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The rapidly developing novel therapies for metastatic melanoma (stage IV) are now starting to prove their value in the adjuvant treatment of stage III melanoma. Two studies recently published in The New England Journal of Medicine, the CheckMate 238 study and the Combi-AD study, both show a significantly increased chance of recurrence-free survival for stage III melanoma patients. In the adjuvant setting, immunotherapy by checkpoint inhibition and targeted therapy may therefore become newly available therapeutic options. Pending EMA approval, this may prove to be good news for patients. In the Netherlands, continued critical appraisal of these expensive treatment modalities in metastatic melanoma is mandatory, as issued by the Dutch Government. This important documentation of expensive oncological therapeutics should also be carried out for adjuvant treatments by the expert centres that are experienced in the use and structured evaluation of these therapies.

Continued development of existing drugs ('drug rediscovery') may offer new therapeutic options and be cost-effective. Rediscovered drugs are commonly prescribed off-label, although licensing can be important to allow safe and controlled prescription of the drugs to patients. Licensing of a new indication for a generic drug, however, is a complicated process since there is no blueprint for this and there is little interest from the pharmaceutical industry due to an unattractive cost-recovery model. In this article, we illustrate the successful license-extension for thioguanine - initially developed in 1950 for leukaemia - as a new treatment for patients with inflammatory bowel disease.

A drug interaction between capecitabine and coumarin may result in an increased INR and bleeding complications.We describe an 80-year-old woman who presented with rectal bleeding and an increased INR due to the concomitant use of acenocoumarol and capecitabine for atrial fibrillation and metastatic cecal cancer, respectively.In patients with a compelling indication for treatment with capecitabine and anticoagulant therapy, conversion to low-molecular weight heparin should be considered.

Myelodysplastic syndrome, a disorder of haematopoiesis, is associated with anaemia and an increased risk of infections, bleeding and the development of acute myeloid leukaemia. The disorder occurs mainly in later life. Until recently the only therapy that could induce sustained remission was allogeneic stem cell transplantation. However in elderly patients caution is needed with this therapy. Increasing awareness of the role of epigenetic changes in cancer development has led to the rediscovery of the cytidine analogues azacitidine and decitabine. At low doses these drugs inhibit DNA methylation. The efficacy of these drugs was demonstrated in the treatment of patients with myelodysplastic syndrome. These drugs showed low toxicity and were relatively well-tolerated in elderly patients. The results with azacitidine and decitabine have demonstrated that manipulation of the epigenetic process offers new antineoplastic treatment options.

A 60-year-old Ghanese woman was treated with radiotherapy and capecitabine for metastatic breast cancer. 6 weeks after starting capecitabine she developed palmar and plantar hyperpigmentation, which preceded symptoms of hand-foot syndrome, a known adverse effect of capecitabine. After a dose reduction, the hand-foot syndrome diminished but the hyperpigmentation remained. 8 months later the patient was well and stable.

Over a period of 1 year in our hospital, 3 patients were diagnosed with 'ileitis following capecitabine use'. The case of 1 of these patients is presented in this article.A 73-year-old man known to be suffering from liver metastases from rectal cancer was treated with oxaliplatin, bevacizumab and capecitabine. He was admitted to our hospital with abdominal pain, diarrhoea, nausea and a subfebrile temperature. A CT scan of the abdomen showed marked bowel wall thickening, particularly of the ileum, consistent with terminal ileitis. The diagnosis was 'ileitis following capecitabine use' since other disorders were excluded or seemed less likely, and the Naranjo score was compatible with 'possible adverse reaction'. Capecitabine treatment was discontinued. Following recovery, treatment was resumed without complications.Small intestine toxicity during capecitabine use has, to our knowledge, not been described previously. It is important to recognise this side-effect in order to avoid obstruction and perforation. Conservative treatment including an adapted diet and intravenous hydration is the therapy of choice. Surgery does not seem to be indicated.

Hydatidiform mole is the most frequently-occurring gestational trophoblastic disease (GTD). Patients with GTD have elevated human chorionic gonadotrophin (HCG) produced by the trophoblast. After evacuation of the mole, weekly serum HCG determinations can be used to assess whether the trophoblast is persisting or regressing based on the standardised normal Nijmegen serum HCG regression curve. The serum HCG pattern is used to establish the diagnosis 'persistent trophoblastic disease'. Treatment with monochemotherapy in the form of methotrexate is the treatment of choice. For about 80% of women with a persistent trophoblastic disease following a molar pregnancy this treatment will lead to a complete remission of the disorder. If resistance to methotrexate occurs then a combined therapy is indicated. A recently developed, and as yet unvalidated, normogram for the serum HCG level during methotrexate treatment might in the near future be able to identify patients with methotrexate resistance at an early stage. Hysterectomy or curettage may be indicated as part of therapy in selected patients. The incidence of choriocarcinoma after a live birth is estimated at 1 in every 40,000 full-term pregnancies. These patients have a high risk for resistance to methotrexate (75%). Treatment of these patients with primary combination therapy at a specialised medical centre is then indicated.

A 53-year-old man and a 76-year-old woman were treated with the cytotoxic drug capecitabine as palliative treatment and adjuvant treatment, respectively, because of colorectal carcinoma. Both developed myocardial ischaemia within a few days. In the man, the capecitabine dosage was reduced and metoprolol was prescribed, while in the woman the capecitabine was stopped. According to the literature, the risk of myocardial ischaemia during treatment with capecitabine is approximately 0.4%, irrespective of the patient's medical history. Except in clinical trials, a history of coronary disease is not considered a contraindication for capecitabine treatment. In case stable angina pectoris develops during treatment, continuation of treatment with a reduced dosage of capecitabine can be considered. A switch to treatment with an alternative fluoropyrimidine, such as fluorouracil or raltitrexed, also appears to be safe. However, raltitrexed is no longer available in The Netherlands.

Intoxication due to insufficient renal clearance developed in 2 patients, a 54-year-old man and a 61-year-old woman, who were under treatment with methotrexate (MTX) for a primary cerebral lymphoma and a recurrence of large-cell B-cell-non-Hodgkin lymphoma, respectively. Both were treated with folinic acid rescue, thymidine, and alkalisation of the urine. MTX is a cytotoxic drug that is often used in oncology and rheumatology. Significant and even lethal toxicity can develop when the elimination ofMTX is delayed or when supportive care, such as folinic acid rescue, is inadequate. Delayed elimination can be caused by reduced renal function, by the 'third space' phenomenon such as in case of ascites, pleural fluid accumulation and oedema, and by drug-drug interactions leading to reduced renal function or a disturbance in the plasma protein binding ofMTX. Once toxicity has developed, the therapy must be directed at protection of the normal tissues, restoration of renal function and hence the renal elimination ofMTX, restoration of the alkalisation of the urine, and general supportive therapy.

In view of recent progressive insight in the diagnosis and treatment of leptomeningeal metastases of solid tumours, a new guideline has been designed on the initiative of the Dutch Association of NeuroOncology and the Netherlands Society of Neurology, with methodological support from the Dutch Institute for Healthcare Improvement (CBO). - There are no neurological symptoms or signs, nor MRI characteristics that are unique to leptomeningeal metastasis. However, clinical suspicion of leptomeningeal metastasis in a patient known to have cancer, in combination with specific MRI characteristics is sufficient to make the diagnosis. If MRI or CT results are negative or inconclusive cerebrospinal-fluid assessment should be conducted. - Management of care of patients with leptomeningeal metastasis without brain metastases can be based on a series of categories that have been developed using prognostic factors such as Karnofsky performance status, serious encephalopathy or neurological dysfunction, systemic disease, sensitivity of the tumour for chemotherapy or hormonal treatment - In the context of meaningful palliation, systemic treatment, if necessary in combination with radiotherapy to clinically relevant sites, is preferable to intrathecal chemotherapy. - Intrathecal chemotherapy combined with local radiotherapy is recommended if effective systemic treatment is not available, and if the tumour is potentially sensitive to methotrexate, cytarabine or thiotepa. The combination of intrathecal methotrexate and whole-brain radiotherapy should be avoided.

For many years there has been a search for an effective treatment of malignant pleural mesothelioma. Surgery is of limited applicability and is reserved for special cases, in which it is combined with radiation therapy. In the previous century, many cytostatic agents have been tested, alone or in combination, but the response was limited, the median survival time was unchanged and the toxicity was high. New drugs, including the new antifolates, are being used much more often in the treatment of malignant pleural mesothelioma in combination with a platinum derivative. Cytostatics such as pemetrexed, an antifolate, and to a lesser extent raltitrexed, have shown good response rates and increased survival in phase III studies, but the survival benefit evaporates within 2 years. Inhibitors of angiogenesis and of epidermal growth factor are being tested, but they have shown only limited activity until now. The current studies focus on the use of chemotherapy and biological agents as part of a more complex treatment schedule.

In a pregnant woman presenting with vaginal bleeding and a vaginal tumour, vaginal metastasis ofa trophoblast tumour from a mola pregnancy was diagnosed.

Two female patients, aged 48 and 52 years, developed severe bone marrow suppression and (gastrointestinal) mucositis following administration of capecitabine. Analysis of the dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells revealed the presence of DPD deficiency. Both patients recovered in 3-4 weeks, and both had a (partial) remission of their tumours. Capecitabine is metabolised to 5-fluorouracil (5-FU) in the body. DPD-deficiency leads to impaired breakdown of 5-FU and hence to severe cytotoxicity following treatment with capecitabine or 5-FU. The most common mutation, IVS14 + 1GA, is found in approximately 2% of the Dutch population. In case of unexpected severe toxicity during 5-FU or capecitabine treatment, DPD deficiency should be considered. Screening could be considered in view of the widespread use of capecitabine and 5-FU, the severe toxicity that may develop in patients with low DPD activity and the prevalence of the mutation.

A 64-year-old male was treated for acute myeloid leukemia with idarubicin and cytarabin. He developed pulmonary mycosis (radiologically consistent with aspergillosis), which responded to intravenous amphotericin B.

In the treatment of chronic myelocytic leukaemia (CML) allogeneic bone marrow transplantation (BMT) from a sibling donor is the treatment of choice in patients younger than 50 years; the overall 5-year survival is about 60%. Donor lymphocyte infusion without chemotherapy may serve as an efficacious therapy for recurrence of CML after allogeneic BMT. Application of allogeneic BMT from a matched unrelated donor is increasing, but the outcome is still inferior to that of sibling BMT, largely due to more severe and more frequent complications. Treatment with interferon-alpha has been shown to prolong the overall median survival, but especially in a subgroup of patients (about 15%) who achieve a major cytogenic response. Combination of interferon-alpha and low-dose cytarabine leads to increased survival and a better cytogenic response than interferon-alpha alone. Current investigations are aimed at further improving survival and cytogenic response by using more intensive chemotherapy, such as high-dose cytarabine, followed by interferon-alpha maintenance therapy.