Gemcitabine and carboplatin chemotherapy safely administered to a patient with homocystinuria.

We report the successful treatment of a patient with homocystinuria with combination chemotherapy and radiotherapy for a non-small cell lung cancer. A 62-year-old man presented in April 2004 to the Acute Medical Unit with three episodes of hemoptysis. He denied shortness of breath or infective symptoms. At age 24 years, he had been diagnosed as having homocystinuria after bilateral downward lens dislocations and had been successfully treated with niacin, betaine, and pyridoxine supplements. On initial assessment, he had a Marfanoid appearance, and his respiratory and cardiovascular systems were unremarkable. Blood tests demonstrated normal hematology and biochemistry, but D dimer was elevated at 928. An electrocardiograph showed Right Bundle Branch Block, and chest radiograph was unremarkable. A computed tomography-pulmonary angiography showed a filling defect in left upper lobe pulmonary artery, which, although consistent with pulmonary embolus, was not typical. Anticoagulation and a repeat computed tomographic scan was advised 4 weeks later to exclude a neoplastic lesion. This repeat scan demonstrated that the left upper lobe bronchus was occluded by a soft tissue mass (Figure 1). In addition, there was a 12-mm subcarinal lymph node, a heterogeneous 6.5-cm left adrenal mass containing a small area of fat and calcification, and the liver contained hemangiomas. The patient underwent bronchoscopy, which confirmed a squamous cell carcinoma occluding the left upper lobe bronchus. The patient was thus referred to the Edinburgh Cancer Centre, and treatment options were discussed at the Lung Cancer Multi-disciplinary Meeting. The appearances of the adrenal mass were inconclusive, consistent with a benign adenoma, a metastatic deposit, or a primary adrenal tumor. Urinary screening for catecholamines was negative for phaechromocytoma; therefore, the patient underwent a biopsy of his adrenal gland, which showed vascularized stroma but no evidence of metastatic cancer, although there was the possibility of it representing scarring within an adrenal neoplasm. In light of this biopsy result, we assessed the response of both the lung and adrenal lesions to chemotherapy. A response in the adrenal tumor would have been consistent with a metastatic tumor. The patient received a total of four cycles of carboplatin at area under the curve 6 on day 1 and gemcitabine 1200 mg/m2 on days 1 and 8 of a 21-day cycle. His second cycle was delayed by a week because of neutropenia, and the day 8 gemcitabine on cycle 3 was omitted for the same reason. He tolerated the treatment well, with only grade 2 fatigue as a significant side effect. Computed tomographic scans performed after the second and fourth cycles demonstrated a minor response from the lung primary, although measurements remained unchanged and the adrenal mass was reduced slightly, from 65 mm to 53 mm. To clarify the true tumor stage, the patient underwent a fludeoxyglucose-positron emission tomography scan, which demonstrated only increased uptake at the site of the primary, with no mediastinal or metastatic deposits. Accordingly, he proceeded to radical radiotherapy, receiving 55 Gy in 20 fractions over 4 weeks, which he tolerated well, and at follow up in December 2005, he was doing well with no evidence of recurrent disease. Homocystinuria is an autosomal recessive condition, which, in the classic form, is the result of a mutation of the long arm of chromosome 21 (21q22.3). This results in a reduction of cystathionine synthase and, hence, accumulation of homocystine. It is characterized by Marfanoid appearances: pale skin and brittle hair, ocular changes (including downward lens dislocation), developmental delay, psychiatric illnesses, osteoporosis, and vascular events, which include both embolic and thrombotic episodes.1Yap S Classical homocystinuria: vascular risk and its prevention.J Inherit Metab Dis. 2003; 26: 259-265Crossref PubMed Scopus (88) Google Scholar A quarter of patients die of a vascular event before their 30th birthday.1Yap S Classical homocystinuria: vascular risk and its prevention.J Inherit Metab Dis. 2003; 26: 259-265Crossref PubMed Scopus (88) Google Scholar Treatment includes the use of pyridoxine, betaine, and high-dose folic acid.2Wilcken DE Wilcken B Dudman NP Tyrrell PA Homocystinuria: the effects of betaine in the treatment of patients not responsive to pyridoxine.N Engl J Med. 1983; 309: 448-453Crossref PubMed Scopus (183) Google Scholar This patient had an abnormal presentation; he had initially been diagnosed with Marfan’s syndrome until, at age 24 years, he developed bilateral downward lens dislocation, which is pathonmonic of homocystinuria. He was then told that he was the oldest known presentation of homocystinuria. The patient has a previous psychiatric diagnosis, well controlled on medication, and hypertension, but had no other signs of vascular disease or osteoporosis. His homocystine levels had not previously responded to methionine deplete diet or to vitamin B injections and high-dose folic acid, but his disease had been controlled with niacin 250 mg four times a day, betaine 10 mg twice a day, and pyridoxine 800 mg once a day. Before we began chemotherapy with this patient, we conducted a MEDLINE search to investigate any previous reports of potential problems in administering cytotoxic agents to a patient with this condition. No previous reports of a patient with homocystinuria receiving chemotherapy could be identified. Theoretically, the chemotherapy could affect the patient’s metabolism, or there could be altered metabolism of anticancer agents.3Schwahn B Rozen R Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences.Am J Pharmacogenom. 2001; 1: 189-201Crossref PubMed Scopus (179) Google Scholar Studies have indicated that children with acute lymphoblastic leukemia have elevated homocysteine levels before chemotherapy (likely related to intracellular folate deficiency and export of homocysteine from leukemic cells) and that these levels transiently increase post methotrexate (an antifolate drug) before decreasing after three methotrexate adminstrations to levels seen in controls.4Refsum H Wesenberg F Ueland PM Plasma homocysteine in children with acute lymphoblastic leukemia: changes during a chemotherapeutic regimen including methotrexate.Cancer Res. 1991; 51: 828-835PubMed Google Scholar Our patient had normal B12 and folate levels. In patients with homocystinuria, it is possible that the administration of anti-folate chemotherapy such as methotrexate or pemetrexed could have significant adverse effects as the reduced availability of folates could lead to decreased availability of the enzyme that converts homocysteine back to methionine (Figure 2). A study has also shown that the administration of a 6-azauridine triacetate, a pyramidine nucleoside analogue previously used in mycosis fungoides, psoriasis, and trophoblastic malignancies, caused amino acid changes similar to homocystinuria.5Slavik M Changes in amino acid metabolism caused by 6-azauridine triacetate: relevance to cancer treatment.Cancer Treatment Rep. 1979; 63: 1041-1044PubMed Google Scholar The use of gemcitabine (also a nucleoside analogue that inhibits DNA synthesis) and carboplatin could potentially have upset the patient’s metabolic balance, or the drugs could have been metabolized less efficiently, leading to increased side effects; however, glutathione (involved in inactivation of platinum drugs) levels have been found to be normal in patients with homocystinuria.6Hargreaves IP Lee PJ Briddon A Homocysteine and cysteine-albumin binding in homocystinuria: assessment of cysteine status and implications for glutathione synthesis?.Amino Acids. 2002; 22: 109-118Crossref PubMed Scopus (18) Google Scholar However, in our patient, chemotherapy was safely administered with no significant clinical complications. In this case, we present a patient with a late presentation of homocystinuria who experienced few of the complications and lived longer than the usual life span of patients with this condition. He is possibly the first patient with homocystinuria to receive chemotherapy, and there were no obvious toxicities from different metabolism of the chemotherapy agents (carboplatin and gemcitabine). However, there is a significant theoretical risk of the use of antifolates in patients with homocystinuria. As the life expectancy of patients with homocystinuria increases with more aggressive management of vascular risk factors, it is likely that such patients may develop neoplasms needing chemotherapy.