Introduction
Hypocalcemia is a commonly encountered metabolic abnormality in hospitalized patients. Drug induced hypocalcemia may be masked by other adverse drug reactions or disease states, and the involvement of a specific agent in its pathogenesis may be overlooked. On the other hand, the degree of severity of drug related hypocalcemia is usually mild and often a symptomatic, though it can be severe sometimes. Among chemotherapeutic agents, cisplatin is a well-known cause of hypocalcemia. In contrast, combination of leucovorin/5-fluorouracil (LV/5-FU) is less commonly addressed cause. In this case we report a case of hypocalcemia developed after starting this chemotherapeutic agent.
Case Report
34 years old woman was referred to our oncology service for further management of metastatic gastric adenocarcinoma. She initially presented to the primary institution with three months history of fatigue, weakness, poor oral intake, dysphagia, vomiting, abdominal pain and 7 kg weight loss. Rest of systemic review was unremarkable. Physical examination showed pleasant young lady who was alert and oriented. She was afebrile and her blood pressure was 123/90 mmHg, heart rate 94 beats/minute with oxygen saturation of 98% in room air. Systemic examination was unremarkable except for diffuse mid-epigastric tenderness with mild to moderate ascites. No rebound and no palpable masses were elicited. There was no detectable lymphadenopathy in neck, axilla or groin.
Work up with esophagogastroduodenoscopy (EGD) revealed narrowing of the esophagus with ingurgitated gastric mucosal folds in the corpus and fundus of the stomach. Multiple biopsies were taken and were consistent with poorly cohesive carcinoma with signet cell features. Further staging with chest, abdomen and pelvis CT showed ascites and abnormal soft tissue density surrounding the celiac artery and superior mesenteric artery extending into the left adrenal fossa and associated with mild left hydronephrosis. Abdominal paracentesis was performed and consistent with a malignancy. In the context of advanced gastric adenocarcinoma with intra-abdominal metastasis and malignant ascites, she was not considered a surgical candidate and a decision was made to start systemic palliative chemotherapy with FOLFOX (combination regimen of leucovorin, 5-fluorouracil and oxaliplatin).
Prior to starting the chemotherapy, baseline investigations showed mild hypokalemia 3 mmol/L (3.6-5.1), bicarbonate 30 mmol/L (22-32) and estimated glomerular filtration rate (eGFR) 89 ml/min/1.73m2. Bone profile was normal with corrected calcium 2.36 mmol/L (2.23-2.58), magnesium 0.77 mmol/L (0.74-1.03) and phosphorus 1.2 mmol/L (0.78-1.53). Six days after first cycle of chemotherapy, the patient was readmitted with 3 days history of weakness, poor oral intake, loss of appetite and severe mucositis, stomatitis, keratoconjunctivitis, mouth and genital ulceration as well as skin discoloration.
Initial investigation showed beside hypokalemia, mild hypocalcemia with corrected calcium level 2.13 mmol/L (2.23-2.58), hypophosphatemia with phosphorus level 0.38 mmol/L (0.78-1.53) and magnesium level 0.67 mmol/L (0.74-1.03). Corrected calcium continued to drop slowly and on the fifth day post admission, her corrected calcium was 1.86 mmol/L with phosphorus level 0.31 mmol/L, magnesium level 0.78 mmol/L and eGFR 95 ml/min/1.73m2. At the same time, intact parathyroid hormone (iPTH) was 51.27 pmol/L (1.6-6.9) and 25- hydroxyvitamin D level was 95 nmol/L (50-150).
Total parenteral nutrition (TPN) was started on the next day and two days post TPN initiation, endocrinology consultation was obtained for hypocalcemia with secondary hyperparathyroidism. Labs were repeated (while on TPN) and showed the following results: corrected calcium 2.15 mmol/L, magnesium 0.91 mmol/L, phosphorus 0.53 mmol/L, iPTH 13.1 pmol/L, 25- hydroxyvitamin D 86 nmol/L, 1,25- dihydroxyvitamin D 24 ng/L (20-80) equivalent to 58 pmol/L (48-192).
Unfortunately, the patient developed pancytopenia with neutropenic fever ended up with septic shock and she passed away few days later.
Discussion
To our knowledge, few studies were published regarding hypocalcemia associated with chemotherapy, especially in the LV/5-FU regimen. Among chemotherapeutic drugs, cisplatin is commonly known to cause hypocalcemia through inducing hypomagnesemia [
1]. This leads to functional hypoparathyroidism and parathyroid hormone (PTH) resistance [
2]. FOLFOX is a chemotherapy regimen that contains beside oxaliplatin, a combination of LV/5-FU. Most of the studies on this combination report the hematological and other non-hematological toxicities including mucositis, stomatitis and other gastrointestinal side effects [
3,
4]. Hypocalcemia as a side effect of this combination is usually overlooked despite the fact that this combination has been reported to cause hypocalcemia in 65% of patients [
5]. Hypocalcemia was observed with different number of chemotherapy courses in which some patients developed it even after one chemotherapy course. It had been found that combination of LV/5-FU was associated with significant reduction of 1,25(OH)2D3 level on measurements obtained on the fifth day post-chemotherapy compared to pre-chemotherapy level [
5]. Despite the fact that the mechanism for the decrease in 1,25(OH)2D3 with this chemotherapy remains obscure, one possibility is inhibition of the renal 1a-hydroxylase activity [
5].
In our case, 1,25 dihydroxyvitamin D was in the lower normal range despite normal 25 hydroxyvitamin D level, appropriate PTH response and normal magnesium level. In profound vitamin D deficiency, the level of 1,25(OH)2D3 is usually low. In moderate vitamin D deficiency, the stimulation of the renal 1a-hydroxylase by PTH can result in a normal or even elevated 1,25(OH)2D3 level. These high levels of 1,25(OH)2D3 reflect the action of PTH on the renal 1a-hydroxylase [
6].
Conclusion
It is assumed that this side effect (hypocalcemia) is transient with the chemotherapy courses and this case emphasizes the importance of monitoring hypocalcemia clinically and biochemically in patients receiving chemotherapy with leucovorin/ 5-fluorouracil regimen and replacing accordingly with calcium and active vitamin D analogue once needed.
References
- Goltzman D, Rosen CJ, Mulder JE. Etiology of hypocalcemia in adults [internet]. 2015: UpToDate. Available from: www.uptodate.com. Accessed on March 24, 2016.
- Njoh RF, Nguyen A, Sadigh M. Cisplatin Induced Hypomagnesemic Hypocalcemia-A Case Report and A Review of the Pathophysiology. Clinical Case Reports. 2013:3(3):259.
- Kim DY, Kim JH, Lee SH, Kim TY, Heo DS, Bang YJ, et al. Phase II study of oxaliplatin, 5-fluorouracil and leucovorin in previously platinum-treated patients with advanced gastric cancer. Annals of Oncology. 2003:14:383-387.
- Tsalic M, Bar-Sela G, Beny A, Visel B, Haim N, et al. Severe toxicity related to the 5-fluorouracil/leucovorin combination (the Mayo Clinic regimen): a prospective study in colorectal cancer patients. American Journal of Clinical Oncology. 2003:26(1):103-106
- Kido Y, Okamura T, Tomikawa M, Yamamoto M, Shiraishi M, Okada Y, Yamamoto M, et al. Hypocalcemia Associated with 5-Fluorouracil and Low Dose Leucovorin in Patients with Advanced Colorectal or Gastric Carcinomas. Cancer. 1996:78(8):1794-1797.
- Bringhust FR, Demay MB, Kronenberg HM. Hormones and Disorders of Mineral Metabolism. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM (eds.), Williams Textbook of Endocrinology. 13th ed. Elsevier: Canada; 2015. pp.1253-1322.