 0 07 (0-02-015) of each of the three hormones and for patients *Calculated from the frequency of individual increases: ACTH 0-29; with no increased levels, compared to patients ADH 0 33; calcitonin (CT) 0 65. with increases of the respective substance and patients with two or three increased substances, Table 2 Response to treatment in 61 patients with but none of these differences was statistically on September 29, 2021 by guest. Protected small cell carcinoma of the lung in relation to levels significant. Considering the long-term results, the of plasma ACTH, serum calcitonin (CT), and proportions of patients surviving more than one inappropriate ADH secretion (SIADH) year, and the number of patients still alive without Number Ratio p* treatment and free of disease are almost identical respondingl (table 3). There is a slight increase in long-term total, number survival in patients without inappropriate ADH 30/43 0 70 secretion as well as for patients with none of the ACTH S 76 ng/l >0 20 >76- 12/18 0-67 three substances raised, but these differences are 12/20 0 60 not statistically significant. CT <1 0ng/ml >0 20 >1-0 30/41 0 73 30/41 0 73 Discusion SIADH- >0 20 + 12/20 0-60 All three normal 6/10 0-60 The finding of Cushing's syndrome in a middle- >0 20 aged man might very well be the result of small Two or three raised 16/23 0 73 cell carcinoma, thereby indicating a diagnostic *x2 test. value,3 26 though the present results show that the Thorax: first published as 10.1136/thx.35.2.101 on 1 February 1980. Downloaded from

104 Mogens Hansen, Mogens Hammer, and Lotte Hummer Table 3 Survival results for 62 patients with small cell carcinoma treated in randomised trials in relation to levels of plasma ACTH, serum calcitonin (CT), and inappropriate ADH secretion (SIADH) Median Range p* Number alive Number alive Ratio survival (days) > 365 days andfree of (%) (days) disease, 76 ng/l 325 1-1210+ 17/44 (39%) 3 7 ACTH >0 05 >76ng/1 298 5-1057+ 8/18 (44%) 2 11 I1 0ng/ml 357 8-1187+ 9/21(43%) 2 10 CT >0 05 >1 0ng/ml 262 1-1210+ 15/40(38%) 3 8 360 5-1210+ 18/41 (44%)t 4 10 SJADH >0-05 + 260 1-874+ 6/21 (29%)t 1 5 All three normal 363 161-1187+ 6/11(55%)j 1 9 >005 Two or three raised 262 1-1057+ 9/24 (38 %)t 2 8 *Mann-Whitney's test tp>020 (X'= 137) : p >0 20 (Fisher's exact test) § without treatment, which was discontinued 18 months after diagnosis clinical syndrome is uncommon in such patients. The inappropriate ADH syndrome was also Clinical symptoms and hypokalaemic alkalosis extremely rare. In only one patient was plasma increased caused clinical were extremely rare, and moderately sodium decreased to a degree that copyright. values of urinary cortisol and plasma ACTH are symptoms. When ADH was related to plasma not specific for patients admitted with scc. In- osmolality, inappropriate ADH secretion was, creased levels of plasma and urinary corticoid however, found in one-third of the patients. In- levels have been demonstrated previously in appropriately increased plasma ADH concentra- patients with lung cancer.'0 27 28 Lichter and tions in asymptomatic patients were also found Sirett28 found that the increased levels occurred by Padfield et al.3 http://thorax.bmj.com/ particularly in patients within six months of death. In this investigation ACTH, ADH, and cal- These results are not in disagreement with the citonin levels were increased in a significant demonstration of ACTH in tumour tissue, as the number of patients with untreated and newly secretion of ACTH from tumour suppresses pitu- diagnosed scc. According to the estimated and itary production of ACTH.8 29 30 To cause in- actual frequencies of concomitant increases, each creased plasma ACTH concentrations the secre- of the three hormonal polypeptides appeared to tion from a tumour must, therefore, exceed the be raised independently of the others. This suggests that property of ectopic hormone production normal pituitary secretion. In this regard it should the on September 29, 2021 by guest. Protected be noted that the median value of plasma ACTH is not confined to a particular group of scc. How- in our patients is twice the median value in ever, preliminary results produced by Coombes healthy control subjects, thus suggesting sub- et al34 indicate that tumour content of ACTH and clinical ectopic production of ACTH. This may calcitonin may be related. The mechanisms that also explain some of the increased urinary cor- cause ectopic production as well as secretion of tisol values in patients with plasma ACTH con- the products are not known. The present results centrations below 76 ng/ml. It is also noteworthy indicate that production and secretion occur con- that increased plasma ACTH concentrations are comitantly in one tumour in more than half the within the usual range for the pituitary Cushing cases. The concept of multiple production is syndrome,2 which may account for the rare occur- further supported by the findings of multiple rence of hypokalaemic alkalosis in the present peptide and amine products in plasma and tumour patients. Although Bagshawe31 and Ross26 sug- from some patients with the ectopic ACTH syn- gested that hypokalaemic alkalosis was particu- drome.4 1 35 36 Investigations on the occurrence larly related to the ectopic ACTH syndrome, of these three polypeptides in the same tumours Prunty et a132 found that potassium depletion was related to the histological subtypes and electron- related to the degree of adrenal hyperfunction microscopical studies would be of interest. independently of the source of ACTH. Median and long-term survival was almost the Thorax: first published as 10.1136/thx.35.2.101 on 1 February 1980. Downloaded from

Diagnostic and therapeutic implications of ectopic hormone production 105 same for patients with and without increased 7 Bartter FC, Schwartz WB. The syndrome of in- plasma ACTH concentrations. Similarly, Yalow appropriate secretion of antidiuretic hormone. et a137 did not observe any relation between Am J Med 1967; 42: 790-806. median survival and the pre-treatment plasma 8 Meador CF, Liddle GW, Island DP et al. Cause level of of Cushing's syndrome in patients with tumors immunoreactive "big" ACTH in patients arising from "non-endocrine" tissue. J Clin with metastatic disease. Median survival was Endocrinol Metab 1962; 22:693-703. shorter and long-term results appeared to be in- 9 Kato Y, Ferguson TB, Bennett DE, Burford TH. ferior for patients with inappropriate ADH Oat cell carcinoma of the lung. A review of 138 secretion compared to patients without. Although cases. Cancer 1969; 23:517-24. no statistical significance was obtained for the 10 Gilby ED, Rees LH, Bondy PK. Ectopic hor- ADH related data, these results are contrary to mones as markers of response to therapy in can- previous general statements claiming that the cer. Am sterdam: Excerpta Medica, 1975. ectopic ACTH syndrome shortened life, while the 11 Vorherr H. Para-endocrine tumor activity with SIADH had no 29 emphasis on ectopic ADH secretion. Oncology influence.2 3 Possibly, the ectopic 1974; 29:382-416. ACTH syndrome may complicate the condition 12 Bloomfield GA, Holdaway JM, Corrin B et al. in untreated patients, while all clinical symptoms, Lung tumours and ACTH production. Clin Endo- hyperglycaemia, and electrolyte disturbances dis- crinol 1977; 6:95-104. appear in patients responding to chemotherapy 13 Horai T, Nishihara H, Tateishi R, Matsuda M, (Hansen, unpublished observations). Accordingly, Hattori S. Oat-cell carcinoma of the lung simul- if tumour response is obtained by the treatment, taneously producing ACTH and serotonin. 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