Mixed Response to Ipilimumab in a Melanoma Patient with Brain Metastases: Case Report and Review of the Literature
In December 2011, a 69-year-old male patient was admitted to our institution for the evaluation of further therapeutic options of metastatic malignant melanoma. Previously, in March 2009, the diagnosis of an ulcerated nodular solid malignant melanoma of the left cheek (thickness 30 mm, Clark level 5) with infiltration of the left parotid gland had been made. The neoplastic cells carried wild-type B-RAF alleles, but an oncogenic mutation in exon 2 of the N-RAS gene was found. The past medical history was unremarkable except for hypertension, for which antihypertensive combination therapy was given. In March 2009, the patient underwent surgical excision and neck dissection, during which a total of 16 lymph nodes were removed, which histologically did not show any signs of tumor invasion at that time. Subsequently, however, in October 2009, a soft tissue metastasis developed at the base of the resection area, which was treated with local irradiation over a course of 2 months. In December 2010, another subcutaneous metastasis was found above the left base of the mandible, which was surgically resected. Histopathological analysis showed clear resection margins.\nAdjuvant immunotherapy with 3 million units of interferon-α thrice weekly was initiated in January 2011 but terminated in May 2011, when increasing serum concentrations of the tumor marker S100 indicated disease progression under therapy. Moreover, by this time, the patient had developed numbness and weakness of the right arm and left leg. A CT scan revealed newly developed lung metastases and lymph node metastases in the right hilar region as well as below the carina, and an MRI scan showed 2 new brain metastases – one in the left frontal region and another one in the area of the head of the right caudate nucleus.\nAfter a course of stereotactic irradiation (7 × 5 Gy, i.e. a cumulative dose of 35 Gy), another MRI scan performed in December 2011 showed regression of the left frontal brain metastasis and constant size of the right caudate nucleus lesion.\nSystemic therapy with temozolomide was started in August 2011. A restaging CT scan was performed in November 2011 and showed progressive disease under therapy, with an increase in the size of 2 lung metastases and a newly diagnosed lymph node metastasis in the left axilla. At this point, temozolomide therapy was abandoned and the patient was referred to our institution for evaluation of further therapeutic options.\nUpon presentation at our clinic, the neurological symptoms had resolved completely, and the patient reported no relevant symptoms except for an overall feeling of fatigue and lack of energy. At this point in time, the patient was on continuous prophylactic steroid therapy with low-dose decortin. In December 2011, second-line therapy with ipilimumab was initiated at a dose of 3 mg/kg intravenously every 3 weeks for a total of 4 courses. The therapy was well tolerated without any signs of toxicity or tangible adverse effects. In particular, the patient did not develop diarrhea or other signs of autoimmune disease and showed no neurological deficits. Routine follow-up laboratory parameters remained mostly normal except for an isolated increase in serum lactate dehydrogenase (LDH) concentrations of up to 348 U/l during the initial 2 cycles of ipilimumab, which spontaneously resolved upon cessation of ipilimumab administration (fig. ).\nA follow-up CT scan performed in March 2012 demonstrated stable disease with respect to extracranial manifestations, with marked size regression of the mediastinal metastases as well as the left axillar lymph node metastasis and constant size of a right-cervical lymph node (1.3 cm in diameter). Of interest, at this point, the tumor marker S100 had dropped from 0.24 µg/l before initiation of ipilimumab administration in December 2011 to 0.16 µg/l in April 2012 after 4 cycles of ipilimumab (fig. ). However, an MRI scan performed in March 2012 revealed size progression of the brain metastasis in the area of the head of the right caudate nucleus, a newly developed metastasis in the left frontal region as well as several new small metastatic lesions in the left parietal region.\nTherefore, administration of ipilimumab had to be stopped, and another round of percutaneous irradiation of the neurocranium was initiated (5 × 2 Gy per week up to a total dose of 40 Gy, i.e. a cumulative dose of 75 Gy).\nA repeat MRI scan done in October 2012 revealed a decrease of the cerebral metastases by 25–50% on average, without occurrence of any new cerebral metastases. A CT scan of the abdomen, thorax and neck performed in November 2012 showed a mixed response, with regression of some distant organ metastases, while others had progressed or newly developed. By November 2012, the tumor marker S100 had again risen to 0.43 µg/l.\nThe patient is currently in a rather good clinical condition and able to perform the tasks of routine everyday life.