Chemotherapy In First-line Treatment Research Articles

A phase II clinical trial of celecoxib combined with platinum-based regimen as first-line chemotherapy for advanced non-small cell lung cancer patients with cyclooxygenase-2 positive expression

To evaluate the efficacy and safety of celecoxib plus platinum-doublet as first-line chemotherapy in treatment of advanced non-small cell lung cancer (NSCLC), and to determine the subgroup benefiting from celecoxib combined therapy by molecular analysis. A total of 44 treatment-naive patients of advanced NSCLC with positive cyclooxygenase-2 (COX-2) expression confirmed by immunohistochemical (IHC) staining were designed to receive celecoxib plus platinum-doublet chemotherapy (cisplatin plus gemcitabine, novelbine or docetaxol) from February 2005 to May 2007. On 5–7 day before chemotherapy, 400 mg celecoxib was administered twice a day orally until obvious evidence of disease progression or intolerable toxicity was found. Adverse events were recorded according to NCI-CTC criteria. The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), 1-year survival rate, response rate (RR) and safety. Additionally, we detected epithelial growth factor receptor (EGFR) status including EGFR gene amplification by real-time PCR and gene mutations by DHPLC followed by sequencing. The response rate was 45% (20/44), and the disease control rate (DCR) was 59% (26/44). The median progression-free survival time and median survival time were 6 m and 18 m, respectively. The 1-year survival rate was 68%. Chemotherapy cycle numbers and best response were found to be the predictive factors for PFS by COX model analysis (P=0.023 and P=0.000, respectively). No factor was found to affect OS. The most common toxicities included neutropenia and nausea/vomit. EGFR gene amplification was an independent prognostic factor influencing OS (P=0.0002). Patients with EGFR mutations (exon 21) had a tendency of disease progression (P=0.041). Encouraging activities of celecoxib combined with platinum-doublet chemotherapy were demonstrated in treatment-naive patients with advanced NSCLC, with good tolerances. For COX-2 IHC positive patients, positive EGFR amplification and mutation might be related to poor clinical outcomes.

Vascular Endothelial Growth Factor plus Epidermal Growth Factor Receptor Dual Targeted Therapy in Metastatic Colorectal Cancer: Synergy or Antagonism?

There has been an intensive effort to develop novel therapies for the treatment of metastatic colorectal cancer (mCRC). The anti-epidermal growth factor receptor (EGFR) antibodies panitumumab and cetuximab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab have demonstrated clinical efficacy and acceptable toxicity in the treatment of mCRC as single agents or in combination with chemotherapy. Recent clinical trials have explored the efficacy and safety of treatment regimens incorporating chemotherapy in combination with bevacizumab and either panitumumab or cetuximab in patients with mCRC. Results from the BOND-2 trial, which investigated cetuximab, bevacizumab, and chemotherapy in mCRC, provided support for this therapeutic approach. Two large randomized phase 3 trials were initiated to evaluate firstline treatment of mCRC. The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study investigated the efficacy and safety of oxaliplatin- or irinotecan-based chemotherapy and bevacizumab with or without panitumumab; CAIRO2 assessed the efficacy and safety of capecitabine/oxaliplatin and bevacizumab with or without cetuximab. In both trials, the combination of bevacizumab, an EGFR-specific antibody, and chemotherapy in first-line treatment of mCRC was associated with increased toxicity and no improvement in patient outcome. These results suggest that these specific combinations should not be used in first-line mCRC outside investigational studies.

Serum vitamin B12 and folate status among patients with chemotherapy treatment for advanced colorectal cancer

Background. There are conflicting results on the role of cobalamin and folate for epidemiology and carcinogenesis in colorectal cancer patients and the need of supplementation for prevention of chemotherapy toxicity.Patients and methods. Serum cobalamin, folate, and homocysteine were analysed before and during the treatment of 93 patients with advanced colorectal cancer (ACRC) with first-line chemotherapy treatment. This cohort was compared with a healthy control group of 224 individuals.Results. Patients with ACRC had similar cobalamin, folate, and homocysteine values as the healthy control group. There were no correlations between serum cobalamin, folate, and homocysteine values and objective response. There were no correlations to anaemia or other severe toxicity for cobalamin and homocysteine. A total of 12 patients had folate deficiency, and 10 of those suffered from severe toxicity (grade 3 or more). All patients had markedly increased folate values after 2 months of treatment. Folate and homocysteine did not predict patient outcome; however, patients with subclinically low cobalamin values (<300 pmol/L) had significant better overall survival and time to progression than patients with normal or high cobalamin values.Conclusion. Patients with ACRC seem to have fairly adequate cobalamin and folate status before and during chemotherapy treatment. This study indicates that ACRC patients receiving chemotherapy do not need supplementation with vitamin B12 and folate. A minor portion of the patients had folate deficiency, and most of those patients had severe toxicity. Patients with subclinically low cobalamin values had surprisingly better survival.

Dasatinib (Sprycel®) and Chemotherapy for First-Line Treatment in Elderly Patients with De Novo Philadelphia Positive ALL: Results of the First 22 Patients Included in the EWALL-Ph-01 Trial (on Behalf of the European Working Group on Adult ALL (EWALL))

Dasatinib (Sprycel®, Bristol-Myers Squibb) is a potent multi-targeted kinase inhibitor (TKI) of BCR-ABL and SRC family kinases. Despite a 33% complete hematological response (CHR) rate in a Phase 2 study in patients with Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL) intolerant or resistant to imatinib, the median duration of progression-free survival (PFS) was 3.3 months (Ottmann et al. Blood . 2007; 110:2309-2315). Second-generation TKI may thus have a place in the management of these patients. As a European consensus has been reached by the EWALL to adopt a common first-line chemotherapeutic schedule for elderly patients (aged 55 years or more) with Ph-positive ALL, this schedule was used here to test the addition of dasatinib. After a prephase with dexamethasone 10 mg/m2 d-7 to d-3, the induction phase consisted in IV injections of vincristine 1 mg combined with 2 days of dexamethasone 40 mg PO repeated weekly for 4 weeks followed by consolidation cycles including methotrexate 1000 mg/m2 IV d1 (500 mg/m2 over 70y) and asparaginase 10,000 UI/m2 IM d2 (5,000 UI/m2 over 70y) for cycles 1, 3 and 5 alternating with cytarabine 1,000 mg/m2/12h IV d1, d3, d5 (500 mg/m2 over 70y) for cycles 2, 4 and 6. Maintenance phase consisted in 6-MP 60 mg/m2/d and methotrexate 25 mg/m2/week orally 1 month every other month and dexamethasone/vincristine in 2 months intervals during the first year and in 3 months intervals during the second year. Dasatinib (provided by Bristol-Myers Squibb) was administered at 140 mg per day (QD) during the induction period in combination with chemotherapy and at 100 mg/d sequentially with the chemotherapy courses during consolidation and maintenance. BCRABL analysis was performed according to the European Leukemia Net recommendations in two centralized laboratories.A total of 22 patients were included from August 2007 to June 2008. Median age was 71 years (range, 61 to 83), sex ratio (M/F) was 0,46, and median follow-up was 5.8 months. The Ph+ chromosome was associated with complex abnormalities in 58% of cases and 84% of the patients were m-BCR. The CHR rate was 95.2% (20 out of 21 evaluable patients). The only case of induction failure was due to death. The rate of complete molecular remission (CMR) after induction was 33% in blood and 28% in bone marrow and MRD level continued to decrease with time. Only one relapse was observed before the consolidation phase. No other relapse occurred for the 13 patients in CHR still in study after a median follow-up of 3.6 months. One patient died during induction from invasive aspergillosis, 3 deaths occurred in CR, 2 before consolidation due to pulmonary embolism and physical deterioration, and one during maintenance from pneumonia. Serious adverse events (SAEs) were reported in 7 out of 22 patients during induction (31.8%) and in 2 out of 13 patients during maintenance and consolidation (15.3%). SAEs consisted in renal failure (n=3, 2 from acute lysis syndrome and 1 tubular necrosis), invasive aspergillosis (n=1), pulmonary embolism (n=2), pneumonia (n=1), atrial arythmia (n=2), pleural effusion (n=1), microangiopathy (n=1), cytolytic hepatitis (n=1) and physical deterioration (n=1). Eight patients discontinued the study after induction (35%). Primary reasons for discontinuation were SAEs (n=4), death (n=3) and relapse (n=1).The EWALL-PH-01 protocol is highly effective with a 95.2% RCH rate in elderly patients with Ph-positive ALL. Of importance, responses appeared to be durable and MRD level was decreasing over time. An expected 40% rate of SAEs was observed in this elderly population. Reduced doses of therapy are now applied for patients over 70y (20 mg for dexamethasone, 100 mg/d for dasatinib).

Reduced Erlotinib Sensitivity of Epidermal Growth Factor Receptor-Mutant Non–Small Cell Lung Cancer following Cisplatin Exposure: A Cell Culture Model of Second-line Erlotinib Treatment

Epidermal growth factor receptor (EGFR) kinase inhibitors induce dramatic clinical responses in a subset of non-small cell lung cancer (NSCLC) patients with advanced disease, and such responses are correlated with the presence of somatic activating mutations within the EGFR kinase domain. Consequently, one of these inhibitors, erlotinib, has been Food and Drug Administration-approved as a second- or third-line treatment for chemotherapy-refractory advanced NSCLC. However, responses are typically relatively short-lived due to acquired drug resistance, prompting studies to determine whether first-line treatment with EGFR inhibitors could provide greater clinical benefit. NSCLC-derived cell lines have provided a powerful system for modeling EGFR mutation-correlated sensitivity to EGFR inhibitors and for modeling mechanisms of acquired drug resistance that are observed clinically. In a cell culture model of an erlotinib-sensitive EGFR-mutant NSCLC cell line, we tested the hypothesis that prior exposure to platinum agents, a standard component of NSCLC chemotherapy treatment, affects the subsequent response to erlotinib. Indeed, NSCLC cells initially selected for growth in cisplatin exhibit 5-fold reduced sensitivity to erlotinib, even after propagating the cisplatin-treated cells in the absence of cisplatin for several months. This lingering effect of cisplatin exposure appears to reflect changes in PTEN tumor suppressor activity and persistent EGFR-independent signaling through the phosphatidylinositol 3-kinase/AKT survival pathway. These preclinical findings suggest that first-line chemotherapy treatment of EGFR-mutant NSCLCs may reduce the benefit of subsequent treatment with EGFR kinase inhibitors and should prompt further clinical investigation of these inhibitors as a first-line therapy in NSCLC.

A phase II study of adapted chemotherapy for first-line treatment of metastatic colo-rectal cancer (mCRC) in patients aged 70 years or over, systematically evaluated through Comprehensive Geriatric Assessment

A phase II study of adapted chemotherapy for first-line treatment of metastatic colo-rectal cancer (mCRC) in patients aged 70 years or over, systematically evaluated through Comprehensive Geriatric Assessment

Trends and predictors of first-line chemotherapy use among elderly patients with advanced non-small cell lung cancer in the United States

PurposeThis study assessed first-line chemotherapy treatment patterns over time and identified predictors of chemotherapy use and treatment selection among elderly patients with newly diagnosed Stage IIIB/IV non-small cell lung cancer (NSCLC) in the United States. MethodsPatients aged 65 years and older newly diagnosed with Stage IIIB/IV NSCLC between 1997 and 2002 were identified and followed through 2003 using the Surveillance, Epidemiology and End Results (SEER)-Medicare database to evaluate temporal trends in chemotherapy treatment. Multivariate logistic regression models were estimated to identify predictors of chemotherapy treatment and factors associated with use of cisplatin/carboplatin (platinum) and either a taxane or gemcitabine versus other treatments. ResultsChemotherapy use increased from approximately 28% of Stage IIIB/IV NSCLC patients diagnosed in 1997 to 36% of patients diagnosed in 2002. Doublet therapy was most commonly used as first-line therapy, received by 74% of chemotherapy-treated patients across all study years. Use of doublet therapy with platinum and either a taxane or gemcitabine also increased over time (with the largest increase for gemcitabine combinations from 0.3% in 1997 to 11.8% in 2002). Males were more likely than females to be treated with chemotherapy (odds ratios [95% CI]: 1.14 [1.06–1.22]), as were patients in the Northeast and South relative to patients in the West (1.24 [1.13–1.36] and 1.33 [1.20–1.47], respectively). ConclusionUse of first-line chemotherapy treatment among elderly Stage IIIB/IV NSCLC patients is low, but appears to be increasing, with potential regional and gender differences in treatment. These findings are likely to be of interest to clinicians and policymakers.

Phase II trial of sequential bevacizumab (B), erlotinib (E) and chemotherapy for first line treatment of clinical stage IIIB or IV non-small cell lung cancer (NSCLC)

19130 Background: B improves survival in first-line treatment of selected patients (pts) with NSCLC. The addition of an EGFR inhibitor to B appears promising. Methods: Eligible pts with untreated stage IIIB (pleural effusion) or IV NSCLC and good PS were enrolled. Pts with brain metastasis, squamous histology, or hemoptysis were excluded. Treatment consisted of 3 modules. Module A: up to 4 cycles of B (15 mg/kg) every 21 days and E (150 mg qd). Module B: up to 4 cycles of carboplatin (AUC=6), paclitaxel (200 mg/m2) and B (15 mg/kg) every 21 days. Pts who had SD or any response in module A then continued treatment in module C: B every 21 days and E until PD. This study follows a three- stage design, with a maximum sample of 48 pts. The primary objective was to determine the rate of non-PD after module A. Results: 48 pts have been enrolled. Demographics: 30 males (62%), with a median age of 65 years (35–80). 79.2% (n=38) were Caucasian. ECOG PS was 1 in 60% (n=29). 45 (94%) pts had stage IV disease. 66% (n=32) of pts’ tumors were adenocarcinomas, followed by NSCLC not otherwise specified in 25% (n=12). 70% of pts were heavy smokers. In module A, 63% of pts had 4 cycles (n=30). Lack of progression was seen in 64% (n=31), and 12% had a PR. Treatment-related (TR) grade 3/4 AEs: 12% of pts had rash, 6% neuropathy, 4% diarrhea, 4% bowel perforation. 37 pts were treated on module B, with 36 evaluable for response (1 was taken off study due to thrombosis), resulting in PR in 21% (n=8), SD in 45% (n=17) and PD in 29% (n=11). TR grade 3/4 AEs: 10% of pts had neutropenia, 10% neuropathy, 8% infection. 23 pts were treated on module C (median 7 cycles per pt). 19 pts were evaluated for response: 17% (n=4) had PR, 39% (n=9) had SD and 26% (n=6) had PD. TR grade 3/4 AEs: 10% had thrombosis, 10% diarrhea, 10% neuropathy, one patient each with vomiting, anorexia, weight loss and one required an aneurysmal repair. 10 pts remain on study. Median survival for all pts was 12.9 months (95% CI= 7.1 to 18.6 mo). 1-year survival rate was 49%. Pts who had SD or PR in module A had a median survival of 23.2 mo (versus 6.6 mo, p<0.001). Conclusions: The combination of B and E followed by chemotherapy is feasible in pts with advanced NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech

Cisplatin- Versus Carboplatin-Based Chemotherapy in First-Line Treatment of Advanced Non–Small-Cell Lung Cancer: An Individual Patient Data Meta-analysis

Cisplatin- Versus Carboplatin-Based Chemotherapy in First-Line Treatment of Advanced Non–Small-Cell Lung Cancer: An Individual Patient Data Meta-analysis

Phase III Trial of High-Dose Sequential Chemotherapy With Peripheral Blood Stem Cell Support Compared With Standard Dose Chemotherapy for First-Line Treatment of Advanced Ovarian Cancer: Intergroup Trial of the AGO-Ovar/AIO and EBMT

Although ovarian cancer is one of the most chemotherapy-sensitive solid tumors, cure after radical surgery and chemotherapy is uncommon. A randomized trial comparing high-dose sequential chemotherapy with peripheral blood stem cell (PBSC) support with platinum-based combination chemotherapy was conducted to investigate whether dose-intensification improves outcome. One hundred forty-nine patients with untreated ovarian cancer were randomly assigned after debulking surgery to receive standard combination chemotherapy or sequential high-dose (HD) treatment with two cycles of cyclophosphamide and paclitaxel followed by three cycles of HD carboplatin and paclitaxel with PBSC support. HD melphalan was added to the final cycle. The median age was 50 years (range, 20 to 65 years) and International Federation of Gynecology and Obstetrics stage was IIb/IIc in 4%, III in 78%, and IV in 17%. Seventy-six percent of patients received all five cycles in the HD arm and the main toxicities were neuro-/ototoxicity, gastrointestinal toxicity, and infection and one death from hemorrhagic shock. After a median follow-up of 38 months, the progression-free survival was 20.5 months in the standard arm and 29.6 months in the HD arm (hazard ratio [HR], 0.84; 95% CI, 0.56 to 1.26; P, .40). Median overall survival (OS) was 62.8 months in the standard arm and 54.4 months in the HD arm (HR, 1.17; 95% CI, 0.71 to 1.94; P, .54). This is the first randomized trial comparing sequential HD versus standard dose chemotherapy in first-line treatment of patients with advanced ovarian cancer. We observed no statistically significant difference in progression-free survival or OS and conclude that HD chemotherapy does not appear to be superior to conventional dose chemotherapy.

Prediction of response and prognostic factors for Ewing family of tumors in a low incidence population

There is some unknown reason Ewing family of tumors (EFTs) is much less common on Asia and Africa than in the Western Caucasian population. This study analyzed the prediction of response and prognostic factors for Ewing family of tumors (EFTs) in an Asian population with a low incidence. We retrospectively reviewed 94 patients with EFTs between 1978 and 2006. Fifteen patients received local therapy only. Statistical analyses were performed for 79 patients, including those who received systemic chemotherapy, to identify factors related to chemotherapy responsiveness, event-free survival, and overall survival. Of the 79 patients whose records were analyzed, the 5-year event-free rate and overall survival (OS) rate were 41 and 54%, respectively. The response rate to first-line chemotherapy was 61% in 70 patients with assessable lesions. A significant predictor of response was existence of a non-pelvic primary tumor (P = 0.04). Significant prognostic factors for OS were age, performance status, and metastases at the time of diagnosis (P < 0.01, respectively). Fifty-four patients had disease progression or recurrence after first-line treatment. The time to progression was 3.4 months after salvage treatment. Progression during first-line treatment was significantly associated with time to progression after salvage treatment (P = 0.01). All patients treated without chemotherapy in first-line treatment were recurred with poor prognosis. A non-pelvic primary tumor was a favorable predictor of responsiveness to chemotherapy. Chemo-resistant patients might less benefit from second line chemotherapy. Chemotherapy in first-line treatment should not be omitted, even if primary tumor was extirpated completely.

Temporal trends in first-line chemotherapy treatment among elderly stage IIIB/IV non-small cell lung cancer (NSCLC) patients in the United States: Evidence from SEER-Medicare data

17002 Background: Data regarding first-line chemotherapy treatment among advanced-staged NSCLC patients is lacking. The purpose of this analysis was to assess first-line treatment patterns over time among elderly patients with Stage IIIB/IV NSCLC. Methods: Patients aged 65 years and older diagnosed with Stage IIIB/IV NSCLC between 1997 and 2002 were identified and followed over time using the SEER-Medicare database to evaluate temporal trends in first-line chemotherapy treatment. Results: Chemotherapy use increased from approximately 28% of Stage IIIB/IV patients diagnosed in 1997 to 36% of patients diagnosed in 2002. Among identifiable first-line treatments, cisplatin or carboplatin and taxane (C/CT) doublet therapy was the most common treatment in all years (approximately 50% or greater). The use of single-agent taxanes and gemcitabine increased over time (taxane use increased from 3.3% in 1997 to 7.6% in 2002; gemcitabine use increased from 0.6% in 1997 to 5.1% in 2002), while use of single agent cisplatin or carboplatin (C/C) declined (from 10.0% in 1997 to 3.1% in 2002). Use of doublet therapy with C/C and either a taxane or gemcitabine also increased over time (with the largest increase for the gemcitabine combination from 0.3% in 1997 to 11.8% in 2002). Correspondingly, use of doublet C/C and any other therapy declined markedly (from 18.9% in 1997 to 3.7% in 2002). Use of 3 or more agents as first-line treatment was infrequent across study years (&lt;1.0%). Treatment discontinuation was substantial (&gt;60% for all regimens). Conclusions: Our findings indicate relatively low but increasing use of first-line chemotherapy treatment among elderly Stage IIIB/IV NSCLC patients. [Table: see text]

New and Emerging Intraperitoneal (IP) Drugs for Ovarian Cancer Treatment

Chemotherapy after surgical debulking represents an essential component of treatment for patients with advanced ovarian cancer. Three quarters of patients respond very well to initial treatment with platinum-containing drugs used either alone or in combination with a taxane, usually paclitaxel. With relapse rates exceeding 50% and median survival time of 2 years for patients after relapse, efforts are focused on treatment approaches to achieve and extend clinical complete remissions. These approaches include consolidation and maintenance therapy, intraperitoneal (IP) administration of cytotoxic agents, new combination chemotherapy regimens, development of new cytotoxic agents, and molecular-targeted therapies (beyond tumor DNA, the classical target of cytotoxic drugs). IP chemotherapy, which involves direct instillation of chemotherapy into the tumor site in the peritoneal cavity, is the focus of this review article. This article discusses studies involving new and emerging IP drugs for both first-line chemotherapy treatment of advanced ovarian cancer and recurrent platinum-sensitive ovarian cancer.

Spanish Breast Cancer Research Group (GEICAM)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Spanish Breast Cancer Research Group (GEICAM). Clinical trials include: FAC versus CMF as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. GEICAM/8701Phase III study of concomitant versus sequential chemohormonotherapy (EC plus tamoxifen) as adjuvant chemotherapy for node-positive postmenopausal women. GEICAM/9401High-dose DICEP chemotherapy versus observation in metastatic breast cancer patients with monotopic disease responding to induction chemotherapy with paclitaxel plus epirubicin. Phase III GEICAM trial. GEICAM/9601Vinorelbine infusion over 96 hours in heavily pre-treated patients with metastatic breast cancer: a cooperative study by the GEICAM group. GEICAM/9702Phase II trial of gemcitabine in combination with vinorelbine in patients with metastatic breast cancer resistant to anthracyclines. GEICAM/9704A phase II trial for evaluation of sequential doxorubicin and docetaxel as first-line treatment in metastatic breast cancer. GEICAM/9801A multicenter phase III randomized trial comparing docetaxel with doxorubicin and cyclophosphamide (TAC) versus 5-fluorouracil with doxorubicin and cyclophosphamide (FAC) as adjuvant treatment of operable breast cancer patients with negative axillary lymph nodes. TARGET 0 / GEICAM/9805A multicenter phase III randomized trial to compare the sequential and the concomitant administration of doxorubicin and docetaxel, as first-line chemotherapy treatment for metastatic breast disease. GEICAM/9903Docetaxel plus gemcitabine administered every other week as first-line treatment for metastatic breast cancer. GEICAM/9904Weekly docetaxel as neo-adjuvant treatment in stage II and III breast cancer. GEICAM/9905A multicenter phase III randomized trial comparing 5-fluorouracil with epirubicin and cyclophosphamide (FEC) versus 5-fluorouracil with epirubicin and cyclophosphamide (FEC) followed by weekly paclitaxel as adjuvant treatment of operable breast cancer patients with positive axillary lymph nodes. GEICAM/9906An open, multicenter randomized phase IV trial for the administration of pamidronate to breast cancer patients with bone metastatic disease. GEICAM/2000-01A randomized phase III treatment to compare the administration of vinorelbine versus vinorelbine plus gemcitabine in patients with metastatic breast cancer previously treated with anthracyclines and taxanes. GEICAM/2000-04Maintenance phase III/IV study for the administration of Caelyx versus no treatment, after induction chemotherapy for metastatic breast cancer disease. GEICAM/2001-01A multicenter, cross-over, randomized trial with exemestane versus anastrozole as first-line hormonal treatment of postmenopausal women with metastatic breast cancer disease and positive hormone receptors. GEICAM/2001-03A multicenter, open-label randomized phase III trial for the administration of zoledronate to patients with advanced breast cancer disease and non-symptomatic bone metastasis. GEICAM/2001-05A multicenter phase II trial to evaluate the administration of gemcitabine with doxorubicin and paclitaxel (GAT) as neo-adjuvant treatment of stage III disease breast cancer patients. GEICAM/2002–01A phase II trial to evaluate the administration of doxorubicin with cyclophosphamide (AC) followed by weekly docetaxel (T) as neo-adjuvant treatment of stage II disease breast cancer patients. GEICAM/2002–03A multicenter, open-label, randomized phase III trial comparing six courses of FAC (fluorouracil, doxorubicin, cyclophosphamide) with four courses of FAC followed by 8-weekly administrations of Taxol in the adjuvant treatment of node-negative patients with operable breast cancer. GEICAM/2003–02A multicenter, open-label, randomized phase III trial comparing epirubicin plus cyclophosphamide (EC) followed by docetaxel (T) with epirubicin plus docetaxel (ET) followed by capecitabine (X) in the adjuvant treatment of node-positive patients with operable breast cancer. GEICAM/2003–10Open-label, no randomized, phases I–II of the treatment with Myocet/Taxotere/Herceptin as primary antineoplasic treatment in newly diagnosed breast cancer patients with HER2neu overexpression. GEICAM/2003–03Phase IV.II clinical trial with the combination of pegylated liposomal doxorubicin, cyclophosphamide and trastuzumab in patients with metastatic breast cancer with overexpression HER2neu. GEICAM/2004–05Randomized clinical trial to compare the benefit of adding trastuzumab to the combination of capecitabine plus vinorelbine as second-line treatment for patients with locally advanced non-operable breast cancer or metastatic breast cancer with overexpression of HER2, who have progressed to a previous line of treatment for metastatic disease that included trastuzumab in combination with taxanes. GEICAM/2004–06Phase IV.II clinical trial, multicenter, for administration of capecitabine concomitant to radiotherapy in patients with locally advanced breast cancer and HER2neu negatives. GEICAM/2005–01Phase IV.III, multicenter, open, randomized treatment study to evaluate the efficacy of maintenance therapy with capecitabine after standard chemotherapy with anthracyclines in patients with metastatic breast cancer. GEICAM/2005–04

CISCA (cisplatin vs. carboplatin) meta-analysis: An individual patient data meta-analysis comparing cisplatin versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer (NSCLC)

7011 Background: The issue of the equivalence between carboplatin and cisplatin in the treatment of advanced NSCLC is still controversial. To answer this question, we conducted an individual patient (pt) data meta-analysis of randomized trials comparing cisplatin- and carboplatin-based chemotherapy (CT) in first-line treatment of advanced NSCLC. Methods: A literature search was performed to identify randomized trials investigating the substitution of carboplatin for cisplatin, combined with the same agent/s, in the first-line CT of advanced NSCLC. The primary end-point was overall survival (OS) and the secondary end-points were response rate (RR) and toxicity. For each end-point the analysis was based on a fixed-effects model. For the study of the effect on OS, Cox proportional hazards model was used. The probability to have an objective response or an adverse event was studied using a logistic regression model. Results: Nine trials were identified and the relative databases obtained. In total, 2,968 pts were randomized to receive CT with cisplatin (1,489) or with carboplatin (1,479), respectively. The RR was 30% and 24% for cisplatin- and carboplatin-based CT, respectively, with an OR of 1.37 (95% C.I.: 1.16–1.62; p &lt; 0.001). Concerning the OS, carboplatin was associated with a relative risk of death 7% higher compared with cisplatin, even if this difference was not statistically significant (HR = 1.07; 95% C.I.: 0.99–1.15; p = 0.101). Patients on cisplatin-based CT had more nausea-vomiting and nephro-toxicity while thrombocytopenia was more frequent during carboplatin-based CT. Subgroup analyses revealed that cisplatin-based CT led to statistically significant advantage in survival in the subgroups of pts with non-squamous tumours and in those treated with third generation CT. Conclusions: CISCA is the first individual pt data meta-analysis on this subject. We found that cisplatin-based is superior to carboplatin-based CT in terms of RR; however, the increased RR does not translate into an OS benefit. Nevertheless, selected pts with advanced NSCLC may obtain slightly more benefit from cisplatin-based third generation CT. No significant financial relationships to disclose.

Phase II study of docetaxel plus epirubicin versus docetaxel plus cisplatin as first-line chemotherapy for treatment of advanced breast cancer (CHN TAX-618)

10535 Background: The combination of docetaxel plus epirubicin (TE) have demonstrated a significant activity in advance breast cancer (ABC) as first-line chemotherapy. In the meantime, some emerging literatures suggest that docetaxel-cisplatin (TP) combination has a powerful synergistic interaction with less cardiotoxicity. The main objectives of this multicenter study are to evaluate the efficacy and safety of TE versus TP. Methods: From August 2003 to February 2005, 80 patients with at least one measurable lesion were randomized with ratio of 2:1 to receive TE or TP as as first-line chemotherapy. Dosages were as follows: docetaxel 75 mg/m2 plus epirubicin 60 mg/m2 or docetaxel 75 mg/m2 plus cisplatin 75 mg/m2 intravenously once every 3 weeks for a maximum of 6 cycles. Baseline characteristics were well balanced. Results: A total of 55 patients were assigned to TE (median age 48 yearas) and 25 patients were treated with TP (median age 50 yearas). The same of median 4 cycles treatment were administered for two arms. A complete clinical response was observed in 3.6% and 4.0% of patients treated with TE and TP, respectively (P = 1.00). Overall (complete and partial) clinical response rates for TE and TP were 48% and 56%, respectively (P =0.469). Disease control rates (CR + PR + SD) for TE and TP were 83.6% and 80%, respectively (P = 0.755). The median TTP were TE: 10.8months,TP: 11.2 months days (P = 0.247). Grade 3/4 toxicities included: nausea/vomiting (16.3% TE; 12.0% TP); diarrhea (1.8% TE; 0% TP); alopecia (32.7% TE; 12.0% TP); anemia (1.8% TE; 4.0%TP); neutropenia (65.5% TE; 4.8% TP); febrile neutropenia (3.6% TE; 0% TP). Conclusions: Both TE and TP were active and tolerant regimens for ABC. While there may have been a trend toward lower toxicities in favor of the docetaxel/cisplatin combination, although no significant difference was observed during our study. No significant financial relationships to disclose.

The Combination of Raltitrexed (Tomudex) and Mitomycin-C in the Treatment of Advanced Colorectal Cancer — A Phase II Study

Aims To investigate the combination of raltitrexed and mitomycin-C as first-line chemotherapy treatment in patients with advanced colorectal cancer. Materials and methods A phase II study. Results In total, 22 patients were treated with a combination of raltitrexed 3 mg/m 2 every 3 weeks and mitomycin-C 7 mg/m 2 every 6 weeks for up to 24 weeks. The study was closed early for safety reasons as there were three unexpected treatment-related deaths. The overall response rate was 20%, and a further 40% achieved stable disease. The median time to progression was 3.9 months and the median overall survival time was 11.6 months. Conclusion Owing to the potential for increased toxicity, the combination of raltitrexed and mitomycin-C cannot be recommended as first-line treatment in patients with advanced colorectal cancer.

Epidermal Growth Factor Receptor-Targeted Agents for Lung Cancer

Approximately 150,000 people were diagnosed with non-small cell lung cancer (NSCLC) in the United States in 2005. Most presented with inoperable advanced-stage disease. Although combination chemotherapy remains the standard treatment, median survival with these regimens is only 8 to 10 months. Recent advances in our understanding of lung cancer on a molecular level have led to the introduction of targeted therapies. We reviewed the mechanism of action of gefitinib and erlotinib as well as the results of phase I, II, and III trials with these drugs. No survival advantage was seen with the addition of gefitinib or erlotinib to combination chemotherapy in first-line treatment of advanced NSCLC. Erlotinib has shown a survival advantage over placebo in patients with NSCLC after first- or second-line chemotherapy. Recently, mutations in the epidermal growth factor receptor-tyrosine kinase domain have been identified. Patients who express these mutations have shown a higher probability of response to gefitinib. Combination chemotherapy remains the first-line treatment of advanced NSCLC. The benefit of alternating drug schedules and combinations has been small. Targeted therapies such as gefitinib and erlotinib, although to date have shown no survival advantage when combined with chemotherapy in the first-line setting, remain promising. Ongoing studies of patient characteristics of responding patients and molecular studies of tumors may help to identify patients most likely to respond to these therapies.

Concomitant Administration of Bevacizumab, Irinotecan, 5-Fluorouracil, and Leucovorin: Nonclinical Safety and Pharmacokinetics

Bevacizumab (Avastin) is a humanized monoclonal antibody against vascular endothelial growth factor approved for use in combination with 5-fluorouracil (5-FU)-based chemotherapy for first-line treatment of metastatic colorectal cancer. The Saltz regimen (irinotecan/5-FU/leucovorin [LV]) is a first-line treatment for this indication. The objective of this study was to evaluate the safety of bevacizumab when administered concomitantly with the Saltz regimen to cynomolgus monkeys, and to determine if the pharmacokinetics of bevacizumab, irinotecan, SN38 (the active metabolite of irinotecan), or 5-FU were affected by combined administration. Male cynomolgus monkeys were intravenously administered the Saltz regimen (125 mg/m2 irinotecan, 500 mg/m2 5-FU, 20 mg/m2 LV) alone (n = 4) or concomitantly with 10 mg/kg bevacizumab (n = 5) on days 1 and 8. All animals survived to euthanasia on day 15. Adverse effects associated with the Saltz regimen included diarrhea and neutropenia. Macroscopically, two animals from each group had small thymus glands that correlated microscopically with lymphoid depletion. Myeloid hypoplasia and/or erythroid hyperplasia was observed in the sternal bone marrow of most animals. These effects were considered to be associated with the Saltz regimen; concomitant bevacizumab administration did not alter the severity of these findings. Irinotecan and 5-FU were observed to be rapidly eliminated (t1/2 = 1 h and 0.5 h, respectively). Although the number of animals in each group was small and no statistical comparison between groups was performed, bevacizumab did not affect the disposition of either agent. These results indicate that bevacizumab can be safely administered in combination with the Saltz regimen without pharmacokinetic interaction.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Plus Chemotherapy: Case Closed or Is the Jury Still Out?

The cases for and against giving combinations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib concurrently with chemotherapy for first-line treatment of advancedstage non–small-cell lung cancer (NSCLC) have just become even more complex. In this issue of the Journal of Clinical Oncology are two additional pieces of evidence— one favoring the prosecution’s case (EGFR TKIs plus concurrent chemotherapy is a bad idea: “guilty as charged”) and one for the defense (the evidence against the combination is all “circumstantial”: this is a case of the defendant, erlotinib, being “in the wrong place at the wrong time”). Let’s examine the evidence from these two studies. Herbst et al present data from the TRIBUTE trial of paclitaxel/carboplatin plus concurrent erlotinib or placebo, showing that erlotinib added nothing to chemotherapy for any outcome measure in the overall study population. These data are strikingly reminiscent of those published previously in the gefitinib-based INTACT (Iressa NSCLC Trial Assessing Combination Treatment) trials and the similarly designed TALENT trial of gemcitabine/cisplatin plus or minus erlotinib. Altogether, these four trials testing the concept of chemotherapy plus concurrent EGFR TKI account for 4,421 patients, a substantial investment of patient resources. While erlotinib added nothing to efficacy, it did contribute to toxicity. The authors report 48 deaths attributable to an adverse event: 32 (10.2%) of 322 deaths in the erlotinib arm versus 15 (4.4%) of 340 in the placebo arm. So the question at hand is why were TRIBUTE and TALENT negative studies? Similarly, why did gefitinib not add benefit to chemotherapy in INTACT 1 and INTACT 2? After all, we know that chemotherapy by itself produces objective responses and prolongs survival in NSCLC when compared with supportive care alone. In a recently reported trial in patients with NSCLC failing chemotherapy (BR21) erlotinib monotherapy resulted in objective responses and prolonged survival when compared with placebo. Thus, it is logical to conclude that the antitumor activity of these agents should be at least additive (ie, 1 1 should equal 2). (Personal communication, Alisha and Zachary Stickney, April 18, 2005.) However, in the four large clinical trials cited above, 1 1 appears to equal only 1. How could this be? Although there are a number of possible explanations, two hypotheses that seem most likely have been proposed: (1) Lack of patient selection for the target (EGFR) explains the results; or (2) Chemotherapy and EGFR TKIs, given concurrently, result in a negative interaction (antagonism?) in at least a subset of patients treated. The first hypothesis, that negative results are explained by failure to “enrich” the study population(s) by a biomarker predictive of response, clearly has merit. One need only look back to the clinical trials of trastuzumab plus chemotherapy in breast cancer to see the rationale for predetermining a sensitive population most likely to benefit from such a combination. Mathematical probability suggests that if trastuzumab plus chemotherapy had been tested in a nonselected population, no benefit of trastuzumab would have been discernable. In favor of this explanation, the authors of TRIBUTE report a survival benefit for the combination in patients categorized as “never-smokers,” a group previously reported to have a higher response rate to erlotinib or gefitinib as single agents, and as noted below, a group with a higher likelihood of harboring an EGFR-activating mutation. It is here that the study by Eberhard et al describing EGFR and KRAS mutations in a subset of 274 patient tumors from TRIBUTE becomes relevant. A large number of potential biomarkers for sensitivity or resistance to EGFR TKIs have been proposed, including protein expression of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 25 SEPTEMBER 1 2005