fatal tumor lysis syndrome and gastric hemorrhage associated with metastatic small-cell lung...

BRIEF REPORTFatal Tumor Lysis Syndrome and Gastric Hemorrhage Associated With

Metastatic Small-Cell Lung Carcinoma

Mark A. Marinella, MD*

Key words: tumor lysis syndrome; small-cell carcinoma; gastrointestinal bleeding

Tumor lysis syndrome (TLS) typically occurs duringthe treatment of rapidly growing lymphomas and leuke-mias and is characterized by hyperkalemia, hyperphos-phatemia, hypocalcemia, hyperuricemia, elevation of se-rum lactate dehydrogenase (LDH), and metabolic acido-sis [1]. TLS may be life-threatening, especially if acuterenal failure or hyperkalemia ensues. Treatment of solidmalignancies is uncommonly complicated by TLS, butcases have been reported with treatment of sarcoma,seminoma, melanoma, medulloblastoma, and various ad-enocarcinomas [1,2]. Small-cell lung cancer (SCLC) israrely associated with TLS, with only five cases reportedin the literature, all occurring in patients with metastaticdisease. SCLC is typically very sensitive to various che-motherapeutic agents, which may result in rapid celldeath and characteristic TLS if the tumor burden is high.We here report the sixth known case of TLS associatedwith therapy for SCLC, which was complicated by mas-sive gastrointestinal hemorrhage due to treatment-induced ulceration of a gastric metastasis.

Our patient, a 52-year-old male with hypertension anddiabetes mellitus, was evaluated for several weeks ofdyspnea and a 40-pound weight loss. A chest radiographand computed tomographic scanning documented a righthilar mass and multiple liver nodules as well as bilateraladrenal masses. Ultrasound-guided needle biopsy of oneof the hepatic lesions revealed undifferentiated SCLC;the patient was admitted to the hospital for chemo-therapy.

Vital signs were normal. The patient appeared ill witha markedly enlarged nodular liver. No peripheral ade-nopathy was detected. Laboratory values upon admissionincluded hemoglobin 13.8 mg/dl, prothrombin time 21sec, creatinine 0.9 mg/dl, potassium 4.1 meq/L, aniongap 8, calcium 8.3 mg/dl, phosphorus 4.0 mg/dl, uric acid6.0 mg/dl; liver enzymes were not obtained initially. Thepatient was hydrated with saline and administered allo-purinol, 300 mg daily. On the second hospital day, anintravenous infusion of etoposide, 100 mg/m2 (180 mg)daily and cisplatin, 30 mg/m2 (55 mg) daily was com-

menced for a planned total of 3 days. The following day,serum potassium was 6.0 meq/L; creatinine, uric acid,calcium, phosphorus, and anion gap were normal. Theday after the second infusion of chemotherapy, the pa-tient became lethargic and had three voluminous mela-notic stools, which later contained fresh blood. Chemo-therapy was discontinued. Vital signs were pulse 90,blood pressure 74/40 mm Hg, respirations 22, and tem-perature 97.1°F. Laboratory studies revealed hemoglobin5.8 g/dl, hematocrit 18.6%, potassium 6.8 meq/L, uricacid 6.8 mg/dl, calcium 4.0 mg/dl, phosphorus 8.2 mg/dl,creatinine 0.6 mg/dl, anion gap 29, alanine aminotrans-ferase (ALT) 1,600 U/L, aspartate aminotransferase(AST) 4,660 U/L, and LDH 42,820 U/L. The patient wasadministered fresh frozen plasma, packed red blood cells,vitamin K, famotidine, sodium bicarbonate, allopurinol,and saline. The family, in conjunction with the patient’sprior wishes, requested that only comfort care be insti-tuted. The patient became unresponsive, continued topass bright red blood per rectum, and died on hospitalday five.

An autopsy revealed extensive tumor of the rightmiddle lobe involving the right mainstem bronchus withright hilar, carinal, and paratracheal adenopathy; thepleura was studded with tumor. Approximately 80% ofthe hepatic parenchyma was replaced by tumor, whichwas hemorrhagic. There was a gastric ulcer surroundedby erosion and fresh blood. Bilateral adrenal metastaseswere present. Histologic examination of the gastric ulcerrevealed small-cell carcinoma with acute ulceration; theliver contained small-cell carcinoma with extensive hem-orrhage.

Department of Internal Medicine, Wright State University School ofMedicine, Dayton, Ohio

*Correspondence to: Dr. Mark A. Marinella, 33 West Rahn Road,#201 Dayton, OH 45429. E-mail: mmarinella@pol.net

Received 28 September 1998; Accepted 21 October 1998

Medical and Pediatric Oncology 32:464–465 (1999)

© 1999 Wiley-Liss, Inc.

DISCUSSION

This patient experienced severe TLS shortly aftercommencing chemotherapy for widely metastatic SCLC.Treatment was complicated by massive gastrointestinalbleeding due to acute ulceration of a gastric metastasis.The time course of the gastrointestinal bleeding suggeststhat chemotherapy-induced tumor lysis within the gastricwall led to ulceration and bleeding. The elevated pro-thrombin time was likely due to liver dysfunction frommetastatic tumor and may have contributed to the mas-sive gastrointestinal bleeding this patient experienced.

TLS is characterized by the spontaneous or chemo-therapy-induced release of tumor cell constituents suchas potassium, phosphorus, purines, and lactate dehydro-genase and consequent metabolic abnormalities [1–4].Hyperkalemia can be severe and, as with any etiology ofhyperkalemia, may lead to fatal cardiac rhythm distur-bances [5].

TLS uncommonly complicates therapy for solid ma-lignancies, but rarely with SCLC [2–6]. Only five previ-ous cases have been reported, all of which occurred inpatients with extensive-stage disease [6–10]. SCLC istypically quite responsive to initial chemotherapy andresponse rates even in the presence of extensive stagedisease may occur in up to 85% of patients, so that it isnot surprising that rapid tumor lysis may occur [6].

Of the previously reported patients (Table I), three hadhepatic metastases [7–9], and all had an elevated pre-treatment serum LDH level that ranged between 285 and1,396 U/L [6–10]. Pretreatment potassium levels werenormal in all patients, as were serum uric acid levels.Pretreatment serum creatinine was below 2.0 mg/dl in allpatients and peak serum creatinine ranged from 1.6 to 4.7mg/dl. All three patients who survived had pretreatmentLDH levels under 1,000 U/L [6,7,10], and only one hadhepatic involvement [7]. In addition, both patients whodied had hepatic metastases with pretreatment LDH lev-els of 1,320 U/L [9] and 1,396 U/L [8]. Our patient hadhepatic metastases; however, no pretreatment LDH lev-

els were obtained, but these were likely elevated due toextensive liver involvement. The peak LDH in our pa-tient of 42,820 U/L suggests massive tumor cell lysis,probably of hepatic origin. Autopsy confirmed extensiveliver metastases that were acutely hemorrhagic.

We conclude that TLS should be considered as a pos-sible complication during the treatment of extensive-stage SCLC, especially if pretreatment LDH levels areelevated and hepatic metastases are present. A pretreat-ment LDH level of more than 1,000 U/L may indicate apoor prognosis in patients with extensive-stage SCLCand TLS. In addition, gastrointestinal bleeding that oc-curs shortly after commencing chemotherapy may be dueto ulceration of a metastatic focus within the gastrointes-tinal tract from tumor lysis.

REFERENCES

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3. Barton JC. Tumor lysis syndrome in nonhematopoietic neoplasms.Cancer 1989;64:738–740.

4. Persons DA, Garst J, Vollmer R, et al. Tumor lysis syndrome andacute renal failure after treatment of non–small-cell lung carci-noma with combination irinotecan and cisplatin. Am J Clin Oncol1998;21:426–429.

5. Marinella MA. Hyperkalemia in elderly patients associated withtrimethoprim-sulfamethoxazole. J Geriatr Drug Ther 1996;11:93–97.

6. Kalemkerian GP, Darwish B, Varterasian ML. Tumor lysis syn-drome in small cell carcinoma and other solid tumors. Am J Med1997;103:363–367.

7. Baumann MA, Frick JC, Holoye PY. The tumor lysis syndrome.JAMA 1983;250:615.

8. Vogelzang NJ, Nelimark RA, Nath KA. Tumor lysis syndromeafter induction chemotherapy of small-cell bronchogenic carci-noma. JAMA 1983;249:513–514.

9. Heching N, Bonomi P. Tumor lysis syndrome in metastatic smallcell cancer. Proc Ann Meet Am Soc Clin Oncol 1988;29:179.

10. Hussein AM, Feun LG. Tumor lysis syndrome after inductionchemotherapy in small-cell lung carcinoma. Am J Clin Oncol1990;13:10–13.

TABLE I. Characteristics of Patients With Tumor Lysis Syndrome Associated With Small-Cell Lung Carcinoma*

Patient Reference Sex/Age StageLivermets Treatment

Pretreatment/posttreatment laboratory values

Potassium Uric acid LDH Creatinine Outcome

1 [9] M/67 Extensive Yes CCNU/MTXcyclophosphamide

5.3/8.6 9.4/19.2 1,320/5,187 1.9/4.7 Died

2 [8] F/57 Extensive Yes Doxorubicin/VP16cisplatin

5.1/6.5 10.7/4.6 1,396/6,720 1.3/3.8 Died

3 [10] M/57 Extensive No Cyclophosphamide/doxorubicin Vincristine

4.3/3.6 7.2/13.2 766/N.S. 1.7/4.1 Survived

4 [7] M/78 Extensive Yes Cyclophosphamide/doxorubicin Vincristine

4.7/6.4 7.8/25.5 496/1,295 1.3/4.6 Survived

5 [6] F/74 Extensive No Cisplatin VP16 5.3/5.7 6.7/7.5 285/2,059 1.3/1.6 Survived6 M/52 Extensive Yes Cisplatin VP16 4.1/6.8 6.0/6.8 N.A./42,820 0.9/0.6 Died

*CCNU, lomustine; MTX, methotrexate; VP16, etoposide; LDH, lactate dehydrogenase; N.S., not stated; N.A., not available.

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