Hande Turna

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial

BACKGROUND Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. METHODS We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. FINDINGS Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8-15·7] vs 9·6 months [8·6-11·2]; hazard ratio [HR] 0·73 [95% CI 0·62-0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6-18·0] with atezolizumab vs 10·3 months [8·8-12·0] with docetaxel; HR 0·74 [95% CI 0·58-0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59-0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54-0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60-0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. INTERPRETATION To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. FUNDING F. Hoffmann-La Roche Ltd, Genentech, Inc.

Reactivation of hepatitis B virus infection with cytotoxic therapy in non-Hodgkin’s lymphoma

In patients with non-Hodgkin’s lymphoma (NHL), there are some well-known tumor-related adverse prognostic factors that may increase the mortality rate. However, secondary factors such as viral hepatitis carriers that may decrease the cure rates are usually ignored. Reactivation of hepatitis B virus (HBV) infection in patients undergoing cytotoxic treatment for NHL is a well-known complication. Charts of 112 patients with NHL were retrospectively analyzed regarding their hepatitis serology, the indirect effects of seropositivity on disease outcome, and the precautions undertaken in these seropositive patients with NHL. Twelve patients (11%) with HBsAg positivity and two patients (1.7%) with antibody to hepatitis C virus positivity were detected. Eight out of 12 patients (67%) with HBsAg positivity and two patients (50%) with anti-HCV positivity showed reactivation of hepatitis during treatment of NHL. No reactivation was detected in four patients seropositive for HBV, who were given lamivudine prophylaxis before the initiation of chemotherapy schedules. Among patients with hepatitis reactivation, two were treated with lamivudine resulting in dramatic improvement and clinical remission of the disease. The remaining six patients with reactivation were left untreated, resulting in four deaths (67%) due to liver failure secondary to HBV and two deaths secondary to delayed treatment of NHL. One patient seropositive for anti-HCV also developed chronic hepatitis C. Determination of hepatitis serology in all patients with NHL before any chemotherapy administration is crucial, but insufficient, if not taken into consideration. In seropositive patients, HBV DNA should be determined and antiviral prophylaxis with lamivudine should be initiated before any treatment.

Extraskeletal Ewing's Sarcoma Family of Tumors in Adults: Prognostic Factors and Clinical Outcome

OBJECTIVE The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with extraskeletal Ewings sarcoma. METHODS Data of patients with extraskeletal Ewings sarcoma followed up at our center between 1997 and 2010 were retrospectively analyzed. RESULTS The median age of 27 patients was 24 years (range, 16-54 years). The median follow-up was 31.8 months (range, 6-144 months). Tumor size was between 1.5 and 14 cm (median: 8 cm). Eighty-five percent of patients had localized disease at presentation and 15% had metastatic disease. Local therapy was surgery alone in 16% of patients, surgery combined with radiotherapy in 42% and radiotherapy alone in 27%. All patients were treated with vincristine, doxorubicin, cyclophosphamide and actinomycin-D, alternating with ifosfamide and etoposide every 3 weeks. In patients with localized disease at presentation, the 5-year event-free survival and overall survival were 59.7 and 64.5%, respectively. At univariate analysis, patients with tumor size ≥ 8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size 8 ≥ cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. CONCLUSIONS Prognostic factors were similar to primary osseous Ewings sarcomas. Adequate surgical resection, aggressive chemotherapy (vincristine, doxorubicin, cyclophosphamide and actinomycin-D alternating with ifosfamide and etoposide) and radiotherapy if indicated are the recommended therapy for patients with extraskeletal Ewings sarcoma.

Usefulness of the epithelial tumor marker CA-125 in Non-Hodgkin's lymphoma

CA-125, a commonly used tumor marker for epithelial ovarian cancer, is a glycoprotein found in normal tissues derived from coelomic epithelia. Increased serum levels of CA-125 have also been found in nongynecologic tumors and nonmalignant diseases involving the peritoneum. A few recent studies and sporadic case reports have reported increased CA-125 levels in patients with non-Hodgkins lymphoma (NHL). In our study, we aimed to evaluate the serum levels of CA-125 in patients with NHL and determine its potential role to show disease activity in NHL. Serum levels of CA-125 were measured in 61 patients with NHL and were found to be correlated with clinical stage, site of involvement, and disease activity.

Patterns of Complementary and Alternative Medicine Use among Turkish Cancer Patients

BACKGROUND The aim of this study was to determine the tendency to use complementary/alternative medicine (CAM) by patients with cancer in Turkey, and to compare sociodemographic and medical characteristics, perceptions, and quality of life of users and nonusers of CAM. METHODS A total of 1060 cancer patients were asked to complete a questionnaire about the use of CAM along with the European Organization for Research and Treatment of Cancer Life Quality Questionnaire C30 (EORTC QLQ-C30). Medical information was obtained from hospital chart records. RESULTS The response rate was 40.1% (425/1060). Use of at least one kind of CAM was identified in 57.4% of the patients. Herbal medications (95%), spiritual/religious affiliations (23.3%), multivitamins/antioxidants (18.4%), and transcendental meditation/yoga (8.6%) were the leading CAM methods. In multivariate analysis, CAM use was found to be associated with age (>60 years) only. Average expenditure on CAMs was 30 U.S. dollars (USD) per patient per month. The most common causes of CAM use were belief in their efficacy (41.3%) and intimate interaction with CAM users (37.2%). Only 41% of the users had informed their doctors that they used CAM. QLQ scores were similar between CAM users and nonusers. Of all participants, 15.5% had psychiatric support. Proportions of regular antidepressant and analgesic use were 16.4%, and 46.3%, respectively. CAM users had worse appetite scores. There was no difference in terms of other scales between the groups. CONCLUSIONS This study showed that CAM use is widespread among Turkish cancer patients and CAM use does not improve QLQ scores. Physicians should be aware of high CAM utilization rate in patients with cancer and should better understand the factors directing the patients to such treatments.

The relation between pathological complete response and clinical outcome in patients with rectal cancer.

BACKGROUND/AIMS: Preoperative chemoradiotherapy (CRT) is the standard treatment modality in locally advanced rectal cancer. The primary aim was to correlate pathological complete response (pCR) with patient outcome, and the secondary objective was to identify predictive factors of pCR. METHODOLOGY: Patients with clinical stage II/III rectal cancer who received preoperative CRT between 2002 and 2010 were retrospectively studied.The median radiotherapy dose was 54 Gy (range, 45 to 64 Gy), and all patients received concurrent infusional 5-fluorouracil-based chemotherapy. RESULTS: Median follow-up time was 48.3 months (range, 24 to 96 months) and 51 months (range, 44 to 110 months) for no-pCR and pCR groups, respectively. Eighteen patients (18.6%) had pCR. The 5-year overall survival was 95% for patients with pCR and 74.8% in patients without pCR (p=0.009). The 5-year local relapse free survival was 87.5% and 95% for the no-pCR and pCR groups, respectively (p=0.09). The 5-year distant relapse free survival was 93% in pCR group and 79.8% in no-pCR group (p=0.02). The 5-year distant free survival was 94% and 66% in patients with and without pCR, respectively (p=0.017). The clinical T4 (p=0.043) and pretreatment carcinoembryonic antigen level (CEA) >5ng/mL (p=0.012) were significantly associated with a lower pCR rate. In the multivariate logistic regression analysis, pretreatment CEA level >5ng/mL (p=0.008) was the only independent factor associated with a lower pCR rate. CONCLUSIONS: Patients with pCR after preoperative CRT had a significantly improved outcome. Furthermore, the pretreatment CEA level was independently associated with pCR.

Paraneoplastic pemphigus associated with fludarabine use.

Paraneoplastic pemphigus is a severe mucocutaneous disease associated with B-cell lymphoproliferative disorders. A 51-yr-old man presented to the oncology clinic with mucocutaneous skin lesions after six cycles of fludarabine for non-Hodgkin’s lymphoma. A punch biopsy from the skin showed suprabasal acantholysis and blister formation in the epidermis and upper dermis. Direct immunofluorescence demonstrated intercellular IgG deposition in all epidermal layers and complement (C3) at the basement membrane. The indirect immunofluorescence on rat bladder showed intercellular binding of IgG. These findings were consistent with paraneoplastic pemphigus associated with fludarabine use. The temporal association between fludarabine use and paraneoplastic pemphigus suggests there is an etiopathological link between these two entities.

Rituximab-induced tumor progression

Monoclonal antibodies have been gaining a wide role in the treatment of malignant diseases. A human chimeric anti-CD20 monoclonal antibody (Mab) rituximab (Rituxan in USA; Mabthera in Europe) was approved for the treatment of refractory or relapsed low-grade or follicular non-Hodgkins lymphoma (NHL) in 1997 (1-3). Rituximab has efficacy in other refractory CD20+ NHLs, hairy cell leukemia, plasma cell dyscrasias, posttransplant lymphoproliferative syndrome, autoimmune phenomena such as refractory hemo lytic anemias, and immune thrombocytopenias (4-8). Its combination with standard chemotherapy protocols for NHL has been investigated thoroughly owing to its synergistic effect when combined with chemotherapeutic agents (3). Coiffier et al. recently published a randomized trial showing a statistically significant survival benefit of rituximab-CHOP combination over CHOP alone in elderly patients with diffuse large-B-cell lymphoma (9,10). In addition to these widening beneficial therapeutic effects, rituximab has well-known side effects, encountered especially during its first infusion, such as chills, fever, allergic reactions, cardiopulmonary syndrome, and tumor lysis syndrome. We would like to share our clinical observation in a patient with NHL, whose disease seemed to go into an accelerated progression phase after rituximab administration.

Severe liver dysfunction and safe use of 5-fluorouracil leucovorin and oxaliplatin in one patient with metastatic colorectal carcinoma

The liver is the most frequent site of metastases in colorectal cancer. Commonly used anticancer drugs in colorectal cancer are 5-fluorouracil, oxaliplatin and irinotecan 5-fluorouracil (5-FU) and oxaliplatin have very few numbers of studies that support their safety in hepatic dysfunction, but pharmacokinetic studies of anticancer drugs focused on the single-agents; however, there is lack of data about drug combinations such as 5-fluorouracil leucovorin and oxaliplatin (FOLFOX) and 5-fluorourocil, leucovorin and irinotecan (FOLFIRI) regimens. We demonstrated one patient with colorectal cancer and severe liver dysfunction secondary to hepatic metastases. Laboratory investigation on admission showed total bilirubin 22.5 mg/dl, alkaline phosphatase 1137 IU/l, aspartate amino transferase 254 IU/l, alanine aminotransferase 164 IU/l and carcinoembryonic antigen levels 863 ng/ml. We initiated a 5-FU/oxaliplatin-based combination chemotherapy. Our data supports the safety and feasibility of FOLFOX regimen in patients with severe liver dysfunction secondary to liver metastases of colorectal cancer.

Is There Any Effect of Tumor Burden on Hemostatic Parameters in Cancer Patients? A Case—Control Study of Hemostatic Abnormalities and Anticardiolipin Antibodies in Solid Tumors

Hemostatic complications are one of the leading causes of mortality in cancer patients. In the present study, we assessed the hemostatic parameters and anticardiolipin antibodies in patients with solid tumors (n = 104) and healthy controls (n = 25) and also find out whether the abnormalities in these hemostatic parameters vary related to tumor burden. Prothrombin time, activated partial thromboplastine time, D-dimer, and fibrinogen as hemostatic parameters were determined by photo-optometric clot detection system, and serum anticardiolipin levels were measured by enzyme-linked immunosorbent assay. The plasma levels of fibrinogen, D-dimer, and serum anticardiolipin IgM levels in cancer patients were significantly higher compared with those in controls (P < .001, P = .001, and P = .01, respectively). Only fibrinogen levels were significantly higher in metastatic group than nonmetastatic group (P < .001 ). Hemostatic abnormalities that are detected in asymptomatic cancer patients may not give any clue about tumor burden or stage of the cancer patients.