Erkan Dogan

Probable hepatotoxicity related to Nerium oleander extract in a patient with metastatic synovial sarcoma of the knee.

Dear Editor: A 43-year-old female patient was admitted to our hospital with nausea, vomiting, severe stomach pain, and bloating in June 2008. Initial examination revealed ascites confirmed by abdominal computed tomography (CT). History was significant for the diagnosis of a synovial sarcoma of the knee with pulmonary and bone metastasis in 2005. She first received three cycles of chemotherapy with ifosfamide, and doxorubicin HCl (AdriablastinaTM, Deva Ilac, Istanbul, Turkey), following which she had surgery on her primary site. Her operation was followed by radiotherapy. Due to progression of her pulmonary lesions in 2007, she was treated with six courses of ifosfamide, and etoposide. After the six cycles of chemotherapy, progression of pulmonary metastases was observed and she had daily intramuscular injections of Nerium oleander extract (AnvirzelTM, Phoenix Biotech, Mississauga, Ontario) (1.2 mL/m2/day) for the last 2 months without the knowledge of our medical team who were following her up since her last course of chemotherapy in March 2008. She was taking no other medications apart from 50 mg tramadol tablets t.i.d. Laboratory findings revealed elevated aspartate aminotransferase (450 IU/L), alanine aminotransferase (402 IU/L), ã-glutamyltransferase (157 IU/L), and alkaline phosphatase (163 IU/L). Hepatitic markers were hepatitis B surface antigen (Hbs Ag) (-) antiHbsAg immunoglobulin G (IgG) ( ), anti-HbsAg IgM (-), and anti-HbcAg IgM (-). Abdominal CT revealed multiple peritoneal implants consistent with peritoneal carcinomatosis, but no evidence of liver metastasis. During follow-up, liver enzymes gradually decreased, biluribin levels increased, and her ascites worsened for which she required frequent paracentesis. In the third week, laboratory findings were consistent with disseminated intravascular coagulation and the patient died due to cardiopulmonary arrest. N. oleander, a wild shrub growing predominantly around the Mediterranean basin, whose toxicity has been extensively studied both in livestock and humans, appears to have predominantly gastrointestinal (nausea, vomiting, bloating), cardiac (bradycardia, heart blocks), and neurologic (confusion, dizziness, depression) effects.1,2 One phase 1 study3 determined the maximum tolerated dose and safety of N. oleander extract in patients with advanced, refractory solid tumors. Most patients in this study developed mild injection site pain (78%). Other toxicities included fatigue, nausea, and dyspnea without any hepatotoxicity. They found that N. oleander extract can be safely administered at doses up to 1.2 mL/m2/day. We also have found no reported cases of hepatotoxicity in humans in the PubMed database. Studies reported hyperbilirubinemia and leukocyte infiltration, diffuse fatty vacuolation, and hepatocyte necrosis in livers of oleander-poisoned sheep.3 We have found no other reason for the abnormalities in liver function tests apart from possible hepatotoxicity of N. oleander extract.

Successful treatment of primary duodenal carcinoma with bilateral adrenal metastases with docetaxel–cisplatin–5-fluorouracil regimen

A 45-year-old man was admitted to our hospital with epigastric pain, asthenia, emesis and loss of weight. Physical examination was otherwise normal. Endoscopy showed duodenal mass in the third part of the duodenum. Endoscopic biopsy specimens of the lesion revealed duodenal adenocarcinoma. Thorax and abdominal computed tomography (CT) scans were normal. A Billroth’s II gastroduodenectomy was carried out. At surgery, pancreas invasion by the tumor was observed. Pathologic examination of the resected specimen revealed a middifferentiated adenocarcinoma spreading over the pancreas. Three months after the surgery, the patient had severe asthenia, orthostatic hypotension and emesis. The patient was diagnosed with adrenal insufficiency with a typical pigmentation of skin. He received treatment for adrenal insufficiency. Abdominal CT scan showed newly onset bilateral adrenal metastases. The patient was treated with docetaxel, cisplatin, 5-fluorouracil (TCF) chemotherapy regimen. After six cycles of TCF regimen, response evaluation showed complete resolution of metastases in both adrenals. Malignant neoplasms of the small bowel are among the rarest types of cancer [1]. These tumors most commonly involve the ampullary or periampullary regions of the descending duodenum. Metastatic lesions of duodenal adenocarcinoma are often seen in regional lymph nodes, liver and lungs [2]. There is no reported case of duodenal carcinoma with isolated bilateral adrenal metastases in the literature. Early detection of duodenum carcinoma is an extremely rare condition. The most frequent clinical findings of early duodenal cancer include epigastric pain, nausea, vomiting, weight loss and signs of upper gastrointestinal bleeding. Unfortunately, most symptomatic patients with duodenal cancer have advanced lesions at presentation because of delayed diagnosis [3]. Because of the rarity of duodenum adenocarcinoma, the role of chemotherapy in this disease remains undefined. Most centers have only limited experience treating these patients [4, 5]. It has been shown that chemotherapy for patients with inoperable or metastatic small bowel adenocarcinomas (SBA) resulted in an improved overall survival when compared with no chemotherapy [3, 6]. The Eastern Cooperative Oncology Group conducted prospective study of chemotherapy for SBA. In this study, 39 patients with metastatic or advanced SBA received 5fluorouracil (5-FU), doxorubicin and mitomycin C and demonstrated 18% response rate and a median survival of 8 months [6]. A retrospective study reported a 21% response rate for 20 patients with advanced SBA who were treated with a combination of 5-FU and a platinum agent [7]. In a recent large retrospective study from the MD Anderson Tumor Registry, from 1978 to 2005, 80 patients with small bowel adenocarcinoma received chemotherapy regimen with or without 5-FU and platinum agent and it was observed that 5-FU and a platinum agent improved response rate and progression-free survival significantly when compared with other chemotherapy combinations. The response rate was 41% and progression-free survival was 8.7 months [8]. One large randomized phase III study showed clinical benefit with TCF compared with cisplatin and fluorouracil in advanced gastric or gastroesophageal cancer adenocarcinoma [9]. The benefit observed from the addition of a docetaxel chemotherapy agent to cisplatin and fluorouracil in gastric adenocarcinoma suggested a possible role for this kind of chemotherapy in the treatment of SBA and therefore we used TCF regimen in our patient. In conclusion, the choice of chemotherapy in recurrent SBA is not standard. The infrequency of SBA has made it difficult to do randomized study. However, the combination of 5-FU and a platinum 6 docetaxel maybe recommended for the treatment of patients with metastatic SBA.

Impact of adjuvant treatment modalities on survival outcomes in curatively resected pancreatic and periampullary adenocarcinoma.

BACKGROUND We examined the impact of adjuvant modalities on resected pancreatic and periampullary adenocarcinoma (PAC). METHODS A total of 563 patients who were curatively resected for PAC were retrospectively analyzed between 2003 and 2013. RESULTS Of 563 patients, 472 received adjuvant chemotherapy (CT) alone, chemoradiotherapy (CRT) alone, and chemoradiotherapy plus chemotherapy (CRT-CT) were analyzed. Of the 472 patients, 231 were given CRT-CT, 26 were given CRT, and 215 were given CT. The median recurrence-free survival (RFS) and overall survival (OS) were 12 and 19 months, respectively. When CT and CRT-CT groups were compared, there was no significant difference with respect to both RFS and OS, and also there was no difference in RFS and OS among CRT-CT, CT and CRT groups. To further investigate the impact of radiation on subgroups, patients were stratified according to lymph node status and resection margins. In node-positive patients, both RFS and OS were significantly longer in CRT-CT than CT. In contrast, there was no significant difference between groups when patients with node-negative disease or patients with or without positive surgical margins were considered. CONCLUSIONS Addition of radiation to CT has a survival benefit in patients with node-positive disease following pancreatic resection.

Long-term survivors among breast cancer patients with brain metastases

We read the article by Niwinska et al. [1] in which they carried out a comprehensive analysis of 222 consecutive patients with breast cancer and brain metastases. They found that median survival from brain metastases in recursive partitioning analysis Radiation Therapy Oncology Group prognostic class I, II and III were 15, 11 and 3 months, respectively. A recent retrospective study evaluated clinical data from 420 patients who had been diagnosed with breast cancer and brain metastasis from 1994 to 2004 at M. D. Anderson Cancer Center. In this study, median follow-up after brain metastasis was 6 months (range 0.7–95.9 months) and the overall median survival was 6.8 months [2]. Although the survival outlook for patients with breast cancer metastatic to brain is generally poor, there were some long-term survivors. Eighty-two patients in this study (19.5%) were alive at least 18 months after diagnosis of brain metastasis. Of these 82 patients, 25 patients (30%) were human epidermal growth factor receptor 2 positive. Furthermore, 18 (4.2%) were alive at least 60 months after this diagnosis. Compared with an unselected series of breast cancer patients, this longer surviving population was younger and was predominantly premenopausal. Most of these patients had tumors of ductal histologic type, T stage 1 or 2, N stage 0 or 1 and M0 stage at diagnosis. About half of these patients had estrogen receptor-positive or progesterone receptorpositive disease and 73% had grade III disease. Any or all of these characteristics may explain their potential for prolonged survival. In conclusion, detailed molecular characterization of brain metastases from breast cancer may lead to a more in-depth understanding of the biologic abnormalities that drive this malignant behavior and also may lead to the discovery of new therapeutic targets with improved therapeutic indices.

Changing trends and experience with esophageal cancer surgery in a single university hospital: are the results similar or not?

Objective: The main treatment modality for esophageal cancer remains to be surgery. Over the last decades, surgical strategies have evolved remarkably. When neoadjuvant chemoradiotherapy became standard, discussions about the role, type, and timing of surgery began. In this study, we share results we obtained after operating our patients using various surgical techniques. Material and Methods: Reliable data from 51 esophageal cancer patients were evaluated retrospectively. Of the 51 cases, 31 were operable. These operable cases were further classified according to surgical method and neoadjuvant therapy status. Median survival time in months, complications, hospital mortality, length of hospital stay, and pathology results (total lymph nodes harvested and pathologic tumor node metastasis stage [p_TNM]) were documented for the different surgical approaches. Results: Open surgical methods were performed in 21 cases, while in 10 cases the Minimally Invasive Surgery (MIS) method was used. The MIS group received neoadjuvant therapy more frequently than the open surgical methods group (p=0.013). Although more complications were observed in the MIS group, the difference to the open esophagectomy methods group was not significant. Patients in the MIS group also had longer hospital stays, but again the difference was not significant. Although a pathologic complete response was seen in 8 of the 11 (72.7%) patients in our study who received chemoradiotherapy as neoadjuvant treatment, the surgical results of patients who received chemoradiotherapy were worse, although not to a statistically significant extent. Conclusion: Despite changing trends and treatment options in esophageal cancer surgery, we have yet to see the expected improved results.

Acute promyelocytic leukemia in a young patient with breast cancer

To the Editor, A 43-year-old woman had been operated for infiltrative ductal carcinoma of the left breast with modified radical mastectomy in 2006. She was staged as T2N1M0 disease with positive ER/PR and her2/neu. She was given 3 cycles of adjuvant chemotherapy with CEF (cyclophosphamide, epirubicin, 5-fluorouracil), followed by weekly paclitaxel for 12 weeks. She received radiotherapy to the chest wall and surrounding lymphatic regions for 5 weeks. Then, she received adjuvant tamoxifen for two years. Her breast cancer has been in clinical remission after an uneventful follow-up of three years. However, she has experienced gingival bleeding and thrombocytopenia in September 2009. Peripheral smear and bone marrow aspiration and biopsy revealed acute promyelocytic leukemia (APL) with chromosal abnormality of t (15; 17) on cytogenetic examination. Her medical history was noncontributory except for breast fibroadenoma for 20 years and hypothyroidism. The patient was diagnosed as APL secondary to adjuvant therapy for breast cancer, and treatment with alltrans retinoic acid and idarubicin was initiated. We present a rare case of therapy-related APL (classified as AML-M3 in the French-American-British (FAB) classification) that may have been caused by adjuvant chemotherapy and/or regional radiation for breast cancer. Chemotherapy and radiotherapy are important in breast cancer therapy for improving survival of women with high-risk breast cancer [1]. The most common adjuvant chemotherapy agents used for breast cancer are alkylating agents (cyclophosphamide) and anthracyclines (epirubicin, doxorubicin). Although these agents have beneficial effects for the breast cancer, secondary malignancy including acute myeloblastic leukemia (AML) or myelodysplastic syndrome (MDS) may develop with alkylating agents (within 2–3 years) and anthracyclines (within 3–8 years) after the initial cancer treatment [2–4]. The combinations of these leukemogenic antineoplastic agents including epirubicin and cyclophosphamide may increase the risk of treatmentrelated AML and/or MDS. Additionally, the use of regional irradiation for patients with node-positive breast cancer may contribute to this increased risk [5]. Different chromosal abnormalities, especially those involving loss of all or part of chromosome 5 and/or 7, are noted with therapy-related AML/MDS [6]. On the other hand, it has been shown that patients with breast cancer have a higher susceptibility to develop a second malignancy even among patients undergoing only surgical approaches [3, 7]. Although the overall risk for a second malignancy in female patients with breast cancer appeared to be small (20–30% excess risk), it has been established that young age at diagnosis predicts for an increased risk for second malignancy [8]. Age-specific incidences showed peak among women in 40s, and 2.02% of the patients developed secondary malignancy [8]. The series of secondary APL are mostly clustered in patients with breast cancer in the literature. Interestingly, there is a correlation between the BRCA2 mutation and the risk of hematologic malignancy, and that the break point on chromosome 17 in the t (15;17) translocation is at or near the location of BRCA2 [9]. It is also noteworthy that there is an increased incidence of hypothyroidism (as in our case) in acute leukemia patients at diagnosis [10]. Thyroid hormone and retinoic acid receptor genes belong to the same family of nuclear receptor gene superfamily, and thyroid hormones are important regulators of hematopoiesis using receptors similar to differentiating factors such as retinoids [10]. O. Kara E. Ozdemir C. Arslan E. Dogan K. Altundag (&) Department of Medical Oncology, Hacettepe University Institute of Oncology, Sihhiye, Ankara 06100, Turkey e-mail: altundag66@yahoo.com

Other malignancies in patients with breast cancer: a single institute experience.

To The Editor, Patients with breast cancer survive longer after advances in treatment options [1]. During their follow-up, they may develop secondary malignancies or became patients with breast cancer secondary to previously diagnosed malignancies. The aim of our study was to evaluate the other malignancies among patients with breast cancer. Between years 2004 and 2009, 987 consecutive patients with breast cancer presenting at Hacettepe University Institute of Oncology were evaluated retrospectively. Median follow-up of all patients was 3.6 years (range 0.3–28). Of all the study population, 19 (1.9%) had other malignancies. Among all patients with breast cancer, 14 and 5 patients developed secondary malignancies before and after the diagnosis of breast cancer, respectively. The most frequently observed ones were ovarian cancer. The frequency of other malignancies was shown in Table 1. Median age of breast cancer diagnosis was 49, while median age of previous malignancies was 45 years old. Patients with breast cancer can survive longer after the advances in treatments. This can cause enough time to develop secondary malignancies. Secondary malignancies may develop sporadically, or due to environmental factors, genetic susceptibility and treatment complications [2]. Ewertz et al. reported the risk of second primary cancer in approximately 55,000 patients with breast cancer. They found that risk of a developing second malignancy was 13% [3]. In our study, frequency of other malignancies was 1.9%. This is most probably due to the short follow-up period. In our series, nearly 50% malignancies diagnosed were gynecological tumors. Therefore, close follow-up of patients who had gynecological tumors is very important due to risk of developing secondary cancer, especially breast cancer.

Docetaxel/doxorubicin/cyclophosphamide (TAC) chemotherapy for operable HER2-negative, node-positive breast cancer patients: Results from a single institution.

e11106 Background: TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy is commonly used as adjuvant chemotherapy for node-positive breast cancer. However, data are lacking for HER2-negative s...