Sevil Bavbek

Phase II Randomized Trial Comparing Sequential First-Line Everolimus and Second-Line Sunitinib Versus First-Line Sunitinib and Second-Line Everolimus in Patients With Metastatic Renal Cell Carcinoma

PURPOSE A multicenter, randomized phase II trial, RECORD-3, was conducted to compare first-line everolimus followed by sunitinib at progression with the standard sequence of first-line sunitinib followed by everolimus in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS RECORD-3 used a crossover treatment design. The primary objective was to assess progression-free survival (PFS) noninferiority of first-line everolimus compared with first-line sunitinib. Secondary end points included combined PFS for each sequence, overall survival (OS), and safety. RESULTS Of 471 enrolled patients, 238 were randomly assigned to first-line everolimus followed by sunitinib, and 233 were randomly assigned to first-line sunitinib followed by everolimus. The primary end point was not met; the median PFS was 7.9 months for first-line everolimus and 10.7 months for first-line sunitinib (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.8). Among patients who discontinued first-line, 108 (45%) crossed over from everolimus to second-line sunitinib, and 99 (43%) crossed over from sunitinib to second-line everolimus. The median combined PFS was 21.1 months for sequential everolimus then sunitinib and was 25.8 months for sequential sunitinib then everolimus (HR, 1.3; 95% CI, 0.9 to 1.7). The median OS was 22.4 months for sequential everolimus and then sunitinib and 32.0 months for sequential sunitinib and then everolimus (HR, 1.2; 95% CI, 0.9 to 1.6). Common treatment-emergent adverse events during first-line everolimus or sunitinib were stomatitis (53% and 57%, respectively), fatigue (45% and 51%, respectively), and diarrhea (38% and 57%, respectively). CONCLUSION Everolimus did not demonstrate noninferiority compared with sunitinib as a first-line therapy. The trial results support the standard treatment paradigm of first-line sunitinib followed by everolimus at progression.

Timing of Death From Tumor Recurrence After Curative Gastrectomy for Gastric Cancer

In Western literature, there are few studies investigating the predictors of early versus late recurrence after curative gastrectomy for gastric cancer. The current study analyzed (1) patients who died of recurrent gastric cancer and (2) prognostic factors, which can be applied to timing of death from tumor recurrence. Of 492 patients who underwent curative resection (R0) for gastric cancer in the Department of Surgery, Medical Faculty of Istanbul between 1994 and 2000, 142 patients who died of recurrence were included into study. None of the patients had received postoperative adjuvant treatment. The patients were divided into 2 groups: an early recurrence group that included 102 patients who recurred and died within 2 years after surgery, and a late recurrence group, which included 40 patients who died of recurrence more than 2 years after surgery. Clinicopathologic findings were compared between the early and late recurrence groups. Multivariate analysis was performed to investigate the independent factors, which are predictive for early versus late recurrence, and prognostic factors independently associated with the survival period. In multivariate analysis, the early recurrence group, when compared with the late recurrence group, was characterized by lymph node metastasis (N1-3 versus N0; P = 0.002). Overall survival was influenced by nodal status (N1-3 versus N0; P = 0.003), type of operation performed (radical total versus radical subtotal gastrectomy; P = 0.003), Eastern Cooperative Oncology Group performance status (PS 3–4 versus PS 1–2; P = 0.004), and tumor localization (cardia versus corpus and antrum; P = 0.046). In contrast, T stage of the disease was not prognostic for survival, although it was close to statistical significance (P = 0.066). Multivariate analysis showed that poorer performance status at initial presentation (P = 0.001) and lymph node metastasis (P = 0.032) independently correlated with overall survival (P = 0.002). Lymph node status was the most important factor predictive for early versus late recurrence and patients with lymph node metastases were at more risk of death within 2 years after curative operation for gastric cancer. Postoperative chemoradiotherapy should be especially recommended for patients at high risk of recurrence of adenocarcinoma of the stomach or who have undergone curative resection.

Preliminary analysis of a phase II study of Paclitaxel and CHART in locally advanced non-small cell lung cancer

Paclitaxel (Taxol; Bristol-Myers Squibb) is one of the most active single agents for non-small cell lung cancer (NSCLC), and ideal in combination with radiation therapy. We designed a phase II study to determine the efficacy and toxicity of continuous hyperfractionated accelerated radiotherapy (CHART) and concurrent weekly Paclitaxel (T) in good performance status patients with unresectable stage III A and B NSCLC. T (60 mg/m2) was given as a 3-h infusion on days 1, 8, 15, 22, 29 and 36; CHART was started on day 15 with 150 cGy/fraction given three times a day for a total dose of 54 Gy in 12 days with no weekend break. Twenty patients were evaluable for acute toxicity. The major acute toxicities were esophagitis and pulmonary toxicity; 70% of the patients experienced grade 2-3 esophagitis and 50% experienced grade > or = 3 pulmonary toxicity. Grade 3 anemia developed in only one patient. Of the 17 patients evaluable for late toxicity, 12% of the patients had grade 3 pulmonary toxicity, one patient developed grade 4 esophagitis. Nineteen patients were evaluable response. The overall response rate was 84% (95% confidence interval, 60-97). CHART with concurrent weekly T seems to be an effective regimen, but tolerability needs to be documented with a larger number of patients and longer follow-up.

CD44 variant exons in leukemia and lymphoma

CD44 is a cell surface glycoprotein expressed on different cell types that functions in lymphocyte activation and homing, extracellular matrix adhesion and cellular migration. CD44 is encoded by a single gene composed of at least 20 exons. The standard CD44 protein (CD44S or CD44H) is the hematopoietic form of CD44 in lymphoid cells. Variant isoforms (designated from v1 to v10) are formed by addition of new exons to the extracellular domain. High levels of CD44v6 expression has been observed in some tumors and are associated with metastatic spread. The aim of the present study was to investigate and evaluate expression of the CD44v6 and v6-containing variants as a possible marker in chronic myeloid leukemia and lymphoma by reverse transcriptionpolymerase chain reaction. CD44 exon v6 was detected in all patients and all individuals in the control group. CD44v6-v10 mRNA was observed in 25 patients but in none of the subjects in the control group. CD44v6/v9-10, CD44v6-v7, CD44v6/v10 transcripts were detected in 11, 6, and 2 patients, respectively. CD44v6-7/v9-10 transcripts were not observed in either the patients or the healthy individuals. We conclude that CD44v6-v10 expression may be associated with hematologic malignancies.

Aflibercept versus placebo in combination with docetaxel/prednisone for first-line treatment of men with metastatic castration-resistant prostate cancer (mCRPC): Results from the multinational phase III trial (VENICE).

13 Background: Docetaxel/prednisone is standard first-line chemotherapy for mCRPC. Aflibercept (known as ziv-aflibercept in the US) is a recombinant human fusion protein that binds VEGF-A, VEGF-B and Placental Growth Factor (PlGF), thereby inhibiting angiogenesis. METHODS VENICE was a double-blind, randomized phase III study with overall survival (OS) as primary endpoint. Men with mCRPC, ECOG PS 0-2, adequate organ function and no prior cytotoxic therapy were treated with docetaxel (75 mg/m² iv q3w) and oral prednisone (5mg bid) and randomized double blind 1:1 to receive aflibercept (A) 6 mg/kg or placebo (Pbo), IV every 3 weeks. Pts were stratified by ECOG PS (0-1 vs 2). For final OS analysis, 873 deaths were required to detect a hazard ratio (HR) of 0.8 with 90% power (overall 2-sided α = 0.05). RESULTS From Aug 2007 to Feb 2010, 1224 patients (median age 68 yr, PS 0-1 96%) were randomized. Baseline characteristics were well balanced between arms. Median number of cycles was 8 (A) and 9 (Pbo). Median relative dose intensity was >0.93 for A, Pbo and docetaxel. At final cut-off, median follow-up was 35.4 mos and 873 pts had died. Results for primary and key secondary endpoints with confidence intervals are in the table. Higher incidence of all grade hypertension, stomatitis, appetite disorders, diarrhea, dehydration, epistaxis, dysphonia, cough, headache and infections was observed in the aflibercept arm. CONCLUSIONS Aflibercept in combination with docetaxel/prednisone given as first line chemotherapy for mCRPC did not lead to a statistically significant improvement in OS and added toxicity. (NCT00519285 sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.) Clinical trial information: NCT00519285. [Table: see text].

Prognostic factors and survival in late adolescent and adult patients with small round cell tumors

The primary objective of this study is to review the clinical characteristics of 25 patients in the adult and late adolescent age group, diagnosed and treated with small round cell tumors involving soft tissues (extraosseous Ewing sarcoma, rhabdo-myosarcoma, primitive neuroectodermal tumor, and undiffer-entiated small round cell tumors). Additionally, survival and prognostic factors influencing the outcome with multimodality treatment are evaluated. There were 19 males (76%) and 6 females (24%). The median age was 26 years (range: 15-56 years). In 9 patients (36%), the tumor was located at an extremity, whereas 16 patients (64%) had central localizations. Tumor size was larger than 10 cm in 7 patients (29.2%). Six patients (24%) had metastatic disease. Twelve patients (48%) received radiation and 16 patients (64%) underwent surgery. Among the resected tumors, 2 were resected with contaminated margins (12.5%), whereas 2 were radically resected and 12 (75%) were resected with wide margins. All patients were given a median of 4 cycles of multiagent chemotherapy (1–14 cycles). With preoperative chemotherapy, complete regression (CR) of the tumor was achieved in 6 patients (24%). In 4 patients (16%), a partial response was obtained. After the completion of multimodality treatment, 12 patients (48%) had a CR. Progression-free (PFS) and overall survival (OS) for the entire group was 25.0 ± 10.8% at 1 year and 30.5 ± 15.5% at 3 years, respectively. Nonmetastatic disease, wide and radical resection, and presence of CR to multimodality treatment were associated with a significantly longer PFS and OS by univariate analysis. By multivariate analysis, CR to multimodality treat-ment was the only independent predictive factor for a longer OS (p: 0.0036, relative risk [RR]: 23.6, 95% CI: 2.8; 198.7) and metastatic presentation was the only independent factor predic-tive for a shorter PFS (p: 0.017, RR. 15, 95% CI: 1.6; 141.2). Large-scale, multicenter studies are required for a better eval-uation of the nonpediatric age group with small round cell tumors.

Induction chemotherapy with docetaxel and cisplatin is highly effective for locally advanced nasopharyngeal carcinoma

Radiotherapy (RT) with concomitant chemotherapy (CT) has improved the therapeutic outcome of patients with locally advanced nasopharyngeal carcinoma (LANC). However, the importance of induction CT before definitive therapy is still undefined. Patients (n=59) who had LANC were included in this retrospective study. They received induction CT consisting of cisplatin and docetaxel followed by definitive RT with cisplatin. The median age was 49 years (18-68). All patients were of stages II (15%), III (63%) and IV (22%). Fifty eight patients could receive 3 cycles of CT. Except one patient, there was no grade 3 or 4 toxicity during induction CT. Chemoradiotherapy could be given to 49 patients (83%). Twelve percent of patients had complete response after induction CT and this number had increased to 95% after the completion of the therapy. Objective responses (complete and partial) were 100% after the completion of the therapy. Median follow up time was 29 months. Nine patients had relapse (2 had local only, 4 distant, 3 local and distant). Three patients who had both local and distant relapse died during follow-up. Three year overall and progression free survival rates were 94.9% and 84.7%, respectively. Induction CT with docetaxel and cisplatin is a feasible and tolerable treatment for patients with LANC.

Safety of everolimus by treatment duration in patients with advanced renal cell cancer in an expanded access program

OBJECTIVE To retrospectively analyze the effects of treatment duration on outcomes of everolimus treatment of patients in the RAD001 Expanded-Access Clinical Trial in RCC (REACT) program. METHODS Patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor received everolimus (10 mg once daily), with dosing interruption or modifications allowed for toxicity. All serious and grade 3/4 adverse events and grade 1/2 adverse events leading to a change in drug administration were reported. Tumor response was evaluated using Response Evaluation Criteria In Solid Tumors. RESULTS The study stratified 1367 evaluable patients into treatment duration groups of <3 months, ≥3 and <6 months, ≥6 months and <1 year, and ≥1 year. Pneumonia, noninfectious pneumonitis, and hyperglycemia occurred more frequently in patients receiving everolimus for ≥1 year but did not result in treatment discontinuations. First occurrence of adverse events presented early in the treatment course for most patients. Treatment duration of ≥6 months was associated with improved disease control rates. CONCLUSION Everolimus is well tolerated in patients with metastatic renal cell carcinoma for treatment durations≥1 year and not associated with cumulative toxicity.

Response Rates and Adverse Effects of Continuous Once-daily Sunitinib in Patients with Advanced Renal Cell Carcinoma: A Single-center Study in Turkey

OBJECTIVE Therapy targeted against the vascular endothelial growth factor pathway is a standard of care for patients with metastatic renal cell carcinoma. This study assessed the response rates and toxicity profiles of sunitinib on a continuous once-daily dosing regimen in Turkish patients with metastatic renal cell carcinoma. METHODS Between April 2006 and August 2010, 74 patients with metastatic renal cell carcinoma who received sunitinib on a continuous, once-daily dosing regimen were included. Sunitinib was administered daily at a dose of either 37.5 mg (94% of the patients) or 25 mg (6% of the patients), without interruption, either as a second-line treatment after interferon-α or as a first-line treatment. Response, toxicity, progression-free survival and overall survival were evaluated. RESULTS Of the 74 patients, 65 (88%) were diagnosed with clear cell renal cell carcinoma. The median treatment duration was 10 months (range, 2-42 months). The most common treatment-related adverse events were fatigue (75%), stomatitis (51%) and hypertension (50%). The most common Grade 3 or 4 adverse events were anemia (10%) and hand-foot syndrome (7%). Dose reductions were required in 50% of the patients, and early treatment discontinuation was necessary in 16% of the patients. Cardiovascular events were the most common adverse events that resulted in drug discontinuation. The objective response rate and the disease control rate were 30 and 78%, respectively. The median progression-free survival and overall survival were 13 and 25 months, respectively. CONCLUSIONS Continuous, once-daily administration of sunitinib was generally well tolerated in Turkish patients with advanced renal cell carcinoma in a daily practice setting. This studys response rates were comparable to those in previous randomized trials.

Predictive value of marker half-life in relapsed and nonrelapsed nonseminomatous germ cell testicular tumor patients undergoing chemotherapy.

BackgroundThe aim of this study was to investigate the influence of a marker half-life (MHL) on relapse in nonseminomatous germ cell testicular tumor patients. MethodsMHL was retrospectively analyzed in relapsed (n = 37) and nonrelapsed patients (n = 28) undergoing first-line chemotherapy (CT). Before CT and after the second cycle of CT, serum &agr;-fetoprotein (AFP) and &bgr;-human chorionic gonadotropin levels were measured for MHL analysis. The International Germ Cell Cancer Collaborative Group risk classification system was used to assess the correlation between MHL and relapse. MHL was calculated according to a logarithmic formula. ResultsMedian follow-up was 25 months (range, 6 to 96 mo). A statistically significant difference was not observed between initial AFP (P = 0.266) and &bgr;-human chorionic gonadotropin (P=0.092) in both patient groups. MHL was statistically different between the relapsed and nonrelapsed patients with a good, intermediate, and poor prognosis, except for the half-life of AFP in patients with a poor prognosis. ConclusionsMHL is an indicator that predicted recurrence. Patients with an MHL longer than expected should be investigated to improve the effectiveness of treatment and should be treated with a recovery regimen.