N. Pavlidis

Diagnostic and therapeutic management of cancer of an unknown primary.

Metastatic Cancer of Unknown Primary Site (CUP) accounts for approximately 3% of all malignant neoplasms and is therefore one of the 10 most frequent cancer diagnoses in man. Patients with CUP present with metastatic disease for which the site of origin cannot be identified at the time of diagnosis. It is now accepted that CUP represents a heterogeneous group of malignancies that share a unique clinical behaviour and, presumably, unique biology. The following clinicopathological entities have been recognised: (i) metastatic CUP primarily to the liver or to multiple sites, (ii) metastatic CUP to lymph nodes including the sub-sets involving primarily the mediastinal-retroperitoneal, the axillary, the cervical or the inguinal nodes, (iii) metastatic CUP of peritoneal cavity including the peritoneal papillary serous carcinomatosis in females and the peritoneal non-papillary carcinomatosis in males or females, (iv) metastatic CUP to the lungs with parenchymal metastases or isolated malignant pleural effusion, (v) metastatic CUP to the bones, (vi) metastatic CUP to the brain, (vii) metastatic neuroendocrine carcinomas and (viii) metastatic melanoma of an unknown primary. Extensive work-up with specific pathology investigations (immunohistochemistry, electron microscopy, molecular diagnosis) and modern imaging technology (computed tomography (CT), mammography, Positron Emission Tomography (PET) scan) have resulted in some improvements in diagnosis; however, the primary site remains unknown in most patients, even on autopsy. The most frequently detected primaries are carcinomas hidden in the lung or pancreas. Several favourable sub-sets of CUP have been identified, which are responsive to systemic chemotherapy and/or locoregional treatment. Identification and treatment of these patients is of paramount importance. The considered responsive sub-sets to platinum-based chemotherapy are the poorly differentiated carcinomas involving the mediastinal-retroperitoneal nodes, the peritoneal papillary serous adenocarcinomatosis in females and the poorly differentiated neuroendocrine carcinomas. Other tumours successfully managed by locoregional treatment with surgery and/or irradiation are the metastatic adenocarcinoma of isolated axillary nodes, metastatic squamous cell carcinoma of cervical nodes, or any other single metastatic site. Empirical chemotherapy benefits some of the patients who do not fit into any favourable sub-set, and should be considered in patients with a good performance status.

Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

F. A. Peccatori1, H. A. Azim Jr2, R. Orecchia3, H. J. Hoekstra4, N. Pavlidis5, V. Kesic6 & G. Pentheroudakis5, on behalf of the ESMO Guidelines Working Group* Fertility and Procreation Unit, Division of Gynaecologic Oncology, European Institute of Oncology, Milan, Italy; Department of Medicine, BrEAST Data Centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Department of Radiotherapy, European Institute of Oncology, Milan, Italy; Department of Surgical Oncology, University Medical Centre Groningen, Groningen, The Netherlands; Department of Medical Oncology, University of Ioannina, Ioannina, Greece; Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia;

Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

K. Fizazi1, F. A. Greco2, N. Pavlidis3, G. Daugaard4, K. Oien5 & G. Pentheroudakis3, on behalf of the ESMO Guidelines Committee* Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, France; Tennessee Oncology, Centennial Medical Center, Nashville, USA; Department of Medical Oncology, University of Ioannina, Ioannina, Greece; Department of Oncology 5073, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; University of Glasgow, Institute of Cancer Sciences, Glasgow, UK

Effect of letrozole on the lipid profile in postmenopausal women with breast cancer.

Hormonal therapy plays a central role in the overall treatment of breast cancer. Aromatase inhibitors can inhibit the aromatase enzyme system resulting in a reduction of oestrogens. Letrozole is a non-steroidal aromatase inhibitor that effectively blocks aromatase activity without interfering with adrenal steroid biosynthesis. The drug can significantly reduce the levels of plasma oestrogens, which remain suppressed throughout the treatment. Data are scarce concerning the influence of these drugs on serum lipid levels. In the present study, we evaluated the effects of letrozole on the serum lipid profile in postmenopausal women with breast cancer. A total of 20 patients with breast cancer were treated with letrozole, 2.5 mg once daily. After an overnight fast, serum lipid parameters (total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, apolipoproteins A1, B and E and lipoprotein (a)) were measured before treatment and at 8 and 16 weeks afterwards. A significant increase in total cholesterol (P=0.05), LDL cholesterol (P<0.01) and apolipoprotein B levels (P=0.05) in the serum, as well as in the atherogenic risk ratios total cholesterol/HDL cholesterol (P<0.005) and LDL cholesterol/HDL cholesterol (P<0.005) was noticed after letrozole treatment. We conclude that letrozole administration in postmenopausal women with breast cancer has an unfavourable effect on the serum lipid profile.

Phase II trial with S-1 in chemotherapy-naı̈ve patients with gastric cancer. A trial performed by the EORTC Early Clinical Studies Group (ECSG)

S-1 is a new oral fluorinated pyrimidine derivate, in which the oral 5-fluorouracil (5-FU) prodrug, tegafur, was combined with two 5-FU-modulating substances, 5-chloro-2,4-dihydroxypyridine (gimeracil), and potassium oxonate (oteracil), at a molar ratio of 1:0.4:1. The final mechanism of action is exerted by 5-FU. The present study is the first European phase II trial of S-1 in gastric cancer. The primary study objectives were the safety, toxicity and activity of S-1 in non-pretreated patients with gastric cancer. The secondary objective was the duration of response. Patients had to have histologically- or cytologically-verified metastatic or locally advanced, unresectable gastric cancer; S-1 was administered orally twice daily at 40, then 35 mg/m(2) for 28 days every 5 weeks. The starting dose of 40 mg/m(2) was found to be intolerable due to significant non-haematological toxicity, and this dose was rapidly reduced to 35 mg/m(2) twice daily. Of the 7 patients enrolled at the 40 mg/m(2) level, only 3 were evaluable. At 35 mg/m(2), a response rate of 26.1% (95% Confidence Interval (CI) 12.0-45.1%) in 23 enrolled patients, and 31.6% (C.I. 14.7-53.0%) in 19 evaluable patients according to an independent radiology review, was found. The median duration of response at 35 mg/m(2) (6 patients) was 223 days (range, 108-828 days), and of stable disease was 111 days (range 68-411 days). S-1 can be administered with an acceptable safety and toxicity in European patients at a dose of 35 mg/m(2) days 1 - 28 every 5 weeks and is associated with a moderate response rate similar to the results achieved with other fluoropyrimidines.

Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: A randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG)

BACKGROUND Concurrent platinum etoposide chemotherapy given in combination with hyperfractionated thoracic radiation therapy (HTRT) in limited disease (LD) small cell lung cancer (SCLC) is associated with a high response rate and significant prolongation of survival. Given these results, the Hellenic Cooperative Oncology Group (HeCOG) performed a multicenter randomized phase II study in patients with LD SCLC to evaluate the timing of HTRT (early vs. late) when given concurrently with chemotherapy. PATIENTS AND METHODS To be eligible for the study, patients were required to have histologically or cytologically proven LD SCLC, confined to one hemithorax and/or ipsilateral mediastinal or supraclavicular lymphnodes and absence of pleural effusion or controlateral supraclavicular lymphnode involvement. Moreover, patients had to have a good performance status and adequate haematological, liver and renal function. Patients with LD SCLC were randomized to receive HTRT either concurrently with the first (Group A) or with the fourth (Group B) cycle of chemotherapy. Chemotherapy consisted of carboplatin administered at an AUC of six given as an i.v. 1-hour-infusion immediately followed by etoposide at a dose of 100 mg/m2 i.v. as a two-hour infusion for three consecutive days every three weeks up to a total of six cycles. Prophylactic cranial irradiation was also given to patients achieving a complete response. RESULTS 42 and 39 patients, were eligible for efficacy evaluation in group A and B respectively. The overall response rate was 76% in group A and 92.5% in group B (P = 0.07) with a complete response rate of 40.5% and 56.5%, respectively. After a median follow-up of 35 months, time to progression was 9.5 months in group A and 10.5 in group B (NS) while overall median survival was 17.5 and 17 months respectively (NS). The 2-year survival was 36% in group A and 29% in group B (NS) and the 3-year survival 22% and 13%, respectively (NS). The distant relapse rate was 38% in group A and 61% in group B (P = 0.046). Severe grade 3 4 anemia was recorded in 19% of group A and 12.5% of group B (NS), while severe leucopenia was recorded in 35.5% and 20.5% (P = 0.09) and neutropenic fever in 5% and 2.5% (NS), respectively. Severe thrombocytopenia did not differ significantly between the two treatment groups being 21.5% and 23%, respectively. Severe grade 2-3 esophageal toxicity was 19% in group A and 23% in group B (NS), while grade 3 lung toxicity was 5% and 7.5% (NS), respectively. No toxicity-related deaths were recorded. CONCLUSION Concurrent administration of HTRT with carboplatin etoposide is associated with a high response and survival rate. Although a trend for higher response rate was recorded in the group of patients who received late HTRT, the overall median, 2-year and 3-year survival rates did not differ significantly between the two treatment groups. The toxicity of this promising therapeutic approach was acceptable. Comparative phase III studies with an adequate number of patients are recommended in order to answer this question.

Primary gastrointestinal non-Hodgkin's lymphoma: A clinicopathologic study of 128 cases in Greece. A Hellenic Cooperative Oncology Group study (HeCOG)

The aim of this retrospective study was to illustrate the clinicopathologic data and the treatment results in patients with primary gastrointestinal tract non-Hodgkins lymphoma (GI NHL). Among 810 patients with NHL, 128 cases (15.8%) were diagnosed as primary GI tract NHL. There were 79 males and 49 females with median age of 62 years. The most common primary site was the stomach (68%). Overall, 67.2% of the patients were in stages I – II, and 32.8% in stages III – IV. Simultaneous involvement of the GI tract and other extranodal sites was observed in 26 patients (20%). Extranodal marginal zone B-cell lymphoma (MZBL) (i.e., low-grade lymphoma of mucosa-associated lymphoid tissue type) accounted for 48.4% of lymphomas. Aggressive lymphomas (diffuse large B-cell lymphoma [DLBL]) accounted for 44.5%. Eighty-three patients (67.5%) achieved complete response (CR), either by surgery (43/43 patients, 17 with DLBL and 25 with MZBL) or by primary chemotherapy (40/64 patients, 22 with DLBL and 17 with MZBL). Sixty-two patients remain in CR; 33/43 after surgical resection (13/17 with DLBL and 20/25 patients with MZBL), and 29/40 after only chemotherapy (18/22 with DLBL and 10/17 with MZBL). The major prognostic factor for outcome in the present study was the stage of the disease. Patients with localized lymphoma (stage I and II) had significantly longer DFS and OS (DFS and OS at 3-year: 83% and 87%, respectively) than patients with extended disease (stage III and IV) (DFS and OS at 3-year: 46% and 60%, respectively) (P < 0.0001). The International Prognostic Index (IPI) for patients with aggressive lymphomas was prognostic only for DFS (79% for low-risk patients [IPI score 0 – 1] vs 49% for higher risk groups [IPI score >1] at 3-year, P = 0.0131).

The diagnosis and management of gastric cancer: Expert discussion and recommendations from the 12th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2010

Well-recognized experts in the field of gastric cancer discussed during the 12th European Society Medical Oncology (ESMO)/World Congress Gastrointestinal Cancer (WCGIC) in Barcelona many important and controversial topics on the diagnosis and management of patients with gastric cancer. This article summarizes the recommendations and expert opinion on gastric cancer. It discusses and reflects on the regional differences in the incidence and care of gastric cancer, the definition of gastro-esophageal junction and its implication for treatment strategies and presents the latest recommendations in the staging and treatment of primary and metastatic gastric cancer. Recognition is given to the need for larger and well-designed clinical trials to answer many open questions.

Molecular markers and biological targeted therapies in metastatic colorectal cancer: expert opinion and recommendations derived from the 11th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2009

The article summarizes the expert discussion and recommendations on the use of molecular markers and of biological targeted therapies in metastatic colorectal cancer (mCRC), as well as a proposed treatment decision strategy for mCRC treatment. The meeting was conducted during the 11th ESMO/World Gastrointestinal Cancer Congress (WGICC) in Barcelona in June 2009. The manuscript describes the outcome of an expert discussion leading to an expert recommendation. The increasing knowledge on clinical and molecular markers and the availability of biological targeted therapies have major implications in the optimal management in mCRC.

EO9 phase II study in advanced breast, gastric, pancreatic and colorectal carcinoma by the EORTC Early Clinical Studies Group

In a phase II trial, the activity of EO9, a new bioreductive alkylating agent, was assessed. EO9 was used as second-line chemotherapy in breast cancer patients and as first-line chemotherapy for patients with gastric, pancreatic and colorectal cancer. EO9 was given as a 5 min i.v. infusion at a weekly dose of 12 mg/m2. 92 patients were entered; 22 with breast cancer, 26 with colon cancer, 24 with pancreatic cancer and 20 with gastric cancer. In general, the drug was well tolerated with nausea and vomiting occurring in 26.42 and 13.3% of courses, respectively. Reversible proteinuria was the main toxicity occurring in 45% of courses. Antitumour activity was not observed. At this dose and schedule, EO9 is not an active drug in the type of tumour studied.