Syndrome of inappropriate antidiuretic hormone associated withchemotherapy-induced tumour lysis in small-cell lung cancer:Case report and literature review
S. L.Vanhees,1 R. Paridaens2 & J. F.Vansteenkiste1
Departments of 'Pulmonology (Respiratory Oncology Unit), 2Oncology, University Hospital Gasthuisberg, Catholic University Leuven. Belgium
Summary
A patient with a small-cell lung cancer (SCLC) developed anasymptomatic hyponatremia, with all features of the syndromeof inappropriate antidiuretic hormone secretion (SIADH), twodays after the start of his first cycle of chemotherapy withvindesine, ifosfamide and cisplatin. Progression of the tumourwith an increase in paraneoplastic SIADH, or drug-inducedcauses of hyponatremia, could be ruled out by his furtherclinical course. The event was interpreted as a consequence ofADH release during the initial tumour cell lysis after effectivechemotherapy.
The occurrence of hyponatremia during the initial phase ofchemotherapy for SCLC should be interpreted with caution.Although it is most commonly due to an increase in paraneo-plastic ADH secretion reflecting ineffective therapy, it can alsobe due to release of ADH from malignant cells in the period ofrapid tumour lysis, reflecting effective therapy.
Based on this rare occurrence, a review of the aetiology,clinical findings, diagnosis, prognosis and treatment ofSIADH in general is presented.
The syndrome of inappropriate secretion of antidiuretichormone (SIADH) was first reported by Schwartz et al.in 1957 [1]. They described two patients with lung cancer,who developed unexplained hyponatremia due to renalsodium loss, and thought that production by the tumourof an ADH-like substance might be the responsiblemechanism. The problem was reviewed by Bartter andSchwartz in 1967 [2]. Criteria for the definition of SIADHsecretion are 1) hyponatremia with a serum sodium lowerthan 130 mEq/1; 2) plasma osmolality lower than 275mOsm/kg; 3) urine osmolality higher than the plasmaosmolality and above 500 mOsm/kg; 4) absence ofclinical evidence of volume depletion; 5) normal renaland adrenal function; and 6) normal thyroid function [2].
SIADH has been reported in a variety of medicalconditions including central nervous system and pulmo-nary disorders, and as a paraneoplastic phenomenonaccompanying several malignancies. The tumour mostfrequently associated with SIADH is small-cell lungcancer (SCLC), but the syndrome may also occur in avariety of other carcinomas arising in the brain, pros-tate, bladder, pancreas, adrenal cortex, duodenum, headand neck, in mesothelioma, thymoma or sarcoma, andin Hodgkin's disease [3-6].
In tumour-associated SIADH, hyponatremia can mostproperly be alleviated by effective cancer treatment(tumour removal in operable cancer, radiotherapy and/
or chemotherapy in other cases). Otherwise it is difficultto treat, but water restriction can be of temporary help[7, 8].
Some drugs, especially thiazide diuretics, sulfonylurea's and a number of cytotoxic drugs such as vin-cristine, vinblastine, cisplatin, cyclophosphamide andmelphalan also have been shown to produce SIADH [3,9, 10].
We report a case of hyponatremia following adminis-tration of the first course of chemotherapy in a previouslyuntreated patient with SCLC.
Case report
A 62-year-old man with a history of a radical resection ofa hypernephroma seven years ago, and a curative inferiorlobectomy for a squamous-cell lung carcinoma one yearago, was admitted to the hospital with hemoptysis,anorexia and a five kg weight loss. Clinical examinationwas unremarkable. Initial electrolytes and renal functionwere entirely normal. Neuron specific enolase (NSE)was elevated (24.1 microgram/1, upper limit of normal:12.5). Chest CT-scan showed a nodular opacity in the lefthilum with mediastinal adenopathy. Fiberoptic broncho-scopy revealed a tumour in the left lower lobe andlingula. Pathologic examination of the biopsies showedSCLC (oat-cell carcinoma). Screening for distant metas-tases was negative (limited disease).
Chemotherapy with vindesine, ifosfamide and cisplatinwas started. Each infusion of cisplatin was accompaniedby normal saline prehydration and a 5-HT3 antagonist.No other previous or concomitant medications were used.
The day after the start of the chemotherapy, a hypo-natremia (128 mEq/1) developed. The diagnosis ofSIADH was confirmed by an elevated urine osmolality(590 mOsm/kg), a decreased serum osmolality (255mOsm/kg) and an elevated urinary concentration ofsodium. Fluid restriction (maximum 750 ml per day)was prescribed. Three weeks later, at the onset of thesecond chemotherapy cycle, the sodium was 118 mEq/1.The serum NSE fell to a normal value (4.6) (Figure 1).Response evaluation on chest X-ray showed clear tumourregression (Figure 2). A second course of vindesine-ifosfamide-cisplatin was administered.
Radiological examination after two cycles confirmedthe partial response. Electrolyte abnormalities were nolonger present. Chemotherapy was continued up to sixcycles. Serum sodium remained normal. A major partialremission was obtained. Therapy was completed bylocoregional irradiation (39 Gy divided in 13 fractionsof 3 Gy on the tumour, mediastinum and supraclavic-ular nodes).
Comment to the case report
A case of hyponatremia following the first course ofchemotherapy in a previously untreated patient withSCLC is reported, with spontaneous resolution of hypo-natremia during the second course.
The occurrence of hyponatremia due to SIADH atinitial diagnosis is a well known paraneoplastic featureof SCLC [3, 4, 11-13]. In our patient, however, electro-lyte balance and renal function were perfectly normal atdiagnosis.
Hyponatremia due to SIADH can also occur afteradministration of cytotoxic drugs such as vincristine,vinblastine, cisplatin, cyclophosphamide and melphalan.In our patient, hyponatremia did not occur after re-peated administration of the same chemotherapeuticagents in subsequent cycles. This strongly suggests thatthe cytotoxic medication per se was not responsible forthe SIADH in our patient.
We hypothesise that release of ADH from the malig-nant cells during the early tumour breakdown resultedin the transient hyponatremia. This event must be veryrare. In a Medline search (using the terms 'inappropriateADH syndrome', 'carcinoma, small-cell' and 'tumor lysissyndrome'), we retrieved a few individual reports of thisphenomenon in other tumours such as one case afterchemotherapy for acute myeloid leukaemia [14], onecase after radiotherapy for bladder cancer [15], and twocases after chemotherapy for squamous-cell head-and-neck-cancer [16].
The development of hyponatremia due to SIADHduring the initial treatment of SCLC patients with aperfectly normal sodium balance at diagnosis is rare. In
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neuron specific enolase (ug/L)
start 1st 2nd 3rd 4th 5th 6th cycle
Figure 1. Evolution of the neuron specific enolase and serum sodiumat diagnosis (start 1st cycle) and during subsequent treatment.
his review of 350 SCLC patients, List mentioned onlyone patient with a normal sodium at diagnosis, whosubsequently developed a hyponatremia as low as 101mEq/1 after one cycle of chemotherapy [4]. Although thephenomenon certainly must be very uncommon, it isimportant to be aware of this possibility. The occurrenceof hyponatremia during SCLC treatment could be inter-preted as an increase in paraneoplastic expression re-flecting tumour progression, which could erroneouslylead to discontinuation of effective chemotherapy.
Etiology and clinical expression of SIADH
SIADH is one of the most common causes of hypo-natremia in hospitalised patients. It may occur in a variety
Figure 2 (a) Chest X-ray at diagnosis shows a left hilar tumour and right paratracheal adenopathy (arrows); (b) after one cycle of chemotherapy,a normal mediastinal image and an important decrease of the left hilar mass is noted. The partial response was confirmed at the evaluation aftertwo cycles.
of conditions (Table 1). The most frequent reports havebeen in patients with lung cancer, especially SCLC. Indifferent studies, there is an occurrence of SIADH inSCLC of about 10% with a range of 1.3%-69% [3, 5, 8,17-20], according to the different definitions of thesyndrome. On the other hand, SCLC accounts for about75% of the malignancies associated with SIADH. Abroad spectrum of other malignant tumours have alsobeen reported to cause this syndrome: primary braintumours, haematological malignancies, intrathoracicnon-pulmonary cancers, non-small-cell lung cancer,skin tumours, gastro-intestinal cancers, gynaecologicalcancers, breast cancer, prostate and bladder cancer,head and neck cancer, sarcomas, ... [3-6].
Several non-malignant intrathoracic disorders, suchas pulmonary infections and conditions associated withchanges in intrathoracic pressure can be accompaniedby SIADH.
Disorders of the central nervous system including masslesions and vascular, infectious, or metabolic conditionscan cause SIADH by increased secretion of vasopressin.
A variety of drugs may enhance ADH-secretion or itsaction on the distant nephron [21]. Such effects have beendescribed for cytotoxic agents (vincristine, vinblastine,cisplatin, melphalan, cyclophosphamide) and carbama-zepine, chlorpropramide, clofibrate, narcotics, sulfonylureas, thiazide diuretics, oxytocine, and tricyclic antide-pressants.
The signs and symptoms of SIADH depend on thedegree of hyponatremia and the rate of development [3,11,12].
In mild cases the complaints are usually fatigue,anorexia, nausea, diarrhoea and headache.
When the serum sodium falls below 115 mEq/1, neuro-logical symptoms occur: altered mental status, confusion,lethargy, psychosis, seizures, coma and occasionallydeath [11, 12].
In chronic disease the SIADH is mostly asympto-matic. In these patients, a large fluid intake can cause anacute symptomatic hyponatremia.
Pathophysiology
In SIADH there is an increased release of ADH whichcauses excessive water reabsorption in the collectingducts and a resulting dilutional hyponatremia. Thereare 4 mechanisms for excessive ADH release: 1) ectopicADH secretion (release by tumour tissue, infections,conditions with altered intrathoracic pressure such aspneumothorax or status asthmaticus...); 2) increasedhypothalamic production of ADH-like substances inneurological disorders (infections, Guillain Barresyndrome, brain tumours); 3) administration of drugs(cytotoxic agents, carbamazepine, chlorpropramide, clofi-brate, narcotics, sulfonyl ureas, thiazide diuretics, tri-
cyclic antidepressants); and finally 4) administration ofexogenous ADH or oxytocine [3, 22].
Diagnosis
The medical history and physical examination canprovide important clues to a correct diagnosis. Thehallmarks of SIADH are hyponatremia, low plasmaosmolality and a less than maximally diluted urine inthe absence of volume depletion (Criteria of Bartter andSchwartz) [2]. Plasma ADH levels are usually elevated.Renal, adrenal and thyroid function are normal. A lowserum uric acid is a common finding [23, 24].
Prognosis
The prognosis of SIADH depends on the underlyingcause. Drug-induced SIADH is rapidly and completelyreversed by withdrawal of the causative agent. Effectivetreatment of infections (pulmonary or central nervoussystem infections) usually restores a normal sodiumhomeostasis [3, 11].
In SIADH due to malignancies, the correlation withthe prognosis of the disease is not always clear and theresults are controversial. Lokich et al. described a strongcorrelation with development of cerebral metastases[25], but this was not confirmed by others [4]. In a largeseries of SCLC patients, List found no correlation withhistologic subtype, stage or other metastatic sites [4].
Harper et al. showed that the prognosis was better forpatients without SIADH than those with the syndrome,especially in limited disease SCLC [8]. They hypothesisedthat SIADH is associated with tumours where drugresistance emerges quickly. In the Vanderbilt experience,however, no relationship was found between the presenceof SIADH and the response to chemotherapy or overallsurvival [4].
Management of SIADH in cancer patients
It is important to identify and correct the cause of theSIADH as quickly as possible [3]. Treatment depends onthe rate by which the hyponatremia has developed (acuteversus chronic), the serum sodium concentration, andthe patients clinical condition (symptomatic versusasymptomatic). An acute symptomatic hyponatremia isa medical emergency that needs immediate attention.The correction however must be slow, since a rapidcorrection may cause brain damage, sometimes evendevelopment of brain demyelinating lesions (central pon-tine or extrapontine myelinolysis). The rate of correctionshould be no more than 0.5 mEq per litre per hour andthe initial treatment should be halted when the serumsodium concentration is 125-130 mEq/1 [26, 27].
In individuals with symptomatic hyponatremia andserum sodium less than 130 mEq/1, fluid restriction to
less than 500 ml/day is usually sufficient to cause agradual increase in serum sodium and decrease in symp-toms. Patients with life-threatening symptoms such ascoma or seizures may also be treated by infusion ofhypertonic saline (200-300 ml of 5% saline) togetherwith intravenous loop diuretics (furosemide) at a doseof 1 mg/kg. This treatment requires careful monitoringof urinary sodium and potassium with intravenousreplacement of the appropriate amounts of sodium- andpotassium chloride. Oral potassium chloride or potas-sium sparing diuretics like triamterene or amiloride aresometimes necessary to correct the potassium levels.Thiazide diuretics are contraindicated because theyaggravate the hyponatremia [27].
Patients whose SIADH is refractory or unresponsiveto fluid restriction or who are unable to comply, may betreated with drugs that interfere with ADH at the levelof the renal collecting tubules by blocking ADH-inducedcyclic adenosine monophosphate (cAMP). This actionblocks ADH-dependent water retention and facilitatesfree water excretion. The result of this action is thedevelopment of a nephrogenic diabetes insipidus. Threedrugs have this effect: diphenylhydantoin, dimethyl-chlortetracycline (demeclocycline) and lithium, of whichdemeclocycline is the most widely applied for this pur-pose. The recommended initial dose of demeclocycline is600 mg daily [27-29]. The total dose is divided and givenBID or TID. Demeclocycline is not useful for acutetherapy: the onset of its effect starts after four to sevendays. Significant side effects are gastrointestinal intoler-ance, phosphate diabetes, photosensivity, and most im-portantly renal toxicity.
Urea has also been reported to be effective [27, 30].The recommended dose is 30-60 grams daily, divided inthree to four gifts a day, after the meals, and togetherwith antacids. Ureum is contraindicated in patients withrenal failure (serum creatinine more than 2 mg/dl and/or urea more than 80 mg/dl), gastric ulcer and advancedliver disease (risk of hyperammonemia and hepaticencephalopathy). There must be an adequate intake ofwater to prevent a deficit of water. Ureum is cheap andcan be given orally or intravenously. The most importantside effects are headache and gastrointestinal irritation.
Conclusion
SIADH is the most common cause of hyponatremia inhospitalised cancer patients. Attempts should be madeto identify and correct the cause of SIADH as soon aspossible. The criteria for diagnosis of SIADH should beused and the correct cause identified from the numerouspossible differential diagnoses. The occurrence of hypo-natremia during the initial phase of chemotherapy forSCLC, and other tumours, should be interpreted withcaution. Most commonly, this is due to an increase inparaneoplastic ADH secretion, pointing to ineffectivechemotherapy and tumour progression. In the early treat-ment phase, one should also include in the differential
diagnosis the release of ADH from malignant cells inthe period of rapid cell necrosis. Although the last eventis far more rare, it is important to be aware of itspossibility, since it points to effective chemotherapy.
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Received 26 October 1998; accepted 21 September 1999.
