Fatal tumor lysis syndrome after irinotecan/5-FU/folinic acid/bevacizumab-containing therapy in a patient heavily pretreated for metastatic colon cancer

To the Editor

Tumor Lysis Syndrome (TLS) is a metabolic complication usually arising from treatment of rapidly proliferating and drug-sensitive neoplasms. It comprises a number of metabolic abnormalities such as hyperkalemia, hyperuricemia, hypocalcemia and precipitation of calcium phosphate or urate that occur as a result of spontaneous or treatment-related cell death. Commonly described in hematopoietic malignancies, it occurs rarely in solid tumors [1].

We report on a patient with a ten-year history of metastatic colon cancer who developed TLS after having received 5^th line irinotecan/5-FU/folinic acid/bevacizumab-containing chemotherapy.

In March 1996 a 62-year old man was diagnosed with colon cancer metastasized to the right lung. From May 1996 to August 1997 he received 12 courses of 5-FU/folinic-acid (FA) based chemotherapy (Mayo regimen) followed by surgical excision of the remaining lung metastases. Recurrent lung metastases were excised in June 1999 (1^st relapse) and June 2000 (2^nd relapse). Tumor tissue was negative for expression of epidermal growth factor receptor (EGFR). From May 2002 to April 2003 eight courses of capecitabine were administered for recurrent disease involving lungs and thyroid. A transient partial remission was achieved. However, lung metastases increased in size again and proved unresponsive to two courses of 3^rd line chemotherapy with oxaliplatin and infusional 5-FU/FA (FOLFOX) given from May–July 2003. Treatment was changed to irinotecan/infusional 5-FU/FA in August 2003 with only one course being applied because the patient experienced severe diarrhea refractory to appropriate supportive therapy. He was thus followed by observation from November 2003 to January 2005. As lung metastases increased in size again another cycle FOLFIRI was administered. However, severe diarrhea resulted in early termination of chemotherapy. Since the patient experienced progressive lung disease FOLFIRI was restarted under intensive supportive medication in August 2005. After having responded to two courses of FOLFIRI the patient requested termination of chemotherapy. Radiation was administered for newly diagnosed bone metastases in November 2005. The patient received monthly bisphosphonates but refused any further chemotherapy.

More than ten years after primary diagnosis of metastatic colon cancer the patient presented with progressive bone and lung metastases, the latter involving almost the entire lung. Serum lactatdehydrogenase (LDH), uric acid and creatinine were elevated at 493 U/l, 9.7 mg/dl and 1.4 mg/dl, respectively. The patient received bevacizumab 5 mg/kg i.v. (day 1) in combination with irinotecan (50 mg/m² day 1), FA (400 mg/m² day 1) and 5-FU (1 400 mg/m² as 24 h continous infusion). Over the next two days, massive signs of TLS developed. LDH increased to 2 336 and 5 014 U/l, uric acid to 13.6 mg/dl and serum creatinine to 3.7 mg/dl. Likewise, serum urea and phosphate rose to 196 mg/dl and 3.2 mmol/l, respectively. Despite vigorous hydration, urine alkalisation and rasburicase-based uricolytic therapy the patient deteriorated and died of acute renal failure.

There are two remarkable aspects with this case. First, a ten-year survival may sporadically be achieved in patients with metastatic colorectal cancer (CRC). Second, a fatal TLS developing after the use of bevacizumab in combination with a 5-FU/irinotecan-containing regimen for metastatic CRC has, to our knowledge, not been reported previously. As the patient presented with a high tumor burden, reduced doses of irinotecan, FA and 5-FU were used. Likewise, we favored the AIO-regimen as it is less intensive than the FOLFIRI-protocol [2]. The available literature describes two cases of TLS after treatment with single agent irinotecan and 5-FU/FA/irinotecan given for metastatic CRC, respectively [3], [4]. Our patient differs from these cases not only in that he was not irinotecan-naive but he also did receive bevacizumab-based targeted therapy [5]. Thus, as it is the only novel drug applied, bevacizumab might at least have in part contributed to his rapid metabolic deterioration.

In summary, TLS may occur even in heavily pretreated patients with far advanced CRC. When bevacizumab-containing cytotoxic chemotherapy is initiated [6], patients with bulky CRC might carefully be monitored for signs of TLS.