Cisplatin Etoposide Research Articles

Multicentre phase II study of cisplatin–etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study

BackgroundThe optimal treatment of large-cell neuroendocrine carcinoma (LCNEC) of the lung remains unclear. Here, our primary objective was to assess the efficacy of cisplatin–etoposide doublet chemotherapy in advanced LCNEC. Accuracy of the pathological diagnosis and treatment toxicity were assessed as secondary objectives. Patients and methodsProspective, multicentre, single-arm, phase II study with a centralised review of treatment-response and pathological data. Patients had untreated performance status (PS) 0/1 stage IV/IIIB LCNEC and received cisplatin (80 mg/m22 d1) and etoposide (100 mg/m22 d1-3) every 21 days. ResultsEighteen centres included 42 patients (mean age, 59 ± 9 years; 69% men; median of four cycles/patient). At least one grade-3/4 toxicity occurred in 59% of patients (neutropaenia, thrombocytopaenia, and anaemia in 32%, 17%, and 12%, respectively). The median progression-free survival (PFS) and overall survival (OS) were 5.2 months (95% confidence interval, CI, 3.1–6.6) and 7.7 months (95% CI, 6.0–9.6), respectively. The centralised pathologist review reclassified 11 of 40 (27.5%) patients: 9 as small-cell lung cancer, 1 as undifferentiated non-small-cell lung cancer, and 1 as atypical carcinoid. Survival data were not significantly changed by excluding the reclassified patients. ConclusionsThe pathological diagnosis of LCNEC is difficult. The outcomes of advanced LCNEC treated with cisplatin–etoposide doublets are poor, similar to those of patients with advanced small-cell lung carcinoma (SCLC).

Patterns of presentation and management of non-small cell lung cancer in an Algerian cancer center.

e19063 Background: To evaluate the pattern of management and outcome of patients with NSCLC in our cancer center over the last 8 years. Methods: A retrospective study of all NSCLC patients seen between January 2005 and December 2012 in Medical Oncology Center, Constantine, Algeria. All demographic, clinical data, management and outcome were captured and analyzed. Results: 581 patients with NSCLC, male-female ratio 10:4, median age 59.7 years (21-85), 64.2% were smokers (0.8% were females), and 15% exposed to alcohol. Diagnostic specimens were obtained by CT scanguided biopsy in 62% of cases, bronchoscopy in 26.2%, and surgical biopsy in 9.6%. Median time to diagnosis was 6.1 months (0 months -6 years). During the study period, incidence of squamous cell carcinoma declined from 62.1% to 37.5% and adenocarcinoma incidence doubled(from 29.5% to 57.5%). Most of the patients had an advanced stage disease, 58.5% stage IV, 15.3% stage IIIB, 14.5% stage IIIA, stageIIB 4.1%, stage IIA 0.9%, stage IB 1.9%, and stage IA 0.9%. 8.6% underwent surgery, 13.9% received radiotherapy, 88.6% with PS≤ 2 received first-line chemotherapy which was platinum-based in 95.1% of the cases. 17.2% second-line, and 3.6% third-line. Most used chemotherapy regimens are: etoposide-cisplatin (EP) in 2005-2006, cisplatin-gemcitabine (P/GMZ) 2007-2009, taxotere-cisplatin (TP) 2010-2012. Outcome of these regimens ranged for response rate (RR) between 12.8% and 23.8% and overall disease control (ODC) ranged between 17.8% and 30.5%. Pemetrexed/platinum administered to 20 patients, RR 10.5%, ODC 26.1%. Bevacizumab/carboplatin-paclitaxel to 8 patients, RR 12.5%, ODC 25%. Outcomes in nonsmokers are better compared to smoker patients: RR 16.6% vs 12.1%. ODC 22.5% vs 18.2%. Longer survival (2.3 months more) and higher survival rate noted for women than that for men at all stages of the disease. RR is 16.3% in adenocarcinoma cases, 12.5% in squamous cell. For all groups: One year survival 16.5%, 2 years 5.5%, and 5 years 1%. Conclusions: Patients with NSCLC present with advanced stages. The management of NSCLC at our Center mirrored the evolution of management using conventional chemotherapy.

Complete response and long-term remission to anti-HER2 combined therapy in a patient with breast cancer presented with bone marrow metastases

Presentation with bone marrow metastasis at diagnosis is a rare event in breast carcinoma. Here, we report a rare presentation of metastatic breast cancer patient with bone marrow metastases, who was successfully treated with trastuzumab combined chemotherapy. The regimens initially applied for bone marrow metastasis were docetaxel/adriamycin, gemcitabine/vinorelbine, epirubicin/cyclophosphamide, capecitabine, docetaxel, gemcitabine, and paclitaxel. But, the best response to these regimens was not satisfactory. Our patient was completely treated with etoposide-cisplatin and trastuzumab combination. She is still on remission after five years of metastatic breast cancer diagnosis using letrozole and trastuzumab without complication. Physicians should be careful in treating bone marrow metastases in breast cancer, since patients can show improved marrow function after chemotherapy and long-lasting survival is possible.

Is high-dose chemotherapy superior to conventional chemotherapy as first salvage treatment for patients with metastatic germ cell tumors?

There is little prospective data on the optimal treatment of patients who fail first-line chemotherapy in advanced germ cell tumours (GCT). What makes matters more complicated is the considerable variability in what is broadly referred to as conventional dose chemotherapy (CDCT) and high-dose chemotherapy (HDCT), both considered accepted salvage chemotherapeutic regimens in advanced GCT. While other combinations have been investigated, salvage CDCT commonly consists of cisplatin plus ifosfamide and either etoposide (VIP), vinblastine (VeIP) or paclitaxel (TIP). All three have been studied prospectively, with VIP and VeIP showing complete response (CR) rates ranging from 37% to 50%. More recently, TIP has shown CR as high as 70% and as low as 19% to 41%. However, these studies have been criticized for either selecting a favourable patient population1–3 or using suboptimal dosing of paclitaxel and/or ifosfamide.4,5 In HDCT, the standard is administering chemotherapy at doses of up to five times the norm, with the most commonly used drugs being carboplatin and etoposide (CE). In a retrospective series of 184 patients who received HDCT, 63% achieved a durable response with high-dose CE, either with or without a preceding cycle of VeIP. Patients who achieved remission also received adjuvant oral etoposide.6 In contrast, in a more recent prospective study on 107 patients who received HDCT, 50% (54) achieved CR, with treatment consisting of three cycles of high-dose CE, preceded by two cycles of paclitaxel and ifosfamide given 2 weeks apart (TI-CE).7 Ideally, properly constructed prospective randomized trials must be set up to address the issue at hand, in view of the global differences in what constitutes HDCT and CDCT regimens, and the worldwide variability in treating this disease where HDCT may be offered as first, second or even third-line therapy. Is CDCT enough as first-line therapy in patients with advanced GCT, or should it be consolidated with HDCT? Only one prospective randomized trial has addressed this issue.8 In the IT-94 study, CDCT patients received four cycles of VIP or VeIP, whereas HDCT patients received one cycle of high-dose CE and cyclophosphamide preceded by three cycles of VIP or VeIP. No difference in survival was noted between the two groups. However, criticisms of this study included the use of only one cycle of CE (as opposed to two or three), and the unusually high mortality rate with HDCT (7%).8 In contrast, data based on >1600 patients from two retrospective studies have shown a significant advantage to HDCT,9,10 with a superior advantage noted in patients receiving a sequential rather than single-cycle HDCT.10 Answering the above question is very important, as up to 30% of patients with advanced GCT are not cured with first-line therapy.11 In this current study, Beausoleil and colleagues should be commended for retrospectively reviewing their patients according to the newly developed International Prognostic Factor Study Group (IPFSG) classification.12,13 The high sensitivity of this malignancy to chemotherapy and the fact that most patients with this disease are young encourages urologists/oncologists to seek a cure even if that entails intensive chemotherapeutic regimens. Despite using only one cycle in this study, it is certainly noteworthy that the routine use of HDCT had been offered at their institution since 1990. What should also be mentioned though is the potential curative role of surgery in metastatic GCTs; up to 50% of patients may have active residual disease following salvage chemotherapy.14 Although the authors admit that some of their patients may have had surgery,12 it is not clear how many underwent surgery and which of the two chemotherapy treatment groups they belonged to. Although the number may have been too low to mention, analysis could have been significantly affected given the study’s small sample size. A multimodal approach involving physicians from several specialties, including medical oncology and surgery, should be applied. Researchers have recently proposed the TIGER trial, a prospective international multicentre randomized phase III trial of initial salvage chemotherapy comparing TIP with TI-CE in patients with GCTs.15 Patients in this study will be stratified according to the IPFSG classification system. We look forward to the start of this trial. Until the question is finally tackled in a prospective randomized fashion, standardized therapy will remain difficult to establish.

The Effect of Cisplatin-Etoposide Chemotherapy on Platelet Parameters in Lung Cancer Patients

The aim of this study was to investigate the effect of cisplatin etoposide chemotherapy on platelet indices in advanced stage lung cancer patients. Twenty advanced stage lung cancer patients who received cisplatin and etoposide chemotherapy and 35 healthy subjects were enrolled. The platelet indices (platelet count, mean platelet volume (MPV), plateletcrit (Pct) and platelet distribution width (PDW)) and other blood count parameters were recorded in baseline, before second cycle and after sixth cycle of chemotherapy. In baseline analysis, white blood cell count, but not other blood parameters, were different in patient group compared with control group,. After six cycles of chemotherapy, PDW values were elevated than baseline analysis in lung cancer patients. Other platelet parameters were not changed after chemotherapy. This study showed that MPV, platelet count, or Pct don’t change after cisplatin-etoposide chemotherapy in lung cancer patients.

Primary Pure Ovarian Choriocarcinoma Mimicking as Ruptured Ectopic Pregnancy: A Rare Case Report

Primary choriocarcinoma of ovary is rare. It could be gestational or non-gestational in origin. The distinction between the two is difficult but necessary as the non-gestational type has a bad prognosis. We report a case of a pure ovarian choriocarcinoma likely to be of gestational origin treated by cytoreductive surgery in combination with post-operative chemotherapy. The patient received 4 cycles of Etoposide Metotrexate Actinomycin D Cisplatin Etoposide EMA-CE regimen with a satisfactory decrease in the serum beta-hCG level. There was no evidence of recurrence or metastasis after 6- months follow-up. Our case provides evidence that cytoreductive surgery in combination with post-operative chemotherapy is an effective therapeutic strategy for pure ovarian choriocarcinoma. The pure ovarian choriocarcinoma is aggressive with a high risk of metastasis close follow-up with serum beta-hCG and imaging examinations is essential.

Small cell carcinoma of the prostate after high-dose-rate brachytherapy for low-risk prostatic adenocarcinoma

In the present study, we describe an 80-year-old patient who developed prostatic small cell carcinoma (SCC) following high-dose-rate brachytherapy (HDR-BT) for low-risk prostatic adenocarcinoma. The patient received one implant of Ir-192 and 7 fractions of 6.5 Gy within 3.5 days, for a total prescribed dose of 45.5 Gy. A total of 27 months after HDR-BT, the patient complained of difficulty in urinating. His serum prostate-specific antigen (PSA) levels were 3.2 ng/ml. Systemic examination revealed an enlargement of the prostate, urethral stenosis, pelvic lymph node swelling and multiple lung and bone lesions. His serum neuron-specific enolase (NSE) levels were elevated to 120 ng/ml. A prostate needle biopsy was performed for pathological examination. Histologically, there were tumor cells with hyperchromatic nuclei and scant cytoplasm showing a solid or trabecular growth pattern. Immunohistochemically, they were positive for AE1/AE3, CD56 and synaptophysin, and negative for PSA, PAP and CD57. These findings are consistent with SCC of the prostate. A review of the prostate needle biopsy specimen prior to HDR-BT did not reveal any tumor cells positive for chromogranin A, nor synaptophysin. The final diagnosis was SCC of the prostate with local progression, with lung, lymph node and bone metastases. Three cycles of etoposide/cisplatin (EP) were administered. A greater than 50% decrease in the serum NSE levels was observed. However, there was no objective response. Due to the deterioration of the patient's general condition, EP was discontinued. One month later, his serum NSE showed a rapid increase to 210 ng/ml with aggressive local progression and the patient succumbed to the disease 5.5 months after the start of EP therapy.

O3-007 - Multicenter Retrospective Analysis of Systemic Chemotherapy for Advanced Poorly Differentiated Neuroendocrine Carcinoma of Digestive System

ABSTRACT Background No standard regimen is yet established for advanced poorly differentiated neuroendocrine carcinoma (PDNEC) although regimens for small-cell lung carcinoma are usually adopted such as irinotecan + cisplatin (IP) or etoposide + cisplatin (EP). Our aim was to respectively investigate the outcomes of advanced PDNEC of the digestive system according to patient characteristics and regimens. Materials and methods Data were collected from patients' medical records at 23 hospitals. Selection criteria were as follows: (i) histologically proven PDNEC, small-cell carcinoma, mixed endocrine–exocrine carcinoma with a PDNEC component, or histologically proven neuroendocrine tumor with rapidly progressive clinical course; (ii) primary tumor arising from the Gastrointestinal tract (GI) or the hepato-biliary-pancreatic system (HBP); and (iii) inoperable or recurrent disease treated with systemic chemotherapy (Cx) between April 2000 and March 2011. Results This study included 258 patients (males/females, 182/76) with a median age of 62.5 years. Primary sites were esophagus/stomach/small bowel/colorectum/hepato-biliary system/pancreas in 85/70/6/31/31/35 patients. According to the primary sites, the median overall survival period (mOS) was 13.4/13.3/29.7/7.6/7.9/8.5 months, and that of GI/HBP was 13.0/7.9 months, respectively. Most common regimen was IP (160 patients, 62%), followed by EP (46 patients, 18%). For IP/EP patients, response rates were 50%/27%, the median progression-free survival periods were 5.2/4.0 months. Second line Cx was carried out for 88 patients (55%)/28 patients (61%), and mOS from first line Cx were 13.0/7.3 months in IP/EP groups. Multivariate analysis demonstrated that a primary site of HBP (HR = 1.96, P = 0.003) and performance status of 2 and more (HR = 2.32, P = 0.01) were independent unfavorable prognostic factors of PDNEC. Conclusions PDNEC of HBP had poorer prognosis than GI. IP was the most common treatment regimen and seemed to show better treatment outcomes than EP.

P3-047 - Investigation of Gastrointestinal Neuroendocrine Tumors after Prior Chemotherapy

ABSTRACT Background Evidence-based data regarding the role of chemotherapy in the management of gastrointestinal neuroendocrine tumors are scarce, mainly because the results of only small studies are available. Combination chemotherapy with regimens such as cisplatin–etoposide was reported to have activity against gastrointestinal neuroendocrine tumors. However, few studies have documented a good response of gastrointestinal neuroendocrine tumors to second-line chemotherapy. Patients and methods We studied three patients with unresectable gastrointestinal neuroendocrine tumors who received irinotecan or amrubicin after prior chemotherapy with platinum and etoposide. ResultsThe characteristics of the three patients are shown below. All were men, with a median age of 69 years (range, 62–70). The site of the primary tumor was the stomach in two patients and the esophagus in one. One patient with a gastric neuroendocrine tumor received irinotecan as second-line chemotherapy, and the other received amrubicin as second-line chemotherapy followed by irinotecan as third-line therapy. A partial response was obtained in one patient after two courses of irinotecan, and this patient is now receiving the fifth course of irinotecan. The patient with an esophageal neuroendocrine tumor received amrubicin as second-line chemotherapy, followed by irinotecan as third-line therapy. The second course of irinotecan is now being administered, and response will be evaluated after completion of the second course. Both patients who received amrubicin as second-line therapy had progressive disease after two courses of amrubicin. Conclusions We described our experience with a case of gastrointestinal neuroendocrine tumor that responded to irinotecan after prior chemotherapy. Irinotecan might be effective against gastrointestinal neuroendocrine tumor. However, further clinical studies are required to confirm currently available evidence.

P2-052 - A Case Report of Advanced Pancreatic Neuroendocrine Tumor Treated with Chemotherapy for Cisplatin Containing Resimen Followed by Everolimus in Combination with Octreotide LAR

ABSTRACT Pancreatic neuroendocrine tumor (P-NET) accounts for less than 5% of all pancreatic tumors. Treatment options for advanced P-NET are somewhat limited. At this time, the standard therapy for advanced P-NET is not exist. Everolimus, which targets the mammalian target of rapamycin (mTOR), has recently been approved for patients with advanced P-NETs. We herein present a case of P-NET treated with chemotherapy for the cisplatin–etoposide resimen followed by everolimus in combination with octreotide LAR. A 71-year-old female was referred to our hospital with tumor in the tail of the pancreas with the multiple liver metastasis. The dynamic study of computed tomography (CT) scan showed hypervascular tumors on the early phase in the pancreatic tail and liver, both of which were the same enhanced pattern. No hormonal abnormalities demonstrated. Endosonography-guided fine needle aspiration (EUS-FNA) was underwent to the pancreatic lesion. The cytology and immunological examination suggested both synaptophysin and chromogranin A positive, which led to the diagnosis with class III neuroendocrine tumor. Even histological examination was not carried out, she was diagnosed with stageIV P-NET because imaging studies had already revealed liver metastasis. She began to be treated with systemic chemotherapy of cisplatin–etoposide resimen analogous to that used for small-cell lung cancer and octreotide LAR 30 mg, a long acting somatostatin analog, was given as a intramuscular (IM) injection every 28 days. After recieving two courses cisplatin–etoposide resimen, the CT scan showed a marked increase in the tumor size in the liver and found to be progressive disease. Cisplatin–etoposide resimen were switched to everolimus 10 mg PO daily with octreotide LAR 30 mg IM every 28 days continued. At the time of submission of this abstract, she had been still treated with everolimus–octreotide LAR.

1520PD - Comparative Study Between Belotecan/Cisplatin and Etoposide/Cisplatin (COMBAT) in Patients with Previously Untreated, Extensive Stage Small Cell Lung Cancer - Interim Analysis

ABSTRACT Purpose Belotecan (camtobell™) is a topoisomerase I inhibitor, and effective in small cell lung cancer (SCLC). The objective of this study is to compare the efficacy and safety of belotecan + cisplatin (BP) and etoposide + cisplatin (EP) in first line setting. Methods (materials) This is a multicenter, randomized, prospective controlled trial to prove non-inferiority of BP compared to standard EP regimen. The primary endpoint is overall response rate (ORR), and secondary endpoints are toxicity, overall survival (OS) and progression-free survival (PFS). BP was administrated by belotecan 0.5 mg/m2 for 4 days combined with cisplatin 60 mg/m2 only for first day. Treatment response was evaluated according to version 1.0 of Response Evaluation Criteria in Solid Tumors. Results We enrolled 129 (BP: 63, EP: 66) patients, and response evaluation was possible in 111 (BP: 50, EP: 61) patients. In BP group, there were 1 complete response, 32 partial responses (PR), 7 stable diseases (SD), and there were 33 PR and 11 SD in EP group. There were no significant differences in ORR (BP: 66.0%, EP: 54.1%, p = 0.25) and disease control rate (BP: 80.0%, EP: 72.1%, p = 0.38). Median OS (BP: 483, EP: 340 days, p = 0.21) and PFS (BP: 192, EP: 150 days, p = 0.08) were not significantly different. The frequency of grade ≥ 3 anemia (BP: 29.0%, EP: 7.5%, p Conclusions In this interim analysis, BP and EP have similar ORR, OS and PFS in extensive stage SCLC. Toxicity profiles except anemia and thrombocytopenia were similar between two groups. (ClinicalTrials.gov number, NCT00826644) Disclosure All authors have declared no conflicts of interest.

Successful treatment with a low-dose cisplatin–etoposide regimen for patients with diencephalic syndrome

Diencephalic syndrome (DS) is a rare but rapidly fatal condition, usually occurring during the first year of life, as a result of a hypothalamic/chiasmatic tumor. The purpose of this study was to induce an objective tumor response and to achieve rapid weight recovery by using ten three-day courses of reduced-dose cisplatin-etoposide. Between 2004 and 2009, eight pediatric patients with DS as a result of an hypothalamic tumor and with a median age at diagnosis of 6.5 months (range 4-60 months) received 10 monthly courses of cisplatin (25 mg/m(2)/day on days 1-3) and etoposide (100 mg/m(2)/day on days 1-3). Under chemotherapy, rapid weight recovery was observed for all patients; tumor response was observed for six (75 %; partial response in four and minimum response in two). The other two had stable disease at completion of treatment. Mean time to weight recovery was 6 months (range 5-7 months) for pilomyxoid astrocytoma patients, and 3.3 months (range 3-4 months) for those with pilocytic astrocytoma. For DS patients who received nutritional support (enteral or parenteral nutrition) the mean time for weight recovery was 5 months (range 3-7 months) whereas children who were able to orally ingest a high-energy diet had a mean time for weight recovery of 8.66 months (range 3-19 months). After follow-up ranging from 22 to 89 months (median 38 months) all patients are alive. A low-dose cisplatin-etoposide regimen is highly effective regarding tumor response and treatment of DS symptoms/cachexia without causing significant side-effects.

Multicenter retrospective analysis of systemic chemotherapy for advanced poorly differentiated neuroendocrine carcinoma of the digestive system.

4046 Background: No standard regimen is yet established for advanced poorly differentiated neuroendocrine carcinoma (PDNEC) although regimens for small-cell lung carcinoma are usually adopted such as irinotecan + cisplatin (IP) or etoposide + cisplatin (EP). Our aim was to respectively investigate outcomes for advanced PDNEC of the digestive system according to patient characteristics and regimens. Methods: Data was collected from patient medical records at 23 hospitals in Japan. The selection criteria were as follows: 1) histologically proven PDNEC, small cell carcinoma, mixed endocrine-exocrine carcinoma with a PDNEC component, or histologically proven neuroendocrine tumor with rapidly progressive clinical course; 2) primary tumor arising from the gastrointestinal tract (GI) or the hepato-biliary-pancreatic system (HBP); and 3) inoperable or recurrent disease treated with systemic chemotherapy (Cx) between April 2000 and March 2011. Results: This study included 258 patients (males/females, 182/76) with median age of 62.5 years. Primary sites were esophagus/stomach/small bowel/colorectum/hepato-biliary system/pancreas in 85/70/6/31/31/35 patients (pts). According to the primary sites, the median overall survival period (mOS) was 13.4/13.3/29.7/7.6/7.9/8.5 months, and that of GI/HBP was 13.0/7.9 months, respectively. Most common regimen was IP (160 pts, 62%), followed by EP (46 pts, 18%). For IP/EP patients, response rates (RR) were 50%/27%, the median progression free survival periods (mPFS) were 5.2/4.0 months. Second line Cx was performed for 88 pts (55%)/28 pts (61%) and mOS from first line Cx were 13.0/7.3 months in IP/EP groups. Multivariate analysis demonstrated that a primary site of HBP (HR=1.96, p=0.003) and performance status of 2 and more (HR=2.32, p=0.01) were independent unfavorable prognostic factors of PDNEC patients treated with systemic Cx, while the hazard ratio comparing IP with EP was 0.79 (p=0.305). Conclusions: PDNEC of HBP had poorer prognosis than GI. IP was the most common treatment regimen and seemed to show better treatment outcomes than EP.

Macrophage inhibitory cytokine 1 plasma levels in testicular cancer patients during cisplatin combination treatment and their relation to endothelial damage.

e15035 Background: Chemotherapy- (CTx) related endothelial damage contributes to cardiovascular morbidity in testicular cancer (TC) patients (pts). We used an unbiased translational approach to identify mechanisms of and potential biomarkers for this damage. Methods: During varying time periods human microvascular endothelial cells (HMEC-1) were in vitro exposed to bleomycin, cisplatin or left untreated. From 18k cDNA microarray expression signals were obtained, and quantified with an Affymetrix GMS428 scanner. Differences were analysed at single gene and pathway level, and validated by qRT-PCR. With ELISA, protein levels of 1 candidate biomarker were measured in TC pt plasma before, during and 1 month after bleomycin etoposide cisplatin CTx. Levels were related to endothelial damage plasma markers (von Willebrand Factor [vWF], high-sensitivity C-Reactive Protein [hs-CRP]). Results: Microarray data from 16k genes identified several genes with highly differential expression; Macrophage Inhibitory Cytokine 1(MIC-1), Activating Transcription Factor 3 (ATF3) and Amphiregulin (AREG) had strong differences in >1 experimental setting. We regarded these plausible candidates, and confirmed changes by qRT-PCR. Pathway analysis showed a strong association with ‘P53’ and ‘Diabetes Mellitus’ gene sets. Based on known function, we chose to validate MIC-1 protein levels in 41 TC pts. Pre-CTx MIC-1 levels did not differ from healthy controls (TC pts median 383 pg/mL [range 187-1935] vs 340 pg/mL [range 213-504], p=0.06). During CTx levels of MIC-1, vWF and hsCRP significantly increased. MIC-1 levels correlated with vWF and hsCRP at baseline (vWF rs= 0.35, P=0.03; hsCRP rs= 0.39, P=0.01), during (hsCRP at cycle 1d 8 rs= 0.44, P=0.01; vWF at cycle 3 d8 rs= 0.40, P=0.02) and after CTx (vWF rs= 0.56; P<0.01). Conclusions: An unbiased approach in a preclinical model revealed a set of genes related to bleomycin- and cisplatin-induced endothelial activation, such as MIC-1. The increases in plasma levels and the association with vWF and hsCRP suggest that MIC-1 may be a biomarker for CTx-related endothelial damage. Supported by Dutch Cancer Society grant 2009-4365.

Multicenter retrospective analysis of systemic chemotherapy in poorly differentiated neuroendocrine carcinoma of the digestive system.

274 Background: Poorly differentiated neuroendocrine carcinoma (PDNEC) is a rare and aggressive disease. No standard regimen has yet been established for advanced PDNEC, although regimens for small-cell lung carcinoma such as irinotecan + cisplatin (IP) or etoposide + cisplatin (EP), are usually adopted. The aim of this study was to investigate the outcomes according to the patient’s characteristics and treatment regimens for patients with PDNEC of the digestive system. Methods: Data was collected from the medical records of patients at 23 hospitals. The selection criteria were as follows: 1) histologically proven PDNEC, small cell carcinoma, mixed endocrine-exocrine carcinoma with a PDNEC component, or histologically proven neuroendocrine tumor with rapidly progressive clinical course; 2) primary tumor arising from the gastrointestinal tract (GI) or the hepato-biliary-pancreatic system (HBP); and 3) inoperable or recurrent disease treated with systemic chemotherapy between April 2000 and March 2011. Results: There were 258 patients (pts). The median age was 62.5 years (range, 26-81); male/female, 182/76 pts; the primary site was the esophagus/stomach/small bowel/colorectum/hepato-biliary system/pancreas in 85/70/6/31/31/35 pts. According to these primary sites, the median overall survival period (mOS) was 13.4/13.3/29.7/7.6/7.9/8.5 months, respectively. The most commonly used regimen was IP (160 pts, 62%), followed by EP (46 pts, 18%). For the patients treated with IP/EP, the response rates (RR) were 50%/27%, the progression free survival periods (mPFS) were 5.2/4.0 months, and mOS were 13.0/7.3 months. The subgroup outcome data for patients with HBP or GI cancers are shown in Table. A multivariate analysis demonstrated that a primary HBP cancer (HR=1.96, p=0.002), and a poor PS (HR=2.33, p=0.01) were independent unfavorable prognostic factors. Conclusions: PDNEC of the HBP has a poorer prognosis than GI. IP was the most commonly selected treatment regimen, and seemed to have a favorable treatment outcome. [Table: see text]

RTOG 94-10: Keenly Awaited Results Validating the Best Therapeutic Strategy for Locally Advanced Non-Small Cell Lung Cancer

About 30% of patients diagnosed with non–small cell lung cancer (NSCLC) have inoperable locally advanced disease. Despite therapeutic advances over the past two decades, these patients’ prognosis remains poor, with a 5-year survival rate of only 10%–15%. Until the late 1980s, radiotherapy was the only treatment option. The Radiation Therapy Oncology Group (RTOG) had shown that local disease control was improved by increasing the total dose to 60 Gy delivered in 30 fractions over 6 weeks (1). The 1990s saw the emergence of both sequential and concurrent combinations of chemotherapy and radiotherapy. A number of randomized phase III trials, and several meta-analyses, showed that chemoradiotherapy was superior to radiotherapy alone in terms of overall survival (2,3). Concurrent therapy seemed to give better results than sequential therapy, but this needed to be demonstrated. The Japanese trial published by Furuse et al. (4) was the first randomized phase III trial to show a statistically significant improvement in overall survival after concurrent chemoradiotherapy, with no increase in esophageal toxicity. In this issue of the Journal, Curran et al. (5) report the results of the RTOG 94-10 study, which compared three schedules: sequential treatment with cisplatin–vinblastine induction chemotherapy followed by radiotherapy at a total dose of 63 Gy (arm 1); a concurrent schedule in which two cycles of cisplatin–vinblastine were administered during the same radiotherapy schedule as in arm 1 (arm 2); and another concurrent schedule combining cisplatin–etoposide chemotherapy with bifractionated radiotherapy at a total dose of 69.6 Gy (arm 3), as used in the RTOG 91-06 study. Arm 2 was first compared with the sequential schedule, which served as the reference treatment, and then arm 3 was compared with the better of the other two arms. The results showed that concurrent cisplatin–vinblastine and radiotherapy statistically significantly increased overall survival compared with the sequential treatment, whereas there was no statistically significant difference between the two concurrent schedules. The benefit persisted at 5 years, as in the French GLOT-GFPC NPC 95-01 study in which the improvement in overall survival observed with the concurrent schedule was stable at 5 years (18.5% vs 8.5%) and at 7 years (15% vs 5.8%) (6, 7). The RTOG 94-10 study, already presented partially on two occasions, has been awaited for several years. Individual data from this study were included in the NSCLC Collaborative Group meta-analysis of six randomized trials that confirmed the superiority of concurrent treatment (8). The gain in overall survival was associated with better local control. As expected, acute esophageal toxicity was more

Unusual liver locations of growing teratoma syndrome in ovarian malignant germ cell tumors

► Growing teratoma syndrome (GTS) with unusual liver locations are described after fertility preserving surgery and chemotherapy treatment for mixed malignant ovarian germ cell tumors (MGCT). ► It's a rare syndrome of mixed malignant ovarian germ cell tumors and in both cases enlarged and growing liver masses appeared during cisplatin-etoposide-bleomicin (BEP) chemotherapy. ► Radiological exams (CT scan and MRI) were suggestive for secondary metastasis and serum markers became negative during chemotherapy.

Etoposide, cisplatin–etoposide, methotrexate, actinomycin-D as primary treatment for management of very-high-risk gestational trophoblastic neoplasia

Objective To evaluate the efficacy of etoposide, cisplatin–etoposide, methotrexate, actinomycin-D (EP–EMA) chemotherapy as the frontline treatment for gestational trophoblastic neoplasia (GTN) patients with very high (≥ 12) FIGO prognostic scores. Methods Nine patients with very-high-risk GTN were treated with EP–EMA at the Cancer Institute, Adyar, India, between January 1, 2001, and December 31, 2007. Salvage chemotherapy, adjuvant surgery, and radiotherapy were used when indicated. Clinical response, toxicity, and survival were analyzed separately. Results The median FIGO score was 15. Six (66.7%) patients had a complete clinical response, whereas progressive disease occurred for 3 (33.3%) women. None of the patients relapsed. This translated to an overall survival rate of 66.7% in the primary setting. All patients with liver-only metastases were survivors after treatment with EP–EMA. Grade 3 neutropenia was detected in 3 (33.3%) patients only. No life-threatening toxicity was observed after EP–EMA treatment. Conclusion EP–EMA was highly effective for the primary management of very-high-risk GTN.

Randomised phase II study of amrubicin as single agent or in combination with cisplatin versus cisplatin etoposide as first-line treatment in patients with extensive stage small cell lung cancer – EORTC 08062

PurposeThe EORTC 08062 phase II randomised trial investigated the activity and safety of single agent amrubicin, cisplatin combined with amrubicin, and cisplatin combined with etoposide as first line treatment in extensive disease (ED) small cell lung cancer (SCLC). Patients and methodsEligible patients with previously untreated ED-SCLC, WHO performance status (PS) 0–2 and measurable disease were randomised to 3 weekly cycles of either amrubicin alone 45mg/m2 i.v. day(d) 1–3 (A), cisplatin 60mg/m2 i.v. d1 and amrubicin 40mg/m2 i.v. d1–3 (PA), or cisplatin 75mg/m2 i.v. d1 and etoposide 100mg/m2 d1, d2–3 i.v./po (PE). The primary end-point was overall response rate (ORR) as assessed by local investigators (RECIST1.0 criteria). Secondary end-points were treatment toxicity, progression-free survival and overall survival. ResultsThe number of randomised/eligible patients who started treatment was 33/28 in A, 33/30 in PA and 33/30 in PE, respectively. Grade (G) ⩾3 haematological toxicity in A, PA and PE was neutropenia (73%, 73%, 69%); thrombocytopenia (17%, 15%, 9.4%), anaemia (10%, 15%, 3.1%) and febrile neutropenia (13%, 18%, 6%). Early deaths, including treatment related, occurred in 1, 3 and 3 patients in A, PA and PE arms, respectively. Cardiac toxicity did not differ among the 3 arms. Out of 88 eligible patients who started treatment, ORR was 61%, (90% 1-sided confidence intervals [CI] 47–100%), 77% (CI 64–100%) and 63%, (CI 50–100%) for A, PA and PE respectively. ConclusionAll regimens were active and PA met the criteria for further investigation, despite slightly higher haematological toxicity.

Time and dose-related changes in radiological lung density after concurrent chemoradiotherapy for lung cancer

Radiation pneumonitis is an important cause of morbidity after concurrent thoracic chemoradiotherapy (CCRT). However, asymptomatic changes in lung density on computed tomography (CT)-scans occur more commonly, and correspond to regions of inflammatory changes. Characterization of dose- and time-related changes in radiological lung density (RLD) may facilitate improved radiation planning, and allow for a more objective measure for assessing damage. We studied changes in RLD following CCRT with cisplatin–etoposide, using deformable registration to co-register follow-up scans. All CT-scans performed for up to 24 months post-treatment were evaluated in 25 patients treated with CCRT for stage III non-small-cell lung cancer. A total of 104 scans (median of 3 per patient) were co-registered with planning scans using a deformable registration tool (VelocityAI, Atlanta, USA). Last follow-up scan was at median 9.4 months (range 3.4–22.6 months). Seven patients developed clinical radiation pneumonitis. RLD changes (in Hounsfield units) were measured in regions receiving 3–66Gy. Linear mixed models were used to study dose–density changes over time. No significant changes in RLD were observed in the first 3 months post-treatment. Increases in RLD were observed at 3–6 months (p<0.0001) and 6–12 months (p=0.006), but stabilized at 1 year. Increases were most evident in regions receiving >30Gy, with only minor density changes at lower dose levels. Planning target volume size was significantly associated with RLD changes (p=0.03). Limiting lung doses to ≤30Gy during CCRT may limit sub-clinical damage, and the time-course of RLD changes may allow for early quantification of pulmonary damage when evaluating novel treatment strategies.