Tag Archive for: adverse drug reaction

1. Oncology Registrar, Flinders Medical Centre

Avascular necrosis (AVN) is a rare musculoskeletal disorder associated with multiple medical conditions and therapeutic interventions. The exact etiology and pathogenesis is not completely understood but is widely thought to be related to microvascular compromise causing bone marrow infarction eventually leading to mechanical failure. Sunitinib (Sutent) is an inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor (VEGFR1, VEGFR2, and VEGFR3), platelet-derived growth factor (PDGFR) and FMS-like tyrosine kinase-3 (FLT3). It is currently being used as first line therapy in the management of metastatic renal cell carcinoma (mRCC).  Avascular necrosis secondary to anti-angiogenic agents is possibly a rare complication of these drugs and the likely pathogenesis is microvascular compromise. We report a case of a 73 year old patient who developed AVN of her left hip while on sunitinib for mRCC.

A 73 year old woman was investigated for chest pain and found to have multiple pulmonary lesions and a mass in her right kidney.  Biopsy of the renal mass (FNA) was performed.  Histology was consistent with renal cell carcinoma (ovoid to irregular, pleomorphic nuclei, dispersed chromatin, obvious, single nucleoli and abundant vacuolated lightly staining cytoplasm).  She was commenced on sunitinib 50mg daily on 9 March 2007.  After a couple of weeks she developed an upper torso rash, mucositis and thrombocytopaenia, and sunitinib was ceased temporarily and recommenced at a dosage of 25mg daily on 20 April 2007 with a planned cycle of four weeks on and two weeks off.  This dosage was tolerated well, with no clear treatment related side effects. A computed tomography (CT) scan performed on 10 July 2007 showed a radiologic response to treatment. Besides sunitinib, the patient was taking the following medications on a daily basis; enalapril 10mg, simvastatin 40mg, diltiazem 360mg, pantoprazole 40mg, furosemide 40mg, hydroxychloroquine 200mg, and thyroxine 100mcg. She had also taken warfarin, which was ceased recently.

She developed left hip pain for the first time in November 2007. A whole body bone scan at that time revealed diffuse uptake involving the left femoral head and neck, which was thought to be atypical for both degenerative change and bony metastatic disease (figure 1).

She subsequently developed erythema and swelling of the lower limb which was thought to be due to sunitinib.  This was ceased on 19 December 2007 along with her diltiazem and thyroxine.  The patient’s pain deteriorated with time, with reduction in her mobility and restriction of movement at the left hip . She had an antalgic gait. X-ray of the hip revealed degenerative changes, with reduction of the joint space, and altered contour of the left femoral head in addition to collapse. There was no fracture or dislocation. An MRI performed in February 2008 showed a large left hip joint effusion with synovial thickening and a crescentic low signal focus consistent with a fragment of cortical bone. The femoral head demonstrated marked deformity with collapse of the superior contour and crescentic fluid cleft, associated with cortical defect superoanteriorly. The femoral head showed a low T1 and intermediate T2 signal consistent with diffuse edema. The overall appearances were thought to reflect avascular necrosis with collapse of the left femoral head, diffuse edema and advanced secondary degenerative changes (figure 2 and 3).

No convincing evidence of metastatic deposits was found. She was referred to an orthopaedic surgeon and a total hip replacement was performed.

The patient did not have any predisposing medical conditions for avascular necrosis of the hip and had never used steroids. She was a non-smoker with minimal alcohol consumption. There was no history of trauma to the left hip and she had never received any radiotherapy. This led to the hypothesis that sunitinib could have led to this through compromise of the microvasculature of the left femoral head (due to its antiangiogenic activity), which is thought to be the main pathologic process underlying this condition eventually leading to mechanical compromise of the hip.

Osteonecrosis (ON), also known as avascular necrosis (AVN) is a rare musculoskeletal disorder associated with multiple medical conditions and therapeutic interventions. The exact etiology and pathogenesis is not completely understood but is widely thought to be related to microvascular compromise causing bone marrow infarction eventually leading to mechanical failure. According to Kerachain et al , decreased local blood flow to the femoral head and microvascular thrombosis is the most accepted mechanism in the pathogenesis of ON. It is associated with traumatic and various non-traumatic causes including corticosteroid use, smoking, alcohol consumption, radiotherapy (osteoradionecrosis), hyperuricaemia and hyperlipidaemia. Corticosteroid and alcohol use are thought to be associated with >90% of cases .

Sunitinib (Sutent) is an inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor (VEGFR1, VEGFR2, and VEGFR3), platelet-derived growth factor (PDGFR) and FMS-like tyrosine kinase-3 (FLT3). It is currently being used as first line therapy in the management of metastatic renal cell carcinoma (mRCC) and as second line treatment in metastatic gastrointestinal stromal tumours (mGIST). Sunitinib was evaluated in a phase III trial of 750 patients with metastatic clear cell RCC who had not received prior systemic treatment . Patients were randomly assigned to sunitinib or interferon alfa. The updated results published by Motzer et al  showed that the median overall survival was greater in the sunitinib group than in the IFN-alpha group but not statistically significant (26.4 v 21.8 months, respectively; hazard ratio [HR]= 0.821; 95% CI, 0.673 to 1.001; P = 0.051). Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-alpha (P<.001). Objective response rate was 47% for sunitinib compared with 12% for IFN-alpha (P<0.001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%).

There have been two of reports of ON related to targeted therapy like bevacizumab and single case reports with sorafenib and sunitinib , . To our knowledge, this is the second case of ON related to suntinib treatment. According to the Naranjo scale  for determining the likelihood of an adverse drug reaction as a side effect of a particular drug compared to other factors, the imputability of sunitinib in this case is ‘probable’ (score 5). Our patient was on diltiazem regularly for management of hypertension before sunitinib was started and its concurrent administration could have lead to toxicity with sunitinib through a pharmacokinetic interaction by inhibiting cytochrome P-450 (CYP3A4) ,  resulting in an increased sunitinib concentration.

Although the targeted agents have revolutionalised the field of medical oncology, we have to be cautious about under recognized and rare side effects of these agents impacting on the quality of life of cancer patients. Osteonecrosis secondary to anti-angiogenic agents is possibly a rare class effect of these drugs and the likely pathogenesis is microvascular compromise eventually ending up in mechanical failure. The treating physician needs to be aware that new onset musculoskeletal hip pain in patients on anti-angiogenic agents could be related to therapy related complication, besides disease progression and secondary skeletal events. Early recognition and prompt treatment of these complications can be beneficial in minimizing the patient symptoms and disability. Therefore, new onset hip pain in a patient on these agents should be investigated sooner rather later with imaging including plain X-rays and MRI.