Abstract
Oxaliplatin plus 5Fluorouracil (5FU) and leucovorin (LV) is the standard treatment of metastatic colorectal cancer (CRC). We describe a rare clinical case of acute renal failure probably oxaliplatin-related at one day from the end of the palliative treatment. A 36 year-old woman developed a stage I CRC. Five months later a liver lesion was detected and treated with FOLFOX4 schedule. Because of progression the patient underwent surgery and she repeated the Oxaliplatin-based therapy for more than one cycle. After many months of therapy, on the second day, the patient noticed urine discoloration. Immediate urinanalysis demonstrated haemoglobinuria. The patient's complete blood count exhibited signs consistent with acute hemolysis, neutrophilic leucocytosis, thrombocytopenia and acute renal failure. She was treated with blood transfusion and hemodialysis and she was managed conservatively with monitored intravenous hydration and loop diuretics. The patient gradually recovered and the results of successive hematological and biochemical tests confirmed the improvement of her condition but a cardiologic evaluation showed a iatrogenic depressed systolic function (ejection fraction of 40%).
Introduction
The randomised study by de Gramont et al. (1) on 420 patients resulted in higher response rate (RR) (50.7% versus 22.3%; p = 0.0001) and improved median progression free survival (PFS) (9 months versus 6.2 months, p = 0.0001) with FOLFOX4 or de Gramont regimen alone, respectively. Overall survival was not statistically different despite a numerical advantage for the group receiving oxaliplatin (median, 16.2 versus 14.7 months, p = 0.12). FOLFOX4 regimen gave higher frequencies of grades 3–4 neutropenia (41.7% versus 5.3%), grades 3–4 diarrhoea (11.9% versus 5.3%), and grade 3 neurosensory toxicity (18.2% versus 0%). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (p = 0.004). The lack of statistically significant survival benefit favouring the addition of oxaliplatin to 5FU/LV in these two studies delayed the FDA approval of oxaliplatin in first-line therapy in the United States (US).
Subsequent phase II studies in first-line therapy with the FOLFOX4 regimen alone (2) reported 6.2% complete remissions, 28% partial remissions and 25% stable disease (SD). Median duration of response was 5 months and 1-year survival 72%. Neutropenia grades 3–4 occurred in 50% of patients. The treatment was well tolerated and effective.
The efficacy of the combination of oxaliplatin plus 5FU/FA compared with bolus 5FU/FA (as the standard Mayo Clinic regimen) has been shown by a more recent phase III clinical trial (3). RR was 51.4% versus 21.5% (p = n.s.); PFS was 8 months versus 5.6 months (p = 0.0001), respectively.
Oxaliplatin administered with 5FU/LV, according to the typical US schedule (weekly bolus of 5FU and low-dose of LV), gave a RR in 74% of cases with 26% SD (4). Median time to progression (TTP) was 8.5 months. The 95% confidence interval for response and TTP overlapped those values reported in the studies using 5FU continuous infusion (c.i.)/LV and oxaliplatin according to the de Gramont regimen with less costs (1).
Case Report
A 36 year old woman with a metastatic CRC was admitted to hospital because of a sudden onset of thrombocytopenia, anemia and renal failure the day after receiving oxaliplatin-based chemotherapy (CHT).
The patient had a quite long history of CRC: she underwent surgery in December of 2002 for a right colon adenocarcinoma. Pathologic staging revealed a stage I disease.
Then she continued periodical follow up until an abdominal ultrasonography performed in April 2003 detected a liver lesion. A Computed Tomography (CT)-scan confirmed the presence of three hepatic nodules of which the secondary nature was assessed by a biopsy. Thereafter the patient started CHT with Oxaliplatin, LV and 5FU c.i. every 2 weeks (FOLFOX4 regimen). After 6 cycles of CHT, a CT-scan showed a SD, so in November 2003 CHT was stopped.
In August 2004, a CT-scan (and a subsequent PET-CT) performed during follow up, detected disease progression (PD) on the liver. So a decision was made to administer three cycles of Oxaliplatin-based CHT before liver surgery. A blood sample drawn the day of diagnosis, showed a haemoglobin level of 12,3 g/dL, a white blood cell count of 7,3 K/μL, platelet count of 230 K/μL. Surgery was performed in March 2005 and was followed by three other cycles of Oxaliplatin-based CHT. A CT-scan in December 2005 detected a new liver PD. The patient underwent a second liver surgery associated with radiofrequency. From December 2005 the patient was treated with intra-arterial CHT (FUDR). A CT-scan performed in May 2006 showed a lung PD, so the patient continued her treatment with intra-arterial (liver) CHT alternated with FOLFOX4 regimen. The last cycle of systemic CHT was administered on 27th June 2006.
A blood sample drawn the day of the last cycle, showed a haemoglobin level of 11,7 g/dL, a white blood cell count of 11,3 K/μL, platelet count of 240 K/μL. The first day the patient received Oxaliplatin 85 mg/m2, LV 100 mg/m2 plus 5FU 400 mg/m2 bolus, followed by 600 mg/m2 by c.i. over 22 hours. The following day, the patient came back to the clinic for the second day of therapy, but she noticed urine discoloration. Immediate urinanalysis demonstrated haemoglobinuria. The patient's complete blood count exhibited signs consistent with acute haemolysis, neutrophilic leucocytosis, thrombocytopenia and acute renal failure. She was absolutely asymptomatic. The patient was admitted to the Hospital for emergency treatment.
A haemolytic reaction was indicated by elevated lactic dehydrogenase and indirect bilirubin indices (4742 U/L and 41,6 μmol/L respectively). The patient exhibited signs of acute renal failure: urea 15,70 mmol/L, serum creatinine 275 μmol/L and uric acid 0,40 mmol/L. Coagulation parameters were as follows: partial thromboplastin time was 39 sec, INR was 1,80 Ul. D Dimmers were >8000. On the blood count leucocytes were 40,11 K/μL, neutrophils were 39,22 K/μL, platelets count and haemoglobin level were 63 K/μL and 10,4 g/dL respectively. The patient was strictly monitored by haematological tests, urinanalysis and vital signs. Over the next days she developed severe oedema of the legs, hypertension and increase of weight (13 Kg over two days). Platelets and haemoglobin levels decreased to 13 K/μL and 7,7 g/dL respectively two days after CHT administration, while serum creatinine and urea levels increased to 742 μmol/L and 21,80 mmol/L respectively with a concomitant alteration of ion levels and urinanalysis showed persistent proteinuria and haemoglobinuria. The direct antiglobulin Coombs test was positive. A peripheral blood smear was not performed. The patient was treated with antibiotics, was transfused with erythrocytes and platelets and underwent hemodialysis. She was managed conservatively with monitored intravenous hydration and loop diuretics. A contemporary chest and abdomen CT-scan reported liver metastases progression. Moreover, a cardiologic evaluation showed a iatrogenic depressed systolic function (ejection fraction of 40%).
After 8 days hospitalisation the patient developed fever. She was treated with another antibiotic association, but all the cultures performed at fever onset resulted negative. The fever resolved after 9 days. The patient gradually recovered and the results of successive haematological and biochemical tests confirmed the improvement of her condition. The patient was discharged after 20 days of hospitalisation and the laboratory values at that time normalized: haemoglobin and platelets levels were 9,9 g/dL and 316 K/μL respectively, serum creatinine and urea levels were 110 μmol/L and 9,00 mmol/L respectively.
Discussion
Oxaliplatin is a third-generation platinum compound, belonging to the 1,2 diamimocyclohexane platinum compounds with well established activity in CRC. Its mechanism of action, like cisplatin, is through the formation of DNA adducts but DACH-platinum adducts are bulkier and more hydrophobic than cisplatin adducts. The conformational DNA distortions caused by Oxaliplatin in the region of the adducts prevent the Mismatch Repair proteins action. Oxaliplatin safety profile compares favourably with the other platinum-based agents and consists mainly of gastrointestinal side effects (nausea, vomiting), myelosuppression and peripheral neuropathy. Neurotoxicity (cumulative and, usually, mild to moderate) is characterized by paresthesia and dysesthesia in the hands, feet and peroral area and is triggered or enhanced by contact with low temperatures.
Patients treated with Oxaliplatin may develop hypersensitivity and idiosyncratic reactions, although these complications are rare. Acute haematological adverse events have been rarely reported. However, there has been some previous reports in the literature of haemolytic uremic syndrome and Evans syndrome following Oxaliplatin-based CHT.
5FU is an antimetabolite. It is a pyrimidine analogue whose main side effects include myelosuppression, mucositis, dermatitis, diarrhoea and cardiac toxicity.
FOLFOX4 is the name of the well known regimen of CHT made up of Oxaliplatin, 5FU and LV. Common side effects of this regimen are a combination of those of the single agents (myelosuppression, mucositis, dermatitis, diarrhoea, nausea, vomiting, cardiac toxicity, neurotoxicity). Rare side effects are tinnitus, hand and foot syndrome, sensitivity to sunlight, hair thinning and allergic reactions.
In this topic, the acute onset of symptoms and signs after infusion of the chemotherapeutic agent suggested a causative role of CHT. The presence of thrombocytopenia and haemolytic anaemia needed a rapid differential diagnosis among some quite rare syndromes that can be life threatening, like disseminated intravascular coagulation (DIC), thrombocytopenic thrombotic purpura (TTP), haemolytic uremic syndrome (HUS), Evans syndrome (ES).
Disseminated intravascular coagulation is a complex systemic thrombohemorrhagic disorder involving the generation of intravascular fibrin and the consumption of procoagulants and platelets. It is characterized by elevated fibrin and/or fibrinogen degradation products, decreased serum fibrinogen, increased prothrombin time and PTT, thrombocytopenia. It is characterized by generalized bleeding, which ranges from petechiae to exsanguinating haemorrhage or microcirculatory and macrocirculatory thrombosis. This leads to hypoperfusion, infarction and end-organ damage. In severe cases, patients may develop fever and a shocklike picture with tachycardia, tachypnea, and hypotension. Supportive measures as continue prehospital measures (monitor vital signs, assess and document extent of haemorrhage and thrombosis, correct hypovolemia, and administer basic haemostatic procedures when indicated), attending to life-threatening issues such as airway compromise or severe haemorrhage, determining the underlying cause of the patient's DIC and initiating therapy, obtaining appropriate imaging studies if necessary, drawing specimens for appropriate coagulation studies and other diagnostic laboratory tests, beginning of anticoagulant therapy if indicated, replacing blood products as indicated (RBC transfusion, Platelet concentrates, Fresh frozen plasma (FFP), Cryoprecipitate) and antithrombin III concentrate need.
In this case the increase of fibrin degradation products did not support a diagnosis of DIC because fibrinogen level was not decreased and PT/PTT were not prolonged.
TTP and HUS are not distinct syndromes: their essential diagnostic criteria, as microangiopathic haemolytic anaemia and thrombocytopenia, are the same. These characteristics belong to a pentad of clinical features such as microangiopathic haemolytic anaemia, thrombocytopenia, neurological and renal abnormalities, fever, which are considered diagnostic of TTP/HUS. However, although neurological abnormalities are commonly typical for TTP and renal failure is commonly typical for HUS, patients with these syndromes may have neither abnormality or both (11, 13, 18).
The patient presented haemolytic anaemia and thrombocytopenia, with a predominance of renal abnormalities (more characteristic of HUS than TTP). We did not perform the peripheral smear so it is not possible to confirm the microangiopathic nature of the hemolysis, fundamental for the diagnosis. The pathogenesis of TTP/HUS is still not fully understood despite recognition of multiple triggers (5).
A significant number of TTP/HUS may result from underlying infectious diseases, but our patient did not suffer any symptom at the time of admission and no clinical sign of either laboratory value but neutrophilia may support this hypothesis. Some rheumatologic syndromes (e.g. SLE) may also present with a TTP/HUS. Organ- and non-organ-specific autoantibodies have been analysed, but antibody positivity, in the absence of any rheumatologic symptom, has been considered by our specialists cancer related. A number of drugs have been implicated as causal agents of thrombotic microangiopathy, either as an acute immuno-mediated toxicity (quinine (6), ticlopidine, clopidogrel) or as a cumulative dose-dependent toxicity (mitomycin C (7), cisplatin (8), gemcitabine). Development of TTP/HUS has been previously reported as a severe toxicity of 5FU/LV CHT (almost always in combination with agents known to cause HUS/TTP) and of Oxaliplatin-based CHT (12, 14–17) too. The time and rapidity with which the thrombocytopenia developed is highly suggestive of an immune-mediated cause with a probably predominant causative role of CHT.
Prompt recognition of TTP is important because of its good response to plasma-exchange treatment but has a high mortality rate if untreated. Some studies reported a deficiency of a Von Willebrand Factor-Cleaving Protease, termed ADAMTS-13, in patients with a diagnosis of TTP but not in patients with a diagnosis of HUS. The intervention of plasma-exchange is ineffective in HUS because its role is antibodies removal and Von Willebrand Factor-cleaving protease replacement. HUS is more common in children and is subdivided into typical HUS, which is associated with intestinal infection with Shiga-toxin producing bacteria or atypical HUS, which is not related to a specific infection and may also be caused by certain drugs (26).
The presence of fragmented red cells and polychromatophilic red cells on the peripheral smear, increased levels of lactic dehydrogenase and indirect-reacting bilirubin, and a negative direct Coombs test, are important tests for TTP/HUS diagnosis. In our case the laboratory tests showed a haemolytic anaemia: we cannot confirm the microangiopathic nature of the anaemia because we did not perform the peripheral smear, mandatory for the diagnosis. The positive direct Coombs test was a bit confounding: we can consider it a pre-existing condition with no pathogenic relevance.
An antiglobulin test performed later on was negative. We did not look immediately for a deficiency of ADAMTS-13. The laboratory is testing now ADAMTS13 activity, but as we know through the literature, it will probably result not informative (9, 10).
Evans syndrome (ES) is characterized by the combination of immune thrombocytopenia and autoimmune haemolytic anaemia with a positive direct antiglobulin test in the absence of known underlying aetiology (19). Features of hemolysis are invariably present, the direct antiglobulin test is almost invariably positive, while assays for anti-platelet antibodies have shown varied results: a negative result does not exclude the diagnosis and testing it at presentation may not be helpful. Prednisone (e.g. 1–2 mg/kg dose, usually divided bid or tid) often effectively controls acute episodes. Although some patients are successfully weaned off steroids, relapses may occur when prednisone is tapered or stopped. Patients with persistent immune cytopenia and those who require prolonged or high doses of steroids may benefit from intravenous immune globulin (e.g. 1–2 gm/kg/d for 1–2 d). Their thrombocytopenia is more likely than their hemolysis to respond. Long-term control of thrombocytopenia reportedly is achieved with interval doses of intravenous immune globulin. One of the newer agents that have been tried in refractory Evans syndrome is rituximab. Rituximab is a humanized monoclonal antibody (chimeric human/mouse monoclonal antibody) directed against CD20 and approved for the treatment of relapsed and refractory B-cell non-Hodgkin lymphoma. Binding of rituximab to cells expressing CD20 results in cell death by means of a combination of mechanisms, including antibody-dependent cell cytotoxicity, complement activation and apoptosis. Hence, it has been used in the treatment of a variety of autoimmune disorders mediated by autoantibodies.
Our patient developed an autoimmune haemolytic anaemia with a positive direct antiglobulin test and thrombocytopenia without known underlying aetiology. Autoantibodies testing for platelets were negative. Like TTP/HUS, ES may be the clinical presentation of some autoimmune conditions. There are a few reports in the literature of drug-induced Evans syndrome (20).
Conclusion
The discussed case was hard to interpret because of the rarity of syndromes it could be caused by, because of the non-specificity of symptoms and signs it presented with and because of the inaccuracy in some diagnostic approach we made. Cancer demonstrates one more time to be a very complex disease. Many complications could occur in a cancer patient, and they are often hard to explain because cancer is able to modify the immunological system, many metabolic pathways and much more that we cannot detect and explain. It was not possible to study all the components of the disease, so in this case we considered cancer a major risk factor and CHT as the main and most probable cause of presented symptoms and signs. There are multiple reports in the literature about haematologic complications in cancer patients (21–26). Here we concluded that HUS/TTP and Evans syndrome are the most probable CHT-induced diseases.
Oxaliplatin-based CHT is nowadays the gold standard for patients with metastatic CRC. Although it is well tolerated because its favourable safety profile, recent reports about severe haematological emergencies need to be taken into account. This report enriches the body of cases of haemolytic anaemia and thrombocytopenia after Oxaliplatin-based CHT (not usually reported after 5FU administration). The HUS/TTP and ES's pathogenetic mechanisms need to be studied to make the diagnosis of such cases easier. The increasing use of Oxaliplatin in the CRC's management could represent the cause of an increasing number of haematological adverse events that need to be recognized promptly. Increased vigilance among oncologists is required. Oncologists should be aware of these facts occurrences.