Umut Dişel

A case report of bevacizumab-related osteonecrosis of the jaw: Old problem, new culprit

Osteonecrosis of the jaw (ONJ) is well-characterized syndrome predominantly reported in advanced stage cancer patients who had used long term bisphosphonates to treat bone metastases. Rarely, ONJ has been reported in patients who have not used bisphosphonates. Here we present an extremely rare occurrence of ONJ that occurred in a patient who received bevacizumab containing chemotherapy without bisphosphonate therapy. A 51-year-old male with history of metastatic carcinoma of the sigmoid colon was diagnosed in December 2010. He was subsequently treated with palliative chemotherapy with infusional fluorouracil, leucovorin, oxaliplatin, and bevacizumab for six cycles. Bevacizumab was initiated at a dose of 5 mg/kg on a 2-week schedule. Two weeks following the last dose of chemotherapy, the patient presented with a 2-week history of lower jaw pain, ulcer in the mouth, and difficulty chewing. He denied any recent history of dental surgery or radiation therapy at affected site. A detailed dental examination revealed a small area of bone exposure and ulcer in the right posterior mandible, measuring approximately 3 3 mm in diameter. The surrounding soft tissue appeared ulcerated and necrotic, with no evidence of infection. Pantomography and axial computerized tomography revealed a minor cortical sclerotic bone lesion (Fig. 1A and B). There was no evidence of fistulae or abcesses. After curettage and primary restoration of the necrotic lesion, pathological findings consistent with osteonecrosis and actinomyces superinfection were noted (Fig. 2). The suspected diagnosis of jaw osteonecrosis was confirmed. It was suggested that the patient’s symptoms were likely related to his use of bevacizumab, even though there was not a period of antecedent bisphosphonate use. Actinomycosis causing infection in this case, we believe that just an incidental findings rather than a causal role. ONJ is defined by the presence and persistence of exposed bone in the jaw over a period of 6–8 weeks. Nitrogen-containing intravenous BP treatment has been implicated in 94% of ONJ cases. Development of ONJ can occur spontaneously or can be facilitated by tooth extraction, dental procedures, poor oral hygiene, and actinomyces infections. The pathogenesis of bisphosphonate-related ONJ is believed to involve inhibition of angiogenesis and bone formation. Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis and bone formation. Bevacizumab (Bev), a VEGF inhibitor, has been shown to effectively treat a variety of malignancies when combined with chemotherapy. Bev has been associated with severe adverse events such as thromboembolic episodes, hypertension hemorrhage, and gastrointestinal perforation. Among Bev users, devleopment of ONJ is very rare, only having been recently reported in a small number of cases. Thus, this case study is important in the understanding

Promising efficacy of sorafenib in a relapsed thymic carcinoma with C-KIT exon 11 deletion mutation

Advanced thymic carcinoma (TC) is a very aggressive disease. To date there are no established treatment options for the refractory and recurrent disease and only a few prospective trials have been conducted in patients with TC. Here we present a case of a relapsed TC patient, who, by using combination chemotherapy, showed a positive response to sorafenib with C-KIT exon 11 mutation.

Secondary malignancy after imatinib therapy: eight cases and review of the literature

Abstract Chronic myeloid leukemia (CML) is a clonal stem cell disorder, and imatinib is a small molecule inhibitor of Bcr–Abl tyrosine kinase (TK) used in cases with CML. Immediate and short-term side effects of this tyrosine kinase inhibitor (TKI) are well known, but the long-term side effects have not yet been clearly identified. Although an increased risk of secondary cancer in cases treated by imatinib was not found in two large series, secondary malignancies have been reported in some cases using TKIs, and this issue is important in daily clinical practice for clinicians. Here we report eight cases with neoplasias that developed during imatinib therapy and review secondary malignant disorders occurring during/after imatinib treatment.

Unilateral hand-foot syndrome: an extraordinary side effect of capecitabine.

Background: Hand–foot syndrome (HFS), the most common toxicity of capecitabine, is characterized by tingling, numbness, pain, erythema, dryness, rash, swelling, increased pigmentation, and/or pruritus of the palmar and/or plantar surfaces of the hands and/or feet. HFS is usually seen in both the hands and the feet, with varying severity. We have previously published a case report of dihydropyrimidine dehydrogenase (DPD) deficiency that manifested a variant of HFS. Case report: We report the case of a 65-year-old Turkish Cypriot male patient with advanced gastric cancer who developed pain, numbness, and reddening in his left palm and left sole 10 days after the fourth cycle of capecitabine at a dose of 1,000 mg/m2/day twice daily (BID) on days 1 to 14 every 21 days. On physical examination, he had unilaterally erythematous changes and skin scaling on his left sole and palm consistent with grade II HFS. After stopping administration of capecitabine and supportive management, the HFS resolved in a week’s time. Conclusions: To the best of our knowledge, this is the first case of capecitabine-induced unilateral HFS. Further investigation related to this toxicity associated with capecitabine is warranted.

Little dose, huge toxicity: profound hematological toxicity of intrathecal methotrexate

A 60-year-old man presented with complaints of blurred vision and inability to raise the right eyelid 15 days after the last cycle of the planned six cycles R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone) for stage IV follicular lymphoma. Complete remission was confirmed after the fourth cycle by positron emission tomography. On physical examination, he had third and fourth cranial nerve palsies, whereas the remainder of the neurological examination was unremarkable. Magnetic resonance imaging of cranium and orbital region with gadolinium enhancement were normal. Upon detection of lymphocytic infiltration in the cerebrospinal fluid (CSF) by cytology, isolated leptomeningeal relapse of follicular lymphoma was diagnosed without any sign of systemic relapse. Treatment with intrathecal methotrexate 12.5 mg twice a week was planned. After the second dose of the intrathecal methotrexate, he developed a grade IV neutropenia, grade IV thrombocytopenia and grade IV oral mucositis. Intrathecal chemotherapy was then stopped. He also developed neutropenic fever and had to receive prolonged antibiotic administration. Intrathecal chemotherapy withmethotrexate, Ara-C, or both with or without hydrocortisone is considered the standard of care for prophylaxis and treatment of central nervous system (CNS) lymphoma [1]. Although, intrathecal methotrexate can cause some neurological complications [2,3], it is quite unusual to observe grade IV hematological toxicity. To the best of our knowledge, profound hematological toxicity has not been reported. Intrathecal methotrexate is not altered by metabolic processes in the CSF and it passes through the systemic circulation slowly via choroid plexus [4]. Its metabolism after intrathecal administration probably resembles the one in the presence of large volume of ascitis or pleural effusions where it is redistributed to the systemic circulation slowly. Even the small amounts at 10–15 mg of intrathecal methotrexate which pass to the systemic circulation can therefore cause the myelosuppression and other feared methotrexate complications. Bruce et al. [5] showed in pediatric patients that systemic methotrexate exposure can be greater after intrathecal than oral route. Our patient had none of the unfavorable factors that predispose for methotrexate toxicity such as renal insufficiency, third spacing of fluid in the body, anatomic abnormality of CSF flow or a history of using albumin bound drugs. In summary, one should be aware that intrathecal methotrexate administration may cause some unexpected toxicities. To our knowledge, this is the first case of profound hematological toxicity reported after intrathecal administration of methotrexate in the adult literature.

Effectiveness of percutaneous metal stent placement in cholangiocarcinoma patients with midterm follow-up: Single center experience

PURPOSE Patients with advanced cholangiocarcinoma present with high rate of local complications. The primary aim of this study is to report clinical course of advanced cholangiocarcinoma patients those who were presented with biliary obstruction and treated with percutaneous biliary stenting. MATERIAL AND METHODS Patients with unresectable locally advanced or metastatic cholangiocarcinoma followed by our center for a period of 4 years were analyzed. For statistical analysis demographic and clinical characteristics of patients, primary biliary drainage method, metal stent occlusion rate, time to stent occlusion, and overall survival rates were recorded. RESULTS A total of 34 eligible patients were analyzed. 27 patients had metal stent placement. These 27 patients formed the basis of this study. Median overall survival (OS) was 6.0 months. After metal stent deployment bilurubin levels were normalized within a mean of 10 days. During the follow-up period, 13 patients were experienced metal stent occlusion. Median TtSO was 10 weeks. Cytotoxic chemotherapy was administered to 14 (52%) patients. Patients without stent dysfunction had significantly higher rate of chemotherapy exposure rate (p=0.021). Statistical analysis, however, failed to exhibit significant effect of stent dysfunction on OS. CONCLUSION In advanced cholangiocarcinoma, relief of bile duct obstruction is an important part of the initial patient management. This study therefore described the clinical value of percutaneous metal stent in cholangiocarcinoma patients and raises the question about patency of metal stent in cholangiocarcinoma whether we can expect success similar to the success achieved in pancreas carcinoma.

How Shall We Name the Chemotherapy Administration Before and After Metastasectomy? How About “M-Neoadjuvant” and “M-Adjuvant”?

Correct and universal terminology to define disease processes or therapies in medicine is an invaluable tool for precise communication among physicians and researchers. Medical oncology, as a quickly developing discipline in every aspects, crucially needs new terminologies. Systemic chemotherapy administration is categorized into several groups such as neoadjuvant, adjuvant, and palliative. In the ‘‘neoadjuvant’’ category, in addition to targeting micrometastatic malignant cells, the intent is usually to shrink a locally advanced tumor enough to be surgically removed. In the ‘‘adjuvant’’ category, our only aim is to eradicate micrometastatic tumor cells after the primary tumor is removed. In the ‘‘metastatic’’ category, the intent is to control malignancy, which is radiologically detectable, for extending survival or symptomatic palliation. However, not every clinical scenario fits into these criteria. The latest developments in surgery and chemotherapy have enabled us to prolong the survival of, and even cure, patients via metastasectomy and chemotherapy, even though they have ‘‘metastatic’’ disease.. The clinical scenario after surgery in patients without detectable cancer by imaging is called ‘‘no evidence of disease’’ (NED). The systemic chemotherapy administered in this setting does not fit into any of the categorizations defined above. Should we call it ‘‘adjuvant’’? But the patient has metastatic disease even though the condition is NED. Should we call it ‘‘metastatic’’? But the patient has no overt disease by imaging. There is a crucial need for a new term to categorize the chemotherapy administration in the NED setting because neither the term ‘‘adjuvant’’ nor the term ‘‘metastatic’’ precisely cover it. We suggest the terms ‘‘m-neoadjuvant’’ and ‘‘m-adjuvant’’ for neoadjuvant and adjuvant administration in potential NED cases before and NED disease after metastasectomy, respectively. The ‘‘m’’ here stands for ‘‘metastatic.’’

Hypertension Associated With Angiogoenesis Inhibitors: What Do Oncologists Really Do in Daily Routine? A Small Survey

Hypertension (HTN) is a commonly encountered adverse event during angiogenesis inhibitor (AI) therapy, accepted as a class effect of agents targeting the vascular endothelial growth factor (VEGF) or VEGF receptors. Currently, bevacizumab, sorafenib, and sunitinib are the most common agents used in daily practice. The incidence and severity of HTN in cancer patients taking anti-VEGF therapy are dependent on type, dosage, and administration schedule of drugs and patients’ comorbidities. It is known that uncontrolled HTN could lead to serious cardiovascular events, thus its early recognition and control is crucial. Clinical significance of and management strategies for HTN have not yet been well addressed. The most consistent recommendations are early recognition and frequent monitoring of blood pressure (BP). Officebased BP monitoring (OBPM), home-based BP monitoring (HBPM), and ambulatory BP monitoring (ABPM) have been used in many clinical trials. But frequency and feasibility of methods are still uncertain. Treatment of HTN secondary to AI is yet another dilemma. There are no data suggesting any antihypertensive treatment options for HTN associated with AI use. Some authors hypothesize that HTN while taking AI therapy might be a biomarker for efficacy of antiVEGF mechanism, which may be decreased by normalization of HTN. Moreover, how oncologists scrutinize, diagnose, and treat hypertension resulting from AI therapy is not well known. We aimed to investigate physician behavior in the management of HTN associated with AI use in daily practice. We organized a short survey with 15 questions and applied it to 60 medical oncologists. It had two sections: The first section contained personal queries and the second section included clinical practice, such as which AI was used, where and how often BP was measured, how HTN was managed, and which anti-HTN drugs were used. Thirty-four medical oncologists and 26 training fellows were recruited. All participants prescribed bevacizumab and 96.0% prescribed >1 AI. Of them, 18 (31.0%) did not measure BP regularly: 30 (51.0%) measured BP only in an office-based setting, 11 (19.0%) only in a home-based setting, and 16 (28.0%) in both. Twenty-nine (50.0%) measured BP at every office visit, while only 20 (35.0%) checked BP in a home-based setting 1 or 2 times a day and 9 (15.0%) only once a week. The majority (93.1%) tended to continue prescribing anti-HTN drugs, only 3 (5.2%) preferred to add a new anti-HTN drug, and 1 (1.7%) tended to withhold antiHTN drugs if patients had preexisting HTN. When BP rose during AI treatment, 53 (96.3%) added a new antiHTN drug, 6 (6.9%) postponed treatment, and 1 (1.7%) stopped AI therapy. Anti-HTN drug choices were as follows: 20 (35.1%) angiotensin receptor blockers and angiotensin-converting enzyme inhibitors, 11 (19.3%) calcium channel blockers, and 16 (26.7%) various combinations. While what is really happening with regard to AIinduced hypertension and its management remains undetermined, our small study gives some clues. There may be a gap between clinical trial data and daily practice. A substantial number of oncologists do not measure BP. The remaining oncologists monitor BP at different schedules with various methods and treat it with several agents.

The prevalence of depression in patients with cancer in Jordan.

To the editor: We have read the article by Mhaidat et al. with great interest [1]. We suggest the paper by Mhaidat et al., however, it may be mitigated by some methodological weaknesses. The study was apparently designed to answer one question: “What is the prevalence of depression among patients with cancer in Jordan?”. The authors found that depression prevalence was 51.9% among cancer patients, and they emphasized that increased likelihood of depression was detected in patients who knew about their diagnosis and in those with advanced disease stages. They also added that more attention should have been paid in these subgroups. Our concern with Mhaidat et al.s paper is its presentation as a “national survey”. This study recruited 208 patients. This small sample size does not suggest a representative, national survey, in our opinion. Indeed, Mhaidat and colleagues cited other cross-sectional studies with significantly larger sample sizes of 456 and 930 patients, respectively [2, 3]. When we search for “national survey in cancer patients” in literature, we can find that these studies had more than a 1,000 patients. For example, a study on “Physical Activity, and Health-Related Quality Of Life in Cancer Survivors” from Canada, which has a population of 30 million according to Globocan 2002, included over 3,000 patients [4]. According to Globocan 2002 [5], Hashemite Kingdom of Jordan has a population about 5 million. For a study to be presented as a national survey, it must represent responses from people or units from the country as whole, not just from one clinic or institution. The chance of responding to that survey must be made available to the majority or all of the institutions, and the response rate must ideally be high enough to cover roughly around at least one third of all the possible respondents, as can be observed in the very recent examples from Belgium, France, USA, Great Britain, and Sweden [6–10]. In conclusion, although this valuable study contributes to knowledge on depression in Jordanian cancer patients, we feel that it falls short of a “national survey.”