Sunitinib and Reversible Posterior Leukoencephalopathy Syndrome: the usual suspect but not always the culprit. A case report.

Renal Cell Carcinoma (RCC) comprises approximately 2% of all adults’ malignancies. Non-clear cell histology represents 20% of RCC^[1]. Papillary renal cell carcinoma (PRCC) is the most common of the non-clear histology subgroup representing 10–15% of all RCC and is divided into type 1 and 2. While PRCC in some patients is indolent, bilateral and multifocal, others present with solitary lesions with aggressive clinical course. Successful systemic therapy of advanced disease is based on small single-arm or randomized phase II trials. Currently, patients with advanced or metastatic PRCC that cannot be treated within a clinical trial, are offered first-line treatment with target agents such as sunitinib, an oral multi-targeted tyrosine kinase inhibitor^[2].

Well-known adverse effects of sunitinib include hypertension, cardiotoxicity, hypothyroidism, fatigue, leukocytopenia, thrombocytopenia, diarrhea and skin toxicity^[3]. A small number of sunitinib-related Reversible Posterior Leucoencephalopathy Syndrome (RPLS) cases have been published in the literature. In almost all cases, hypertension was reported at the time of presentation of RPLS and in all cases treatment with sunitinib was discontinued^[4].

We report a case where sunitinib was reinitiated after complete resolution of RPLS-related symptoms and imaging abnormalities. The patient was receiving this treatment for a recurrence of sporadic PRCC.

A 64-year old woman presented to the Accident and Emergency department with status epilepticus (2 seizures, lasting approximately 10 minutes each, without regaining consciousness). There was a history of headaches 48 hours beforehand and due to unspecified fatigue, the patient had decided to stop all her medication including antihypertensives and thyroxine. On examination, she was afebrile with elevated blood pressure (175/95 mmHg) and truncal ataxia.

Her past medical history included hypertension, controlled on medication, breast cancer for which she had undergone a right breast quadrantectomy, sentinel lymph node biopsy, radiation and was currently on aromatase inhibitors, and finally, local recurrence of PRCC. For the PRCC she had undergone a left sided nephrectomy one year prior to this presentation. Histology confirmed a type 2 PRCC, histologic grade 3, final stage T3N0Mx. 6 months after surgery, during routine oncological follow up, she was found to have local unresectable disease recurrence. Whole exome sequencing was performed with Illumina next Sequencing. This failed to reveal any relevant, clinically significant oncogene mutations. Because of her medical history this patient was not eligible for entering a clinical trial and was started on 1^st line sunitinib, as per international guidelines. The dose was 50mg daily for 4 out of 6 weeks. At the time of her admission, she had been on sunitinib for 1 year with only side effects grade 1 neutropenia and anemia mainly at the initial stages of her treatment. She had also developed hypothyroidism and was on thyroxine. While on sunitinib and 3-montly follow-ups with a chest and abdomen Computer Tomography (CT) scan and a Magnetic Resonance Imaging (MRI) of retroperitoneum, she was found to have disease response initially and stable disease thereafter.

On admission, full blood count showed grade 2 anemia and thrombocytopenia. Biochemical profile was normal. She was hypothyroid, with marked elevation of TSH and low fT3, fT4. Brain CT was normal. Brain MRI showed bilateral high intensity lesions in the white matter of the occipital, parietal and cerebellar lobes, and dorsal brainstem (Figure 1A). Thus, according to the clinical course and imaging findings, a diagnosis of RPLS caused mainly by uncontrolled hypertension was suspected. As hypertension and RPLS are reported side effects of sunitinib, the decision was made to stop treatment, until stabilized.

She received immediately intravenous 10mg diazepam and 1800mg phenytoin with seizure remission and subsequently she was started on oral phenytoin 300mg/day. Cardiology review did not reveal any new abnormalities and hypertension was treated with moxonidine and frusemide in the acute phase, and subsequently she was restarted on valsartan, amlodipine, hydrochlorothiazide and continued moxonidine. Treatment with levothyroxine was reinitiated.

On the second day of her admission, she reported simple visual hallucinations which persisted for 2 days. The patient made an uneventful recovery and brain MRI one month after her admission showed complete resolution of the lesions (Figure 1B).

Unfortunately, a follow-up staging CT and MRI one month after her discharge, and while she was asymptomatic, showed retroperitoneal disease progression.

Since the RPLS presented after the discontinuation of antihypertensive medication and she had already experienced good disease control on sunitinib treatment, and there were not many alternatives, it was thought to be safe to restart sunitinib at a lower dose (37.5mg daily for 4 out of 6 weeks), with close monitoring of blood pressure values, thyroid function, blood tests and clinical status, with good clinical response.

One year later, the patient continues receiving sunitinib treatment, the PRCC is stable, and she has not developed any symptoms associated with RPLS. She remains under close monitoring.

PRCC can be found in hereditary syndromes (type 1 in “hereditary PRCC” and type 2 in hereditary “leiomytosis and renal cancer”). What is known about PRCC is mostly based on the hereditary form of the disease. Because of its rarity, sporadic PRCC has not been well studied. Large genomic profiling efforts, including The Cancer Genome Atlas, have refined our current understanding of this disease. Mesenchymal-epithelial transition factor (MET) dysregulation, somatic mutations (seen in approximately 15% of PRCCs), overexpression, and amplification also contribute to MET pathway activation. MET alterations can be identified in both type 1 and 2 tumors. Other dysregulated pathways beyond the MET pathway include promising targets such as CDKN2A, chromatin remodeling, the antioxidant response pathway, TFE3 translocation, NF2, TERT, and hypermethylation^[2].

In our case, the patient demonstrated no relevant gene mutations. Her disease was not an inherited form but sporadic.

Despite all the current knowledge of PRCC successful systemic therapy of advanced disease is based on small single-arm or randomized phase II trials that, sometimes, encompass PRCC with other non-clear cell histology tumors, overlooking their different natural history. Data from the ASPEN trial (Everolimus Versus Sunitinib for Patients with Metastatic Non–Clear Cell Renal Cell Carcinoma) and the ESPN trial (Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non–Clear Cell Renal Cell Carcinoma) indicate that targeted therapies used for clear cell renal cancer might show activity in patients with non-clear cell histology^[3]. Inferior overall survival (OS) has been reported for metastatic PRCC compared to metastatic clear cell RCC^[5]. Currently, patients with advanced or metastatic PRCC are offered treatment with target agents such as sunitinib, in the first line setting.

Sunitinib is an oral multi-targeted tyrosine kinase inhibitor, that inhibits the vascular endothelial growth factor receptors (VEGFR 1–3), platelet-derived growth factor receptors (PDFRα and PDGFRβ), stem cell factor receptor (c-kit) and glial cell-line derived factor receptor (RET). This agent received approval in 2007 and became a standard treatment option in the first-line treatment of metastatic renal cell cancer (mRCC) after a phase III trial showed superiority compared to interferon alpha (IFN-α)^[2].

Side effects of sunitinib include RPLS that has been reported in only a small number of cases^[4]. VEGF receptor inhibitors, in general, have been associated with RPLS, especially bevacizumab. The most likely mechanism is due to endothelial dysfunction and secondary hypertension^[6].

RPLS is a clinical and radiological syndrome first described in 1996 by Hinchey et al. Different causes including hypertension, eclampsia, systemic lupus erythematous are grouped together because of analogous findings on neuroimaging. Since then, it has been described in case reports and case series in all age groups but most frequently in women, young and middle-aged adults^[7].

The pathophysiology of RPLS is unclear. Currently, the vasogenic theory is accepted. It suggests that rapidly developing hypertension leads to increase in cerebral blood flow, arteriole dilation, with subsequent brain hyperperfusion causing breakdown of the blood brain barrier and extravasation of fluid and blood products into the brain parenchyma. Lack of sympathetic innervation seems to explain why the posterior circulation is more often involved^[7]. Endothelial dysfunction has also been postulated to play a significant role, especially when cytotoxic therapies are the underlying factor, as their direct toxicity on endothelium leads to a deranged autoregulatory response. Cytotoxic drugs associated with RPLS include cyclosporin, tacrolimus, sirolimus, interferon therapies, agents that inhibit angiogenesis such us bevacizumab, pazopanib, sorafenib and sunitinib^[8].

RPLS usually has an acute or subacute onset with symptoms evolving within hours or days while continued progression over weeks has also been reported. It is characterized by a variety of symptoms. Dull, constant, moderate to severe headache is the most frequent symptom^[7]. Encephalopathy may vary from altered mental status and mild confusion to stupor and coma. Up to 39% of patients experience visual disturbances including decreased visual acuity, hemianopia, visual hallucinations or even cortical blindness^[8]. Epileptic seizures are often the presenting symptom as they occur early in the disease course, and they are usually generalized tonic-clonic^[9].

Neuroimaging with brain MRI is the cornerstone of diagnosing RPLS. Typical findings include vasogenic edema in the parieto-occipital regions, cerebellar lobes and brainstem, more often being bilateral and symmetrical and not following a single vascular territory. Frontal lobes and even spinal cord may be involved in rare cases. Lesions usually affect subcortical white matter, but the cortex and basal ganglia have also been involved^[10].

We report quite an unusual case as this patient had been under sunitinib therapy for over a year before developing symptoms. In most cases reported in the literature, the time interval from treatment initiation to symptom onset varies from hours to months. We suspected that the abrupt increase of blood pressure following the discontinuation of related medication had a direct effect on vascular permeability rather than the presence of sunitinib which had been well tolerated so far. The decision to reinitiate sunitinib was based on the point that in this case it was perhaps the only treatment with the best chance of long-term success.

This is the first report in the literature of RPLS associated with sunitinib and reintroduction of the same medication after symptom resolution, obtaining good PRCC disease control. The fact that sunitinib treatment was well-tolerated two months after symptom resolution, provides a positive feedback and specific treatment re-initiation should be considered, especially in cases where therapeutic choices are limited, and poor outcome is expected.