Cisplatin induced cerebral sinus venous thrombosis in cervical cancer patients treated with concurrent chemoradiation: a case series

Cisplatin is a widely used chemotherapeutic agent. Concurrent chemotherapy with cisplatin is an important component in the management of carcinoma cervix. The common side effects of cisplatin chemotherapy include nausea, vomiting, dyselectrolytemia, nephrotoxicity, etc. These side effects are anticipated and managed during chemotherapy. Thromboembolic events are rare complications with cisplatin. We present three cases of cisplatin related cerebral sinus venous thrombosis (CSVT). These patients were receiving concurrent chemoradiation for carcinoma cervix. These patients presented with neurological symptoms and were evaluated and diagnosed with CSVT. They recovered after appropriate management. Clinicians should be aware that CSVT, though uncommon, is a life threatening complication during cisplatin chemotherapy which should be appropriately evaluated and effectively managed.


Introduction
Cisplatin is one of the most potent alkylating antineoplastic agents [1] which is widely used for the treatment of several malignancies including cervical cancer [2][3][4][5]. Concurrent chemotherapy with cisplatin during radiation has shown better local control and overall survival compared to only radiation in cervical cancer trials [6,7].
Cisplatin has been linked to various toxic side effects including nausea, nephrotoxicity, cardiotoxicity, hepatotoxicity and neurotoxicity [8]. Renal and gastric toxicities are the most common and anticipated side effects of cisplatin. Thromboembolic events (TEEs) is not a well known toxicity associated with cisplatin but has been reported in the literature. A study reported that 18.1% of cisplatin-treated cancer patients developed TEEs [9].
We present three patients who developed cerebral sinus venous thrombosis (CSVT) while on concurrent chemotherapy with cisplatin during the treatment for cervical cancer.

Summary 1
A 49-year-old female patient with no known co-morbidities was diagnosed with carcinoma cervix stage IIB. She received external beam radiotherapy to pelvis along with three cycles of concurrent chemotherapy with cisplatin at 40 mg/m 2 . After 12 days of last chemotherapy, she presented to the emergency department with complaints of fall at home, tongue bite and loss of consciousness. She was evaluated with Computed Tomography (CT) of the brain which showed hyperdensity along superior sagittal and right transverse venous sinuses suggesting the likely diagnosis of CSVT. The Magnetic Resonance Imaging (MRI) of the brain showed thromboses in posterior half of superior sagittal sinus, right transverse and sigmoid sinuses ( Figure 1). She was managed with anticoagulants, antiepileptics, analgesics and intravenous fluids. She gradually improved and was discharged in stable condition. Post recovery she completed her planned intracavitary brachytherapy. She is on regular follow-up since 1.5 years with complete response.

Summary 2
A 37-year-old female with no known co-morbidities was diagnosed with carcinoma cervix stage IVA. She received external beam radiotherapy to pelvis along with four cycles of concurrent chemotherapy with cisplatin at 40 mg/m 2 . She developed right hemiparesis, 9 days after last cycle of cisplatin. On evaluation, the MRI of the brain showed thrombosis in posterior part of superior sagittal sinus, right transverse and sigmoid sinus. She was managed with anticoagulants, antiepileptics and intravenous fluids. She improved clinically and was discharged. Post recovery she completed the remaining course of radiation treatment. Now she is on regular follow-up since 1.5 years with complete response.

Summary 3
A 47-year-old female with no known co-morbidities was diagnosed with carcinoma cervix stage IIB. She received external beam radiotherapy to pelvis along with four cycles of concurrent chemotherapy with cisplatin at 40 mg/m 2 . During the course of radiation (post 7 days of fourth cycle chemotherapy), she presented to the hospital with complaints of right upper limb weakness. She was evaluated with the MRI of the brain which showed anterior superior sagittal sinus and bilateral superficial cortical venous thrombosis along with subarachnoid haemorrhage ( Figure 2). She was managed with anticoagulants, antiepileptics and intravenous fluids. She recovered clinically and completed planned radiation treatment. She is on follow-up and disease-free since 1 year.

Discussion
These patients presented with neurological symptoms while on concurrent chemoradiation for cervical cancer. They were evaluated and diagnosed with CSVT early and were managed appropriately. The patients improved clinically post treatment and completed the standard treatment for cervical cancer as planned. All the three patients had no co-morbidities and no prior history of thrombosis. Evaluation for other systemic causes was negative. The time interval between chemotherapy and CSVT among these cancer patients suggests a cisplatin related cause.
Cancer and cisplatin chemotherapy are well-recognised risk factors for coagulation disorders and thrombosis [10]. Cancer is associated with an increased risk of venous and arterial TEEs. These events include deep venous thrombosis, pulmonary embolism, cerebrovascular accident and unstable angina/myocardial infarction. On an average the annual incidence rate of venous TEE in general population is approximately 117 per 100,000, whereas the incidence in cancer patients is around one in 200 [11,12]. A large cohort study reported cancer alone increases the risk of TEE by 4.1 times and addition of chemotherapy by 6.5 times [13].
CSVT during chemotherapy is rare and only few cases are reported in literature [10].This condition is less common than other types of stroke. It commonly affects large sinuses like superior sagittal sinus. Mostly no underlying cause is identified. Around 30% of cases are attributed to inherited and systemic inflammatory diseases. The International Study on Cerebral Venous and Dural Sinuses Thrombosis reported 7.4% of cases of CSVT were associated with cancer [14]. It is more common in females with female to male ratio of 3:1.
Antineoplastic drugs like L-asparaginase and tamoxifen are established risk factors for CSVT [15]. Other treatment regimens with increased risk of CSVT are (i) Folinic acid, 5fluorouracil and Irinotecan (FOLFIRI) regimen/bevacizumab regimen in colon cancer management [16], (ii) concurrent chemoradiation with temozolomide and bevacizumab in brain tumour management [17] and (iii) cisplatin, ifosfamide, adriamycin and vincristine regimen in Ewing sarcoma management [18]. CSVT caused by micrometastases from cutaneous melanoma has also been reported [19].
The mechanism for cisplatin-induced coagulopathy is thought to be endothelial injury activating the coagulation cascade and resulting in TEEs [20]. Degenerative processes of vessel walls are initiated which eventually causes occlusive vascular disease. There is evidence regarding excess of myocardial infarctions, arterial hypertension and cerebral strokes in these patients. These complications have been reported in several malignancies but germ cell tumours on cisplatin based regimens are at higher risk. Serum lactate dehydrogenase levels and the body surface area are important risk predictors in these patients [21]. Anticoagulation, treating the underlying cause, controlling the intracranial haemorrhage, antiseizure medication and management of focal deficits are the main treatment strategies [22].
A study observed early occurrence of cardiovascular complications secondary to cisplatin-based chemotherapy. These complications may occur during the chemotherapy cycles or immediately after it. Karam and Koussa [10] reported two cases who presented with cerebral dural sinus thrombosis while on cisplatin based chemotherapy regimen. These patients developed neurological symptoms while on chemotherapy. MRI and Magnetic Resonance Angiography (MRA) brain findings in these patients were suggestive of CSVT. They were managed with anticoagulants and supportive care. Evaluation for other causes of CSVT was negative. They concluded that the development of CSVT in these patients was chemotherapy related. Yamada et al [23] reported a case of superior sagittal sinus thrombosis in a 5-year-old girl treated with cisplatin and etoposide regimen for a suprasellar germ-cell tumour. The patient presented with symptoms post two cycles of chemotherapy.
A large retrospective analysis [9], done by Memorial Sloan-Kettering Cancer Center confirms the incidence of TEEs in patients receiving cisplatin-based chemotherapy. They included 932 patients with various cancers. They included 39 (4.2%) patients who had uterine/cervical or vulvar cancers. TEE was reported in 169 (18.1%) patients during treatment or within 4 weeks of the last dose. They concluded that unacceptably high incidence of TEEs (18.1%) is observed during the cisplatin-based chemotherapy for a variety of cancers during the period of administration or within 4 weeks of completion of treatment. They also suggested that TEE prophylaxis may be advisable for patients receiving cisplatin-based chemotherapy.
CSVT was reported in two patients who were on cisplatin based chemotherapy for germ cell tumours [24]. The authors suggested a cisplatin related hypercoagulability as a leading risk factor in both these cases as other causes for cancer related TEEs were ruled out. In one patient, they replaced cisplatin with carboplatin in the third cycle of chemotherapy. The patient again developed CSVT post carboplatin. This further confirms platin based complication.

Conclusion
Cisplatin is a common and essential antineoplastic drug in the management of several malignancies. CSVT as a complication of cisplatin chemotherapy is uncommon and alarming. Clinicians should be aware of the potential risk of development of this neurological side effect. Early diagnosis and appropriate treatment are necessary for complete recovery.