Abstract
Background/Aim: Tumour lysis syndrome (TLS) is a life-threatening oncological emergency. TLS is rare and associated with a higher mortality rate in solid tumours than in haematological malignancies. Our case report and literature review aimed to identify the distinctive features and hazards of TLS in breast cancer. Case Report: A 41-year-old woman complained of vomiting and epigastric pain and was diagnosed with HER2-positive, hormone-receptor-positive breast cancer with multiple liver and bone metastases and lymphangitis carcinomatosis. She had several risk factors for TLS: high tumour volume, high sensitivity to antineoplastic treatment, multiple liver metastases, high lactate dehydrogenase levels, and hyperuricaemia. To prevent TLS, she was treated with hydration and febuxostat. One day after the first course of trastuzumab and pertuzumab, she was diagnosed with disseminated intravascular coagulation (DIC). After 3 further days of observation, she was relieved of DIC and administered a reduced dose of paclitaxel without life-threatening complications. The patient achieved a partial response after four cycles of anti-HER2 therapy and chemotherapy. Conclusion: TLS in solid tumours is a lethal situation and can be complicated by DIC. Early recognition of patients who are at risk of TLS and initiation of therapy is essential to avoid fatal situations.
Tumour lysis syndrome (TLS) is an oncological emergency associated with malignancies and their treatment. TLS results from the release of intracellular contents including potassium, phosphate, nucleic acids, and other metabolites into the bloodstream secondary to the rapid breakdown of tumour cells. This condition may lead to acute kidney injury and cardiac arrhythmias; all of which could be life-threatening (1). TLS is a well-known clinical problem in haematological malignancies. In solid tumours, TLS is rare but the risk can be increased by factors including bulky tumours, extensive metastatic diseases including visceral or bone marrow involvement, pre-existing high serum uric acid or lactate dehydrogenase levels, tumours with high sensitivity to antineoplastic treatment, and underlying renal dysfunction (1, 2). TLS is associated with a higher mortality rate in solid tumours than in haematological malignancies (2).
We report a case of metastatic human epidermal growth factor receptor 2 (HER2)-positive, hormone-receptor-positive breast cancer with successful prevention of TLS. We discuss the importance of assessing the risk of TLS and taking appropriate preventive measures.
Case Report
A 41-year-old Japanese woman with no significant medical or family history of breast and ovarian cancer initially presented to another hospital with complaints of vomiting and epigastric pain. Computed tomography revealed a 3.0×1.5-cm right breast mass, multiple liver and lumbar spinal lesions, and thickening of the interlobular septa in both lung fields (Figure 1 and Figure 2). Subsequently, the patient presented to our Department for evaluation and treatment. Ultrasound-guided biopsy of the right breast mass yielded an invasive ductal carcinoma, positive for oestrogen receptor, progesterone receptor, and HER2 by immunohistochemistry. We diagnosed HER2-positive, hormone-receptor-positive breast cancer with multiple liver and bone metastases, and lymphangitis carcinomatosis. Initial laboratory results indicated hyperuricemia (9.8 mg/dl) and high lactate dehydrogenase (LDH) level (4,361 U/l), but no complications of renal failure. However, the patient was considered to be at risk for TLS because of high tumour volume, high sensitivity to antineoplastic treatment, multiple liver metastases, and high LDH levels. To prevent TLS, high-dose saline hydration and febuxostat were initiated. Three days later, after uric acid levels had decreased, we decided to initiate anticancer therapy. We scheduled weekly paclitaxel with triweekly trastuzumab and pertuzumab (PHP) therapy, but considering the risk of TLS, only trastuzumab (8 mg/kg) and pertuzumab (840 mg/body) were initially administered. On the day of administration, her blood tests showed platelet count 8.4×104/μl (from 24×104/μl at baseline), fibrin/fibrinogen degradation products 186.9 g/ml, D-dimer level 66.6 μg/ml, fibrinogen level 124mg/dl, and prolonged prothrombin time 3.2 s. The calculated disseminated intravascular coagulation (DIC) score by the International Society on Thrombosis and Haemostasis was 5 (3), and she was definitively diagnosed with DIC. Three days later, platelet cell count recovered to 17.9×104/μl, within the normal range, and LDH level peaked. Therefore, we administered low-dose paclitaxel (40 mg/m2) on the same day. After 18 days in hospital, she was discharged with no further problems. After four cycles of PHP therapy, she was evaluated by computed tomography and it was found that she had achieved a partial response, according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 system (Figure 3). Three years after diagnosis, she is still alive and has been receiving the same therapy with good performance status.
CT before treatment showed a right breast mass (A, arrowhead), multiple liver lesions that were enhanced in the portal phase (B) and thickening of the interlobular septa in both lung fields (C, arrowheads). CT: Computed tomography.
Pre-treatment magnetic resonance imaging. Multiple tumours in the spine showed low intensity on T1-weighted images (A, arrowheads) and T2-weighted images (B, arrowheads).
CT findings after four cycles of weekly paclitaxel with triweekly trastuzumab and pertuzumab. CT showed high therapeutic efficacy for the right breast mass (A, arrowhead) and multiple liver metastases (B, arrowheads). CT: Computed tomography.
Discussion
TLS occurs most often in patients with haematological malignancies. TLS in solid tumours is rarely observed and its incidence was <0.3% in a single-centre study (4). However, in recent years, it has been increasingly reported because of the widespread use of molecular targeted therapies, and other therapies with high response rates (5-7).
The mortality rate related to TLS is about 33% in solid tumours and is higher than in haematological tumours (8). High mortality of solid-cancer-related TLS is mostly caused by the disease itself or other treatment-related complications such as infection or organ failure (2). TLS can classically occur following any active anticancer therapy, such as chemotherapy, radiotherapy, or immunotherapy, and it can also spontaneously occur from tumour necrosis prior to onset of anticancer therapy (9). Spontaneous TLS can occur in tumours with high proliferative capacity. In solid tumours, spontaneous TLS relative to overall TLS ranges from 14% to 47% and is more frequent than in haematological tumours (9, 10). Aggressive fluid resuscitation to maintain a large urine output remains the mainstay of management. In our case, spontaneous TLS was suspected because of hyperuricaemia and high LDH level, and hydration and febuxostat may have prevented the onset of spontaneous TLS and allowed anticancer therapy to be administered.
Our literature review revealed 21 cases of breast cancer with the development of TLS (Table I) (5-7, 11-26). The histology of these tumours was mainly invasive ductal carcinoma and tumours of all subtypes were included. All cases had distant metastasis and 15 of 21 (71.4%) had liver metastasis. Most cases of TLS were induced by chemotherapy (52.4%), but also by hormone therapy (19.0%), anti-HER2 therapy (9.5%), immunotherapy (4.8%), or radiotherapy (4.8%). The mortality rate of these cases was 52.4% (11 of 21 patients died). These data confirm the theory that TLS has worse prognosis in patients with breast cancer. Patients who successfully recovered from TLS were often treated with the addition of aggressive hydration, plus allopurinol or rasburicase for hyperuricaemia. However, there were two cases (23, 25) in which the simultaneous utilization of fluid replacement and uric acid reduction therapy did not lead to preservation of life. The shared feature in these cases was the presence of renal dysfunction, which was observed from the initiation of TLS treatment. There were two cases of spontaneous TLS, both with liver metastases; the case of Sklarin et al. (15) had lobular carcinoma and the case of Parsi et al. (24), like our case, had HER2-positive, hormone-receptor-positive invasive ductal carcinoma. This indicates that TLS can develop after induction of therapy in all subtypes of breast cancer, or spontaneously in tumours with high proliferative potential, such as HER2-positive breast cancer. After renal dysfunction has occurred, it may be difficult to preserve the patient’s life. It is important to initiate treatment immediately when any suspicious symptoms are noticed.
Comparison of our case with reported cases of TLS in breast cancer.
Second, patients with TLS or at high risk for TLS may be complicated with DIC. Cancer patients are more likely to develop DIC from infection as well as anticancer therapy (27). DIC has been reported in 7%–15% of patients with metastatic solid tumours (28, 29). The mortality rate of cancer-related acute DIC is high because of severe thrombocytopenia, organ dysfunction, and bleeding complications (30). Malignancy results in a hypercoagulable state caused by the production and release of procoagulant factors by tumour cells, and the release of procoagulant factors associated with the disintegration of tumour cells in the blood (27). This suggests that tumour cell disruption causes both TLS and DIC.
The cornerstone of DIC treatment in cancer patients includes treatment of the underlying disease, anticoagulant therapy, replacement therapy, and systemic control (31). Treatment of the underlying disease is the most important, and success in this treatment contributes to withdrawal from DIC (27). There are several reports in the literature of TLS complicated with DIC (Table II) (32-34). Watanabe et al. presented a case of prostate rhabdomyosarcoma with multiple bone metastases, with TLS and DIC before treatment (33). Rasburicase was administered on day 1 of chemotherapy. On day 3, the patient developed worsening DIC secondary to TLS, but the patient ultimately recovered as a result of early recognition of TLS (33). In contrast, concurrent TLS and DIC after chemotherapy were reported in a patient with pancreatic cancer with liver metastasis who died despite allopurinol and anti-DIC therapy (34). Fatal situations arising from combination of TLS and DIC are difficult to manage but may be prevented with early detection. In our case, early initiation of treatment for TLS may have resulted in improvement of DIC without anti-DIC therapy.
Comparison of our case with reported cases of co-occurrence of TLS and DIC in solid tumours
In conclusion, TLS in solid tumours is associated with a high risk of death and can be complicated by DIC; therefore, it is important to recognize patients at risk for TLS early and initiate treatment to avoid a fatal situation.
Acknowledgements
We thank Cathel Kerr, BSc, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
Footnotes
Authors’ Contributions
SO researched the literature, and wrote the manuscript. TS provided direct patient care, researched the literature, and edited the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received January 31, 2023.
- Revision received February 22, 2023.
- Accepted March 7, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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