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1.  Optimal chemotherapy treatment for women with recurrent ovarian cancer 
Current Oncology  2007;14(5):195-208.
Question
What is the optimal chemotherapy treatment for women with recurrent ovarian cancer who have previously received platinum-based chemotherapy?
Perspectives
Currently, standard primary therapy for advanced disease involves a combination of maximal cytoreductive surgery and chemotherapy with carboplatin plus paclitaxel or with carboplatin alone. Despite initial high response rates, a large proportion of patients relapse, resulting in a therapeutic challenge. Because these patients are not curable, the goal of therapy becomes improvement in both quality and length of life. The search has therefore been to find active agents for women with recurrent disease following platinum-based chemotherapy.
Outcomes
Outcomes of interest included any combination of tumour response rate, progression-free survival, overall survival, adverse events, and quality of life.
Methodology
The medline, embase, and Cochrane Library databases were systematically searched for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. The systematic review and recommendations were approved by the Report Approval Panel of the Program in Evidence-Based Care, and by the Gynecology Cancer Disease Site Group (dsg). The practice guideline was externally reviewed by a sample of practitioners from Ontario, Canada.
Results
Thirteen randomized trials compared various chemotherapy regimens for patients with recurrent ovarian cancer.
In five of the thirteen trials in which 100% of patients were considered sensitive to platinum-containing chemotherapy, further platinum-based combination chemotherapy significantly improved response rates (two trials), progression-free survival (four trials), and overall survival (three trials) when compared with single-agent chemotherapy involving carboplatin or paclitaxel. Only two of these randomized trials compared the same chemotherapy regimens: carboplatin alone versus the combination of carboplatin and paclitaxel. Both trials were consistent in reporting improved survival outcomes with the combination of carboplatin and paclitaxel. In one trial, the combination of carboplatin and gemcitabine resulted in significantly higher response rates and improved progression-free survival when compared with carboplatin alone. Median survival with carboplatin alone ranged from 17 months to 24 months in four trials.
In eight of the thirteen trials in which 35%–100% of patients had platinum-refractory or -resistant disease, one trial reported a statistically significant 2-month improvement in overall survival with liposomal doxorubicin as compared with topotecan (15 months vs. 13 months, p = 0.038; hazard ratio: 1.23; 95% confidence interval: 1.01 to 1.50). In that trial, because of the limited clinical benefit and the unusual finding that a survival difference emerged only after a year of treatment with no corresponding improvement in the rate of response or of progression-free survival, the authors concluded that further confirmation by results from randomized trials were needed to establish the superiority of one agent over another in their trial. In one trial, topotecan was superior to treosulphan in patient progression-free survival by a span of approximately 2 months (5.4 months vs. 3.0 months, p < 0.001).
Toxicity was reported in all of the randomized trials, and although data on adverse events varied by treatment regimen, the observed adverse events correlated with known toxicity profiles. As expected, combination chemotherapy was associated with higher rates of adverse events.
Practice Guideline
Target Population
This clinical recommendation applies to women with recurrent epithelial ovarian cancer who have previously received platinum-based chemotherapy. Of specific interest are women who have previously shown sensitivity to platinum therapy and those who previously were refractory or resistant to platinum-based chemotherapy. As a general categorization within what is actually a continuum, “platinum sensitivity” refers to disease recurrence 6 months or more after prior platinum-containing chemotherapy, and “platinum resistance” refers to a response to platinum-based chemotherapy followed by relapse less than 6 months after chemotherapy is stopped. “Platinum-refractory disease” refers to a lack of response or to progression while on platinum-based chemotherapy.
Recommendations
Although the body of evidence that informs the clinical recommendations is based on randomized trial data, those data are incomplete. Based on the available data and expert consensus opinion, the Gynecology Cancer dsg makes these recommendations:
Systemic therapy for recurrent ovarian cancer is not curative. It is therefore recognized that each patient must be individually assessed to determine optimal therapy in terms of recurrence, sensitivity to platinum, toxicity, ease of administration, and patient preference. All suitable patients should be offered the opportunity to participate in randomized trials, if available.
In the absence of contraindications, combination platinum-based chemotherapy should be considered for patients with prior sensitivity to platinum-containing chemotherapy. As compared with carboplatin alone, the combination of carboplatin and paclitaxel significantly improved both progression-free and overall survival.
If combination platinum-based chemotherapy is not indicated, then a single platinum agent should be considered. Carboplatin has demonstrated efficacy across trials and has a manageable toxicity profile.
If a single platinum agent is not being considered, then monotherapy with paclitaxel, topotecan, or pegylated liposomal doxorubicin are seen as reasonable treatment options.
Some patients may be repeatedly sensitive to treatment and may benefit from multiple lines of chemotherapy.
For patients with platinum-refractory or platinum-resistant disease, the goals of treatment should be to improve quality of life by extending the symptom-free interval, by reducing symptom intensity, and by increasing progression-free interval, and, if possible, to prolong life.
With non-platinum agents, monotherapy should be considered because no advantage appears to accrue to the use of non-platinum-containing combination chemotherapy in this group of patients. Single-agent paclitaxel, topotecan, or pegylated liposomal doxorubicin have demonstrated activity in this patient population and are reasonable treatment options.
No evidence either supports or refutes the use of more than one line of chemotherapy in patients with platinum-refractory or platinum-resistant recurrence. Many treatment options have shown modest response rates, but their benefits over best supportive care have not been studied in clinical trials.
PMCID: PMC2002482  PMID: 17938703
Chemotherapy; drug therapy; ovarian cancer; ovarian neoplasms; practice guideline; systematic review
2.  Advanced Gastric Cancer: An Update 
Worldwide, gastric cancer continues as a significant healthcare issue with an unacceptably high mortality rate. Although it is clear that combination chemotherapy for advanced gastric/esophageal gastric cancer is superior to best supportive care and monotherapy, the median survival over the past two decades persists at less than 10 months. Multiple combination regimens have been evaluated in the phase III setting, producing response rates ranging between 9% and 45%. There is still debate as to whether doublet vs. triplet chemotherapy combinations represent the most appropriate platform from which to build other regimens, including those with biologic therapy.
Two published clinical trials have significantly influenced clinical practice. A randomized trial including 545 advanced gastric cancer patients compared first-line treatment with DCF (docetaxel, cisplatin, 5-FU) vs. the cisplatin/5-FU regimen. The cisplatin/5-FU combination has, over time, become a standard comparator regimen and has been supported by the FDA. Although the trial showed a significant survival advantage favoring DCF, there has been concern about toxicity, particularly the risk of increased diarrhea, neutropenia, and neutropenic fever. The REAL2 trial was a 2x2 randomized, first-line advanced gastric cancer study that compared two different platinum compounds and two different fluoropyrimidines in combination therapy. The regimens consisted of ECF (epirubicin, cisplatin, and infusional 5-FU), ECX (epirubicin, cisplatin, and capecitabine), EOF (epirubicin, oxaliplatin, and infusional 5-FU) and EOX (epirubicin, oxaliplatin, and capecitabine). The authors concluded that the oxaliplatin combinations appeared to be safer than those with cisplatin and that oxaliplatin was not inferior to cisplatin, nor was capecitabine inferior to infusional 5-FU. Furthermore, EOX appeared to have improved efficacy compared to the reference regimen (ECF).
The National Comprehensive Cancer Network (NCCN) has encompassed a listing of potential combination regimens for metastatic or locally advanced cancer in the Clinical Practice Guidelines. The NCCN cites category 1 level of evidence in support of DCF and ECF, with category 2B evidence and consensus for irinotecan plus cisplatin, oxaliplatin plus a fluoropyrimidine, DCF modifications, irinotecan plus fluoropyrimidine, and paclitaxel-based regimens.
A recently completed ECOG/CALGB collaborative, randomized phase II trial (E1206/C80403) is of interest since it integrates the monoclonal antibody cetuximab as a component of three different platform regimens: ECF, irinotecan and cisplatin, and FOLFOX (5-FU, oxaliplatin, and leucovorin). A significant challenge for future trial design will continue to address optimal chemotherapy platforms and how to best choose among a host of different biologic agents to potentially improve median survival. Identifying tumor-specific molecular/genetic characteristics that will help inform the choice of biologic agents is a significant obstacle.
A trial that generated considerable interest during the American Society of Clinical Oncology (ASCO) 2009 meeting evaluated the addition of trastuzumab to standard first-line chemotherapy for patients with human epidermal growth factor receptor (HER2)-positive advanced gastric cancer (ToGA trial). The trial screened 3,807 patients to identify the 22.1% who were HER2-positive and were subsequently randomized to receive 5-FU or capecitabine plus cisplatin (n=290) vs. 5-FU or capecitabine plus cisplatin plus trastuzumab (n=294). The trial stratified patients on the basis of gastric vs. GE cancers, measurable vs. nonmeasurable disease, ECOG performance status, capecitabine vs. 5-FU, and advanced vs. metastatic disease. Assessment was by central evaluation and included immunohistochemistry (IHC) 3+ and/or FISH+. Patients who received trastuzumab had a significant improvement in overall survival, which was the primary study end point, as well as a significant improvement in progression-free survival. Toxicity was considered acceptable, including incidence of cardiac toxicity.
During ASCO 2009, there was also an update of the FLAGS study, a randomized phase III trial comparing cisplatin/S1 (CS) with cisplatin/5-FU (CF) as first-line therapy in patients with advanced gastric cancer. This follow-up analysis confirmed the initial findings, demonstrating that the CS regimen was not inferior to CF and appeared to be safer. An unplanned subset analysis was of interest, because it suggested a significant increase in the diffuse type of gastric cancer since 1973 and a significant decrease in the intestinal type of gastric cancer. Results of the unplanned analysis also suggested that the S1/cisplatin combination may be more effective in patients with the diffuse type of pathology, and this will require further investigation in prospective studies.
Finally, another trial updated during ASCO was the randomized phase III study of single-agent 5-FU vs. the combination of irinotecan and cisplatin vs. single-agent S1 in advanced gastric cancer (JCOG9912). The initial analysis demonstrated the superiority of irinotecan with cisplatin compared to continuous-infusion 5-FU and the non-inferiority of S1 compared to infusional 5-FU. This updated analysis showed that overall survival and hazard ratios were identical to those in the previous reports. In addition, multivariate analysis showed that the number of metastatic sites, performance status, and presence of target lesion were associated with shorter survival.
PMCID: PMC3047034
3.  Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial 
The Lancet Oncology  2013;14(4):317-326.
Summary
Background
In the UK, chemotherapy is the standard treatment for inoperable, locally advanced, non-metastatic pancreatic cancer. Chemoradiotherapy is also an acceptable treatment option, for which gemcitabine, fluorouracil, or capecitabine can be used as concurrent chemotherapy agents. We aimed to assess the activity, safety, and feasibility of both gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy for patients with locally advanced pancreatic cancer.
Methods
In this open-label, randomised, two-arm, phase 2 trial, patients aged 18 years or older with histologically proven, locally advanced pancreatic cancer (with a tumour diameter of 7 cm or less) were recruited from 28 UK centres between Dec 24, 2009 and Oct 25, 2011. After 12 weeks of induction gemcitabine and capecitabine chemotherapy (three cycles of gemcitabine [1000 mg/m2 on days 1, 8, 15 of a 28-day cycle] and capecitabine [830 mg/m2 twice daily on days 1–21 of a 28-day cycle]), patients with stable or responding disease, tumour diameter of 6 cm or less, and WHO performance status 0–1 were randomly assigned to receive a further cycle of gemcitabine and capecitabine chemotherapy followed by either gemcitabine (300 mg/m2 once per week) or capecitabine (830 mg/m2 twice daily, Monday to Friday only), both in combination with radiation (50·4 Gy in 28 fractions). Randomisation (1:1) was done via a central computerised system and used stratified minimisation. The primary endpoint was 9-month progression-free survival, analysed by intention to treat including only those patients with valid CT assessments. This trial is registered with ISRCTN, number 96169987.
Findings
114 patients were registered and 74 were randomly allocated (38 to the gemcitabine group and 36 to the capecitabine group). After 9 months, 22 of 35 assessable patients (62·9%, 80% CI 50·6–73·9) in the capecitabine group and 18 of 35 assessable patients (51·4%, 39·4–63·4) in the gemcitabine group had not progressed. Median overall survival was 15·2 months (95% CI 13·9–19·2) in the capecitabine group and 13·4 months (95% CI 11·0–15·7) in the gemcitabine group (adjusted hazard ratio [HR] 0·39, 95% CI 0·18–0·81; p=0·012). 12-month overall survival was 79·2% (95% CI 61·1–89·5) in the capecitabine group and 64·2 (95% CI 46·4–77·5) in the gemcitabine group. Median progression-free survival was 12·0 months (95% CI 10·2–14·6) in the capecitabine group and 10·4 months (95% CI 8·9–12·5) in the gemcitabine group (adjusted HR 0·60, 95% CI 0·32–1·12; p=0·11). Eight patients in the capecitabine group had an objective response at 26 weeks, as did seven in the gemcitabine group. More patients in the gemcitabine group than in the capecitabine group had grade 3–4 haematological toxic effects (seven [18%] vs none, p=0·008) and non-haematological toxic effects (ten [26%] vs four [12%], p=0·12) during chemoradiation treatment; the most frequent events were leucopenia, neutropenia, and fatigue. Two patients in the capecitabine group progressed during the fourth cycle of induction chemotherapy. Of the 34 patients in the capecitabine group who received chemoradiotherapy, 25 (74%) received the full protocol dose of radiotherapy, compared with 26 (68%) of 38 patients in the gemcitabine group. Quality-of-life scores were not significantly different between the treatment groups.
Interpretation
Our results suggest that a capecitabine-based regimen might be preferable to a gemcitabine-based regimen in the context of consolidation chemoradiotherapy after a course of induction chemotherapy for locally advanced pancreatic cancer. However, these findings should be interpreted with caution because the difference in the primary endpoint was non-significant and the number of patients in the trial was small.
Funding
Cancer Research UK.
doi:10.1016/S1470-2045(13)70021-4
PMCID: PMC3620899  PMID: 23474363
4.  Phase II study of continuous infusional 5-fluorouracil with epirubicin and carboplatin (instead of cisplatin) in patients with metastatic/locally advanced breast cancer (infusional ECarboF): a very active and well-tolerated outpatient regimen. 
British Journal of Cancer  1996;73(3):391-396.
Infusional 5-fluorouracil (F) with cisplatin (C) and epirubicin (E), so-called infusional ECF, is a highly active new schedule against locally advanced or metastatic breast cancer. Cisplatin, however, is a major contributor to toxicity and usually requires inpatient treatment. In an attempt to overcome this, we have investigated the effect of substituting carboplatin for cisplatin in our original infusional ECF regimen. Fifty-two patients with metastatic (n = 36) or locally advanced/inflammatory (n = 16) breast cancer were treated with 5-fluorouracil 200 mg m-2 day-1 via a Hickman line using an ambulatory pump for for 6 months, with epirubicin 50 mg m-2 intravenously (i.v.) and carboplatin AUC5 i.v. every 4 weeks, for six courses (infusional ECarboF). The overall response rate (complete plus partial) was 81% (95% CI 67%-90%), with a complete response rate of 17% (95% CI 6-33%) in patients with metastatic disease and 56% (95% CI 30-80%) in patients with locally advanced disease. Median response duration and survival for metastatic disease was 8 and 14 months respectively, and two patients with locally advanced disease have relapsed. These results are very similar to those previously achieved with infusional ECF. Severe grade 3/4 toxicity was low. Infusional ECarboF is a highly active, well-tolerated, outpatient regimen effective against advanced/metastatic breast cancer and now warrants evaluation against conventional chemotherapy in high-risk early breast cancer.
PMCID: PMC2074421  PMID: 8562348
5.  A randomized phase II study of carboplatin plus pegylated liposomal doxorubicin versus carboplatin plus paclitaxel in platinum sensitive ovarian cancer patients: a Hellenic Cooperative Oncology Group study 
BMC Medicine  2010;8:3.
Background
Platinum-based combinations are the standard second-line treatment for platinum-sensitive ovarian cancer (OC). This randomized phase II study was undertaken in order to compare the combination of carboplatin and pegylated liposomal doxorubicin (LD) with carboplatin and paclitaxel (CP) in this setting.
Methods
Patients with histologically confirmed recurrent OC, at the time of or more than 6 months after platinum-based chemotherapy, were randomized to six cycles of CP (carboplatin AUC5 + paclitaxel 175 mg/m2, d1q21) or CLD (carboplatin AUC5 + pegylated LD 45 mg/m2, d1q28).
Results
A total of 189 eligible patients (CP 96, CLD 93), with a median age of 63 years, median Performance Status (PS) 0 and a median platinum free interval (PFI) of 16.5 months, entered the study. Discontinuation due to toxicity was higher in the CP patients (13.5% versus 3%, P = 0.016). The overall response rate was similar: CP 58% versus CLD 51%, P = 0.309 (Complete Response; CR 34% versus 23%) and there was no statistical difference in time-to-progression (TTP) or overall survival (OS; TTP 10.8 months CP versus 11.8 CLD, P = 0.904; OS 29.4 months CP versus 24.7 CLD, P = 0.454). No toxic deaths were recorded. Neutropenia was the most commonly seen severe toxicity (CP 30% versus CLD 35%). More frequent in CLD were severe thrombocytopenia (11% versus 2%, P = 0.016), skin toxicity and Palmar-plantar erythrodysesthesia (PPE) grade 1-2 (38% versus 9%, P< 0.001), while grade 3 neurotoxicity and alopecia were higher in CP (7% versus 0%, P = 0.029, 20% versus 5%, P = 0.003). PS and PFI were independent prognostic factors for TTP and OS.
Conclusions
The combination of pegylated LD with carboplatin is effective, showing less neurotoxicity and alopecia than paclitaxel-carboplatin. It thus warrants a further phase III evaluation as an alternative treatment option for platinum-sensitive OC patients.
Trial Registration
Australian New Zealand Clinical Trials Registry: ACTRN12609000436279
doi:10.1186/1741-7015-8-3
PMCID: PMC2823653  PMID: 20055981
6.  A phase I dose-finding study of a combination of pegylated liposomal doxorubicin (Doxil), carboplatin and paclitaxel in ovarian cancer 
British Journal of Cancer  2002;86(9):1379-1384.
Standard chemotherapy for advanced epithelial ovarian cancer is a combination of platinum-paclitaxel. One strategy to improve the outcome for patients is to add other agents to standard therapy. Doxil is active in relapsed disease and has a response rate of 25% in platinum-resistant relapsed disease. A dose finding study of doxil-carboplatin-paclitaxel was therefore undertaken in women receiving first-line therapy. Thirty-one women with epithelial ovarian cancer or mixed Mullerian tumours of the ovary were enrolled. The doses of carboplatin, paclitaxel and doxil were as follows: carboplatin AUC 5 and 6; paclitaxel, 135 and 175 mg m−2; doxil 20, 30, 40 and 50 mg m−2. Schedules examined included treatment cycles of 21 and 28 days, and an alternating schedule of carboplatin-paclitaxel (q 21) with doxil being administered every other course (q 42). The dose-limiting toxicities were found to be neutropenia, stomatitis and palmar plantar syndrome and the maximum tolerated dose was defined as; carboplatin AUC 5, paclitaxel 175 mg m−2 and doxil 30 mg m−2 q 21. Reducing the paclitaxel dose to 135 mg m−2 did not allow the doxil dose to be increased. Delivering doxil on alternate cycles at doses of 40 and 50 mg m−2 also resulted in dose-limiting toxicities. The recommended doses for phase II/III trials are carboplatin AUC 6, paclitaxel 175 mg m−2, doxil 30 mg m−2 q 28 or carboplatin AUC 5, paclitaxel 175 mg m−2, doxil 20 mg m−2 q 21. Grade 3/4 haematologic toxicity was common at the recommended phase II doses but was short lived and not clinically important and non-haematologic toxicities were generally mild and consisted of nausea, paraesthesiae, stomatitis and palmar plantar syndrome.
British Journal of Cancer (2002) 86, 1379–1384. DOI: 10.1038/sj/bjc/6600250 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600250
PMCID: PMC2375380  PMID: 11986767
ovarian cancer; liposomal doxorubicin; carboplatin; paclitaxel
7.  Final results of a phase I/II pilot study of capecitabine with or without vinorelbine after sequential dose-dense epirubicin and paclitaxel in high-risk early breast cancer 
BMC Cancer  2010;10:430.
Background
The integration of the non-cross-resistant chemotherapeutic agents capecitabine and vinorelbine into an intensified dose-dense sequential anthracycline- and taxane-containing regimen in high-risk early breast cancer (EBC) could improve efficacy, but this combination was not examined in this context so far.
Methods
Patients with stage II/IIIA EBC (four or more positive lymph nodes) received post-operative intensified dose-dense sequential epirubicin (150 mg/m² every 2 weeks) and paclitaxel (225 mg/m² every 2 weeks) with filgrastim and darbepoetin alfa, followed by capecitabine alone (dose levels 1 and 3) or with vinorelbine (dose levels 2 and 4). Capecitabine was given on days 1-14 every 21 days at 1000 or 1250 mg/m2 twice daily (dose levels 1/2 and 3/4, respectively). Vinorelbine 25 mg/m2 was given on days 1 and 8 of each 21-day course (dose levels 2 and 4).
Results
Fifty-one patients were treated. There was one dose-limiting toxicity (DLT) at dose level 1. At dose level 2 (capecitabine and vinorelbine), five of 10 patients experienced DLTs. Therefore evaluation of vinorelbine was abandoned and dose level 3 (capecitabine monotherapy) was expanded. Hand-foot syndrome and diarrhoea were dose limiting with capecitabine 1250 mg/m2 twice daily. At 35.2 months' median follow-up, the estimated 3-year relapse-free and overall survival rates were 82% and 91%, respectively.
Conclusions
Administration of capecitabine monotherapy after sequential dose-dense epirubicin and paclitaxel is feasible in node-positive EBC, while the combination of capecitabine and vinorelbine as used here caused more DLTs.
Trial registration
Current Controlled Trials ISRCTN38983527.
doi:10.1186/1471-2407-10-430
PMCID: PMC2928799  PMID: 20712886
8.  A randomised study of carboplatin vs sequential ifosfamide/carboplatin for patients with FIGO stage III epithelial ovarian carcinoma. The London Gynaecologic Oncology Group. 
British Journal of Cancer  1993;68(6):1190-1194.
In a study designed to compare response rates of patients with stage III epithelial ovarian carcinoma to ifosfamide and carboplatin, 152 patients were randomised to receive either sequential therapy with three cycles of ifosfamide followed by three cycles of carboplatin, or to six cycles of single agent carboplatin. Ifosfamide was given every 3 weeks in a dose of 5 gm m-2 as a 24 h infusion with mesna, 1 gm m-2 by i.v. bolus prior to ifosfamide, 3 gm m-2 with ifosfamide, and 1 gm m-2 as an 8 h infusion after ifosfamide. Carboplatin was given in a dose of 400 mg m-2 by short i.v. infusion every 4 weeks. Sixty-eight evaluable patients were randomised to sequential ifosfamide/carboplatin, and 67 to single agent carboplatin. Median follow-up is 36 months (range 5.5-82.3). After three cycles of treatment two patients in the ifosfamide/carboplatin arm achieved complete remission (CR), and 12 partial remission (PR) for an overall response rate of 29%, whereas in the carboplatin arm ten patients achieved CR, and 23 PR, for an overall response rate of 63% (P = 0.0008). Seven of 15 patients with progressive disease, and nine of 20 patients with stable disease at the initial response evaluation, following three cycles of ifosfamide, subsequently responded to carboplatin therapy so that the final response rate to the complete regimen was 65% for the ifosfamide/carboplatin arm, compared to 71% for the carboplatin arm (NS). For the ifosfamide/carboplatin arm, median recurrence free survival and overall survival were 14.1 months and 18.7 months. Corresponding figures for the carboplatin arm were 14.5 months and 21.5 months (NS). Both treatments were generally well tolerated. However 47% of patients in the ifosfamide/carboplatin arm developed alopecia sufficient to require a wig, compared to only 2% in the carboplatin arm. Ifosfamide is clearly less effective, and more toxic than carboplatin. Ifosfamide failures can however be effectively salvaged by subsequent carboplatin treatment. Ifosfamide cannot be recommended for single agent therapy in ovarian carcinoma, however the combination of carboplatin plus ifosfamide might be a suitable treatment to be tested in a future randomised study against carboplatin alone.
PMCID: PMC1968655  PMID: 8260372
9.  A phase I pharmacokinetic and pharmacodynamic study of BGC9331 and carboplatin in relapsed gynaecological malignancies 
British Journal of Cancer  2005;93(8):868-875.
BGC9331 is a rationally designed, specific nonpolyglutamatable thymidylate synthase (TS) inhibitor that is active in gynaecological malignancies. In the light of the sensitivity of human ovarian tumour cell lines to BGC9331 and non-cross resistance to platinum drugs, we studied the combination BGC9331/carboplatin (BCA) in a phase I (PI) pharmacokinetic (PK) and pharmacodynamic (PD) study in platinum pretreated gynaecological malignancies. Patients were ⩾18 years or over, with a histologically confirmed gynaecological malignancy, radiological evidence of relapse, and a platinum treatment free interval of at least 6 months. Up to three prior lines of chemotherapy were permitted. Carboplatin (AUC5) and BGC9331 were administered on day 1, and BGC9331 was also given on day 8 of a 21-day cycle. In total, 14 patients were enrolled, and treated with BGC9331 at four dose levels, 40, 65, 85 and 100 mg m−2. The principal grade 3 and 4 haematological toxicity was neutropaenia. The principal nonhaematological toxicities were lethargy and nausea. Dose-limiting toxicities were seen in two patients at 100 mg m−2 BGC9331 (grade 4 neutropaenia >7 days, and grade 4 fatigue >7 days). Plasma BGC9331 was measured by an ELISA that was adapted for use in humans. Carboplatin was assayed by flameless atomic absorption spectrometry. There was no PK interaction between the two drugs. Plasma deoxyuridine was elevated indicating TS inhibition to at least day 12. Antitumour activity was observed in four out of 14 (28%) of patients. In conclusion, the combination of BGC9331 and carboplatin is well tolerated with no significant PK interaction between the two drugs. There is evidence of TS inhibition with the combination. We have demonstrated antitumour activity in platinum pretreated gynaecological malignancy. Further exploration of this combination in this disease is warranted.
doi:10.1038/sj.bjc.6602811
PMCID: PMC2361661  PMID: 16222320
10.  Phase I trial of GTI-2040, oxaliplatin, and capecitabine in the treatment of advanced metastatic solid tumors: a California Cancer Consortium Study 
Cancer chemotherapy and pharmacology  2009;64(6):1149-1155.
Background
GTI-2040 is a 20-mer antisense oligonucleotide targeting the mRNA of ribonucleotide reductase M2. It was combined with oxaliplatin and capecitabine in a phase I trial in patients with advance solid tumors based on previous studies demonstrating potentiation of chemotherapy with ribonucleotide reductase inhibitors.
Methods
Patients at least 18 years of age with advanced incurable solid tumors and normal organ function as well as a Karnofsky performance status of ≥60% were eligible. One prior chemotherapy regimen for advanced disease or relapse within 12 months of adjuvant chemotherapy was required. Patients could have received prior fluoropyrimidines, including capecitabine, but not oxaliplatin. Treatment cycles were 21 days. In each cycle, GTI-2040 was given as a continuous intravenous infusion over 14 days, oxaliplatin as a 2-h intravenous infusion on day 1, and capecitabine orally twice a day for 14 days. In cycle 1 only, oxaliplatin and capecitabine were started on day 2 to allow ribonucleotide reductase mRNA levels to be measured with and without oxaliplatin and capecitabine. Doses were escalated in cohorts of three patients using a standard 3 + 3 design until the maximum tolerated dose was established, defned as no more than one first-cycle dose-limiting toxicity among six patients treated at a given dose level.
Results
The maximum tolerated dose was estimated to be the combination of GTI-2040 3 mg/kg per day for 14 days, capecitabine 600 mg/m2 twice daily for 14 days, and oxaliplatin 100 mg/m2 every 21 days. Dose-limiting toxicities were hematologic. GTI-2040 pharmacokinetics, obtained at steady-state on days 7 and 14, showed the high inter-patient variability previously reported. Two of six patients had stable disease at the maximum tolerated dose and one patient, with heavily pre-treated non-small cell lung cancer, had a partial response at a higher dose level. In samples from a limited number of patients, there was no clear decrease in ribonucleotide reductase expression in peripheral blood mononuclear cells during treatment.
Conclusion
A combination of GTI-2040, capecitabine and oxaliplatin is feasible in patients with advanced solid tumors.
doi:10.1007/s00280-009-0977-x
PMCID: PMC3046108  PMID: 19322566
GTI-2040; Oxaliplatin; Capecitabine; Ribonucleotide reductase; Pharmacokinetics
11.  Phase II Trial of Simple Oral Therapy with Capecitabine and Cyclophosphamide in Patients with Metastatic Breast Cancer: SWOG S0430 
The Oncologist  2012;17(2):179-187.
A simple oral combination of capecitabine and cyclophosphamide for the treatment of patients with metastatic breast cancer was evaluated. The addition of cyclophosphamide did not result in outcomes superior to those seen with capecitabine alone.
Learning Objectives:
After completing this course, the reader will be able to: Compare outcomes in patients treated with capecitabine plus CPA with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone.Identify patients for whom single-agent capecitabine is recommended.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
Interest in oral agents for the treatment of metastatic breast cancer (MBC) has increased because many patients prefer oral to i.v. regimens. We evaluated a simple oral combination of capecitabine with cyclophosphamide (CPA) for MBC.
Methods.
The trial was designed to determine whether or not combination therapy would achieve a 42% response rate (RR) using the Response Evaluation Criteria in Solid Tumors (RECIST) in MBC. Patients with two or fewer prior chemotherapy regimens for MBC were eligible. Those with estrogen receptor–positive MBC had to have progressed on endocrine therapy. Patients had measurable disease or elevated mucin (MUC)-1 antigen and received CPA, 100 mg daily on days 1–14, and capecitabine, 1,500 mg twice daily on days 8–21, in 21-day cycles.
Results.
In 96 eligible patients, the median progression-free survival (PFS) interval was 5.9 months (95% confidence interval [CI], 3.7–8.0 months) and median overall survival (OS) time was 18.8 months (95% CI, 13.1–22.0 months). The RR was 36% (95% CI, 26%–48%) in 80 patients with measurable disease. The MUC-1 antigen RR was 33% (95% CI, 20%–48%), occurring in 15 of 46 patients with elevated MUC-1 antigen. Toxicity was mild, with no treatment-related deaths.
Conclusions.
PFS, OS, and RR outcomes with capecitabine plus CPA compare favorably with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone. The addition of these other agents to capecitabine does not improve OS time in MBC patients, and this single-arm study does not suggest that the addition of CPA to capecitabine has this potential in an unselected MBC population. When OS prolongation is the goal, clinicians should choose single-agent capecitabine.
doi:10.1634/theoncologist.2011-0235
PMCID: PMC3286166  PMID: 22267853
Metastatic breast cancer; Capecitabine; Cyclophosphamide; Oral therapy
12.  Accelerated cisplatin and high-dose epirubicin with G-CSF support in patients with relapsed non-small-cell lung cancer: feasibility and efficacy 
British Journal of Cancer  2001;85(10):1456-1461.
The purpose of this study is to determine whether it is feasible to administer high-dose epirubicin (135 mg m−2) combined with a fixed dose of cisplatin every 2 weeks with G-CSF support in patients with metastatic non-small-cell lung cancer (NSCLC). Subsequently, the efficacy of the recommended dose of this regimen was tested in a phase II study in patients with relapsed NSCLC. In the initial feasibility study at least 6 patients were entered at each of the 4 dose levels tested. A fixed dose of cisplatin 60 mg m−2was given. Epirubicin was administered at 120 mg m−2on dose level 1, 135 mg m−2on dose level 2 and 3 and 135 mg m−2on dose level 4. Patients treated at dose level 3 and 4 received G-CSF support on days 3–12. Cycles were repeated every 3 weeks on the first 3 dose levels and every 2 weeks on the fourth dose level. A total of 27 patients were then treated on dose level 4, which appeared to be feasible in the initial study. In the initial study, a total of 86 courses were administered. Haematological toxicity was the principal side effect. None of the patients encountered dose-limiting toxicity in the first course, which confirmed that epirubicin 135 mg m−2could be combined with cisplatin 60 mg m−2and accelerated by G-CSF support to a 14-day-schedule. In the subsequent phase II study with this schedule, 89 courses were administered. The relative dose intensity of cisplatin and epirubicin was 0.90 and 0.91, respectively. Myelosuppression was frequent with 70% and 63% of patients experiencing WHO grade III or IV leukocytopenia and thrombocytopenia, respectively. 6 cases of febrile neutropenia were observed, with 2 treatment-related deaths. Non-haematological toxicity consisted mainly of nausea and vomiting, which was grade III in 22% of patients. Renal toxicity grade I and II occurred in 37% and 4% of patients, respectively. 55% of these patients had received prior cisplatin-containing chemotherapy. On an intention-to-treat basis 9 partial responses were recorded in 27 patients (33%; 95% confidence interval, 15%–51%). Accelerated cisplatin and high-dose epirubicin with G-CSF support is a feasible and promising regimen in relapsed NSCLC. Myelosuppression limits the use of this regimen in the second-line setting to a selected group of patients with a good performance status. Since the activity of this regimen is encouraging, it is probably best studied in untreated patients.© 2001 Cancer Research Campaign  http://www.bjcancer.com
doi:10.1054/bjoc.2001.2013
PMCID: PMC2363962  PMID: 11720428
non-small-cell lung cancer; chemotherapy; second-line; cisplatin; epirubicin
13.  RANDOMIZED TRIAL OF PEGYLATED LIPOSOMAL DOXORUBICIN (PLD) PLUS CARBOPLATIN VERSUS CARBOPLATIN IN PLATINUM-SENSITIVE (PS) PATIENTS WITH RECURRENT EPITHELIAL OVARIAN OR PERITONEAL CARCINOMA AFTER FAILURE OF INITIAL PLATINUM-BASED CHEMOTHERAPY (SOUTH WEST ONCOLOGY GROUP PROTOCOL S0200) 
Gynecologic oncology  2007;108(1):90-94.
Objective
Because debate continues over the role of combination, platinum-based chemotherapy for platinum sensitive (PS), recurrent ovarian cancer (OC), we compared overall survival (OS), progression-free survival (PFS), confirmed complete response rate and time to treatment failure in this population.
Methods
Patients with recurrent stage III or IV OC, a progression-free and platinum-free interval of 6- 24 months after first-line platinum-based chemotherapy and up to 12 courses of a non-platinum containing consolidation treatment were eligible. Patients were randomized to IV pegylated liposomal doxorubicin (PLD) (30 mg/m2) plus IV carboplatin (AUC=5 mg/mL × min) once every 4 weeks (PLD arm) or IV carboplatin alone (AUC=5mg/mL × min) once every 4 weeks.
Results
The PLD arm enrolled 31 patients and the carboplatin alone arm 30 for a total of 61 patients out of 900 planned. Response rates were 67% for the PLD arm and 32% for the carboplatin only arm (Fisher’s exact p=0.02). The estimated median PFS was 12 and 8 months for PLD versus carboplatin alone. The estimated median OS on the PLD arm was 26 months and 18 months on the carboplatin only arm (p=0.02). Twenty-six percent of the patients on the PLD arm reported grade 4 toxicities, all hematological in nature.
Conclusion
This study was closed early because of slow patient accrual. The response rate, median PFS and OS results are intriguing. These data suggest that there may be an advantage to the PLD plus carboplatin combination treatment in patients with PS, recurrent OC. The regimen should be further tested.
doi:10.1016/j.ygyno.2007.08.075
PMCID: PMC2276605  PMID: 17949799
14.  Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial 
The Lancet Oncology  2013;14(6):481-489.
Summary
Background
EGFR overexpression occurs in 27–55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma.
Methods
In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1–21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1, capecitabine 1000 mg/m2 per day on days 1–21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785.
Findings
Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6–13·0) compared with 8·8 months (7·7–9·8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1·37, 95% CI 1·07–1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3–4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥3 neutropenia 35 [13%] vs 74 [28%]).
Interpretation
Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma.
Funding
Amgen, UK National Institute for Health Research Biomedical Research Centre.
doi:10.1016/S1470-2045(13)70096-2
PMCID: PMC3669518  PMID: 23594787
15.  Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer 
Introduction
Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. Combination of everolimus also known as RAD001 (oral mammalian target of rapamycin (mTOR) inhibitor) and carboplatin may have activity in metastatic triple-negative breast cancer (TNBC).
Methods
The primary objective of this study was to determine clinical benefit rate (CBR), that is (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting ≥6 months) and the toxicity of everolimus/carboplatin in women with metastatic TNBC. Prior carboplatin was allowed. Treatment consisted of intravenous carboplatin area under the curve (AUC) 6 (later decreased to AUC 5 and subsequently to AUC 4) every 3 weeks with daily 5 mg everolimus.
Results
We enrolled 25 patients in this study. Median age was 58 years. There were one CR, six PRs, seven SDs and eight PDs (progression of disease). CBR was 36% (95% confidence interval (CI) 21.1 to 57.4%). One SD was achieved in a patient progressing on single agent carboplatin. The median progression free survival (PFS) was 3 months (95% CI 1.6 to 4.6 months) and overall survival (OS) was 16.6 months (95% CI 7.3 months to not reached). There were seven patients (28%) with ≥ grade 3 thrombocytopenia; three (12%) with grade 3 neutropenia (no bleeding/febrile neutropenia) and one (4%) with grade 3 anemia. Greater hematological toxicity was seen in the first seven patients treated with carboplatin AUC5/6. After the amendment for starting dose of carboplatin to AUC 4, the regimen was well tolerated with only one out of 18 patients with grade 3 neutropenia and two patients with grade 3 thrombocytopenia. There was only one case of mucositis.
Conclusion
Everolimus-carboplatin was efficacious in metastatic TNBC. Dose limiting hematological toxicity was observed when AUC5/6 of carboplatin was combined with everolimus. However, carboplatin AUC 4 was well tolerated in combination with everolimus with continuing responses.
Trial registrations
ClinicalTrials.gov NCT01127763.
doi:10.1186/bcr3634
PMCID: PMC4053575  PMID: 24684785
16.  A phase 3 tRial comparing capecitabinE in combination with SorafenIb or pLacebo for treatment of locally advanced or metastatIc HER2-Negative breast CancEr (the RESILIENCE study): study protocol for a randomized controlled trial 
Trials  2013;14:228.
Background
Sorafenib is an oral multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized phase 2b screening trial in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer demonstrated a significant improvement in progression-free survival (PFS) when sorafenib was added to capecitabine versus placebo (median 6.4 versus 4.1 months; hazard ratio = 0.58; P = 0.001). Most drug-related adverse events were Grade 1/2 in severity with the exception of Grade 3 hand-foot skin reaction/syndrome (44% versus 14%, respectively). These results suggest a role for the combination of sorafenib and capecitabine in breast cancer and supported a phase 3 confirmatory trial. Here we describe RESILIENCE - a multinational, double-blind, randomized, placebo-controlled, phase 3 trial - assessing the addition of sorafenib to first- or second-line capecitabine in advanced HER2-negative breast cancer.
Methods/design
Eligibility criteria include ≥18 years of age, ≤1 prior chemotherapy regimen for metastatic disease, and resistant to/failed taxane and anthracycline or no indication for further anthracycline. Prior treatment with a vascular endothelial growth factor inhibitor is not allowed. Patients with significant cardiovascular disease or active brain metastases are not eligible. Patients are stratified by hormone-receptor status, geographic region, and prior metastatic chemotherapy status and randomized (1:1) to capecitabine (1000 mg/m2 orally twice daily (BID), days 1 to 14 of 21) in combination with sorafenib (orally BID, days 1 to 21, total dose 600 mg/day) or matching placebo. Capecitabine and sorafenib/placebo doses can be escalated to 1250 mg/m2 BID and 400 mg BID, respectively, as tolerated, or reduced to manage toxicity. Dose re-escalation after a reduction is allowed for sorafenib/placebo but not for capecitabine. This dosing algorithm was designed to mitigate dermatologic and other toxicity, in addition to detailed guidelines for prophylactic and symptomatic treatment. Radiographic assessment is every 6 weeks for 36 weeks, and every 9 weeks thereafter. The primary endpoint is PFS by blinded independent central review (Response Evaluation Criteria in Solid Tumors 1.1 criteria). Secondary endpoints include overall survival, time to progression, overall response rate, duration of response, and safety. Enrollment began in November 2010 with a target of approximately 519 patients.
Discussion
RESILIENCE will provide definitive PFS data for the combination of sorafenib and capecitabine in advanced HER2-negative breast cancer and better characterize the benefit-to-risk profile.
Trial registration
Clinicaltrials.gov, NCT01234337
doi:10.1186/1745-6215-14-228
PMCID: PMC3724697  PMID: 23876062
Metastatic breast cancer; Sorafenib; Capecitabine
17.  Ixabepilone as Monotherapy or in Combination with Capecitabine for the Treatment of Advanced Breast Cancer 
Breast Cancer is the most prevalent cancer in the world with 4.4 million survivors up to 5 years following the diagnosis.1 In the US alone approximately forty thousand women die annually of metastatic breast cancer (MBC). Despite many effective systemic treatment options approximately 50% of women with MBC succumb to the disease within 24 months of the diagnosis.2 Ixabepilone is a novel, first in class member of the epothilone class of antineoplastic agents. Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and Capecitabine. Ixabepilone is also indicated in combination with Capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Ixabepilone was extensively studied as a single agent in patients with MBC and was found to be effective and well tolerated with a predictable and manageable safety profile. Not surprisingly prior exposure to anthracyclines and taxanes affects significantly the potential for response to therapy with single agent Ixabepilone in metastatic setting. MBC patients with taxane resistant MBC have objective response rate (RR) of 12%, patients with prior low exposure to taxanes and/or resistance RR = 22%, Ixabepilone treatment after adjuvant anthracycline therapy exposure renders RR = 42% and in Taxane naïve patients RR = 57%. In two large phase III studies of Ixabepilone + Capecitabine versus Capecitabine alone, progression free survival (PFS) and overall response rates (RR) were higher in the combination treatment arms, but no survival advantage was seen overall. Treatment with Ixabepilone + Capecitabine in a phase II study resulted in an overall response rate (ORR) of 23% in ER/PR/HER2 negative, triple-negative breast cancer patients (TNBC) while ORR of 31% was seen in a preplanned pooled analysis of TNBC in the phase III trials of Ixabepilone + Capecitabine. Significantly prolonged median PFS was seen for TNBC treated with the combination of Ixabepilone + Capecitabine compared to Capecitabine alone 4.2 vs. 1.7 months respectively. Ixabepilone as single agent appears to show excellent antitumor activity in patients with TNBC MBC. Addition of Ixabepilone to Capecitabine results in approximately doubling in median PFS for TNBC versus Capecitabine alone. Single agent Ixabepilone is generally well tolerated, and its toxicity profile does not overlap with that of Capecitabine and therefore depending on prior exposure to chemotherapy both single agent Ixabepilone or in combination with Capecitabine can be used safely and effectively for treatment of advanced breast cancer.
doi:10.4137/BCBCR.S5331
PMCID: PMC3076013  PMID: 21494397
Ixabepilone; metastatic breast cancer; monotherapy; in combination with capecitabine; triple negative breast cancer
18.  First-line chemotherapy with docetaxel plus capecitabine followed by capecitabine or hormone maintenance therapy for the treatment of metastatic breast cancer patients 
Oncology Letters  2014;9(2):987-993.
The primary aim of the present study was to evaluate whether maintenance therapy with capecitabine or hormone replacement therapy (HRT) results in improved progression-free survival (PFS) in metastatic breast cancer (MBC) patients who had previously achieved disease control with first-line docetaxel plus capecitabine (TX) chemotherapy. Seventy-nine metastatic breast cancer patients treated between January 2008 and June 2013 with TX chemotherapy were retrospectively analyzed. Following successful initial disease control by the combination chemotherapy, 39 patients received single-agent capecitabine maintenance therapy and 40 patients received HRT as maintenance therapy. The PFS time, objective response rate, clinical benefit rate and safety of the two groups were compared. The median PFS of the total cohort (n=79) was 11.0 months. Furthermore, the median PFS time of the capecitabine (n=39) and HRT groups (n=40) were 10.9 and 11.1 months, respectively (P=0.283). Compared with the PFS time of maintenance treatment only, single-agent capecitabine treatment following TX chemotherapy prolonged the PFS time by 6.8 months and HRT following TX chemotherapy prolonged PFS time by 5.8 months (P=0.551). Of the total cohort, 49 patients did not receive palliative endocrine therapy prior to chemotherapy, including 22 patients in the capecitabine maintenance group and 27 patients in the HRT maintenance group. The PFS time from the commencement of maintenance treatment was significantly different between the two groups, 6.1 months in the capecitabine group compared with 11.5 months in the HRT group (P=0.045). For the 30 patients who underwent palliative endocrine therapy prior to TX chemotherapy, the PFS times of the capecitabine and HRT maintenance treatment groups were 7.5 and 4.1 months, respectively (P=0.043). However, the occurrence of adverse events, such as hematological and gastrointestinal toxicity, as well as hand-foot syndrome, were not significantly different between the two groups. The current study indicated that single-agent capecitabine maintenance therapy may be a potential treatment strategy for MBC patients who responded to capecitabine-based chemotherapy. In particular, capecitabine may provide a more effective maintenance treatment duration compared with HRT for patients who had previously undergone first-line palliative HRT for MBC.
doi:10.3892/ol.2014.2787
PMCID: PMC4301516  PMID: 25621076
capecitabine; maintenance therapy; docetaxel; metastatic breast cancer
19.  A phase II trial of preoperative chemotherapy with epirubicin, cisplatin and capecitabine for patients with localised gastro-oesophageal junctional adenocarcinoma 
British Journal of Cancer  2009;100(11):1725-1730.
Preoperative cisplatin/fluorouracil is used for the treatment of localised oesophageal carcinoma. This phase II study aimed to assess the efficacy and safety of administering preoperative epirubicin/cisplatin/capecitabine (ECX). Patients with stage II or III oesophageal/gastro-oesophageal junctional adenocarcinoma from one institution received 4 cycles of ECX (epirubicin 50 mg m−2 day 1, cisplatin 60 mg m−2 day 1, capecitabine 625 mg m−2 b.i.d. daily) followed by surgery. The primary end point was the pathological complete response (pCR) rate based on a Simon two-stage design. Secondary end points included overall and progression-free survival (OS/PFS). Thirty-four patients were recruited: median age 60 years (range 41–81), 91% male, 97% PS 0/1, 80% T3, 68% N1. Thirty-one patients completed four ECX cycles. Grade 3/4 toxicities ⩾5% included neutropenia (62%), hand–foot syndrome (15%) and nausea/vomiting (9%). Thirteen out of 28 (46%) evaluable patients responded to chemotherapy by EUS (⩾30% reduction in maximal tumour thickness). Twenty-six out of 34 (76%) patients underwent resection (R0=73%, R1=27%). Post-operatively, two patients died within 60 days of surgery. The pCR rate was 5.9% (95% CI 0–14%) in the intent-to-treat population. According to the statistical design, this prompted early study termination. However, with a median follow-up of 34 months the median OS and 1- and 2-year survival rates were 17 months, 67 and 39% respectively. Median PFS was 13 months. Of the 14 relapsed patients, 10 presented with distant metastases. Preoperative ECX is feasible and well tolerated. Although associated with a low pCR rate, survival with ECX was comparable with published studies suggesting that pCR may not correlate with satisfactory outcome from preoperative chemotherapy for localised oesophageal adenocarcinoma.
doi:10.1038/sj.bjc.6605070
PMCID: PMC2695693  PMID: 19436301
oesophageal adenocarcinoma; preoperative chemotherapy; pathological complete response
20.  Role of Farletuzumab in Epithelial Ovarian Carcinoma 
Current pharmaceutical design  2012;18(25):3812-3815.
Epithelial ovarian cancer (EOC) is the most lethal of the gynecologic malignancies, largely due to the advanced stage at diagnosis in most patients. Standard treatment for EOC is surgical debulking followed by platinum-based chemotherapy. While the majority of ovarian cancer patients will respond to initial chemotherapy, most will ultimately relapse. The major focus of current clinical trials for treatment of recurrent ovarian cancer is the use of targeted biologic agents.
Folate receptor alpha (FRα) is upregulated in majority of EOC and correlated with tumor stage and grade. It is hypothesized that the presence of overexpressed FRα correlates with the propagation rate of the tumors. FRα is largely absent from normal tissue, making it an attractive therapeutic target. Farletuzumab (MORAb-003), a humanized monoclonal antibody against FRα, has shown antitumor activity in preclinical xenograft models. A Phase 1 dose escalation study did not demonstrate dose-limiting toxicities, or severe adverse effects. A phase 2 efficacy and safety study of farletuzumab with carboplatin and taxane in patients with platinum-sensitive EOC in first relapse, have shown an improved response rate and time to progression compared with historical controls. Recently, preliminary safety data from a phase 1 trial reported that the combination of farletuzumab, carboplatin and PLD has an acceptable safety profile in patients with platinum-sensitive EOC following first or second relapse.
Two randomized, double-blind, placebo-controlled Phase 3 studies with farletuzumab plus chemotherapy have been done. A trial of: farletuzumab with weekly paclitaxel in platinum-resistant EOC closed in December 2011 with full report pending. A second trial of farletuzumab with carboplatin and taxane in platinum-sensitive EOC in first relapse is slated to complete accrual in early 2012. Results from these trials will help define the role of farletuzumab in EOC.
PMCID: PMC3576870  PMID: 22591419
farletuzumab; epithelial ovarian cancer
21.  Oral fluoropyrimidines among the new drugs for patients with metastatic breast cancer 
British Journal of Cancer  2001;84(11):1437-1442.
Although drugs such as the taxoids and vinorelbine have increased the options available for anthracycline-resistant metastatic breast cancer, new therapeutic options are needed, particularly for taxoid-refractory tumours. Increasing emphasis is being placed on the development of oral agents, which many patients prefer provided efficacy is not compromised, particularly if the oral agents are less toxic than current intravenous agents. Capecitabine, a new, oral fluoropyrimidine, mimics continuous infusion 5-FU and is activated preferentially at the tumour site. Phase II studies of capecitabine have demonstrated encouraging response rates in patients with few further treatment options (20% response with an additional 43% achieving stable disease in paclitaxel-refractory patients; 36% response with a further 23% achieving stable disease in anthracycline-refractory patients). In addition, a randomized, phase II trial demonstrated a response rate of 30% (95% Cl: 19–43%) with capecitabine as first-line treatment for metastatic breast cancer, compared with 16% (95% Cl: 5–33%) in patients receiving low-dose CMF. These trials also showed that capecitabine has a favourable safety profile typical of infused fluoropyrimidines. Both alopecia and myelosuppression were rare. Capecitabine may therefore provide an effective, well-tolerated and convenient alternative to intravenous cytotoxic agents, not only in taxoid-resistant patients, but also in anthracycline-resistant metastatic breast cancer or as first-line therapy. Furthermore, the low incidence of myelosuppression makes capecitabine an attractive agent for incorporation into combination regimens with agents such as epirubicin/doxorubicin, the taxoids and vinorelbine. © 2001 Cancer ResearchCampaign http://www.bjcancer.com
doi:10.1054/bjoc.2001.1819
PMCID: PMC2363663  PMID: 11384089
breast cancer; anthracyclines; capecitabine; 5-FU; taxoids; vinorelbine; oral
22.  Advanced Gastric Cancer: An Update and Future Directions 
Gastrointestinal Cancer Research : GCR  2008;2(4 Suppl 2):S47-S53.
Gastric cancer is a common malignancy worldwide with a high mortality rate. Multiple single agents have produced response rates ranging from 5% to 45% in patients with metastatic gastric cancer. Combination chemotherapy regimens with two or three agents have more than doubled survivorship compared with best supportive care. Recent clinical trials include the evaluation of docetaxel, cisplatin, and 5-fluorouracil (5-FU), showing a survival advantage compared with cisplatin and 5-FU, although with high rates of toxicity, particularly neutropenia and neutropenic fever. The REAL-2 trial evaluated epirubicin and cisplatin with either infusional 5-FU (ECF) or capecitabine (ECX), and epirubicin and oxaliplatin with either infusional 5-FU (EOF) or capecitabine (EOX); results favored the EOX regimen. Oxaliplatin-containing triplets appear to have a favorable safety profile compared with cisplatin-containing triplets. Additional randomized data are available for the oral fluoropyrimidine, S-1. In a randomized trial comparing 5-FU vs. irinotecan plus cisplatin vs. S-1, conducted by the Japan Clinical Oncology Group, S-1 was associated with a favorable safety profile, response rate, and time-to-treatment failure with longer survival compared with 5-FU. The Japanese SPIRITS trial was a phase III comparison of S-1 vs. S-1 plus cisplatin and showed favorable 1- and 2-year survivals and a progression-free survival advantage for S-1 and cisplatin. Cooperative group strategies are evaluating the role of chemotherapy combinations, including cisplatin and docetaxel with biologic agents. In addition, there is interest in developing oxaliplatin-based combinations. The expanding list of potential molecular markers for gastric cancer may provide the opportunity to better understand the biology of the disease and to develop new treatment strategies.
PMCID: PMC2661550  PMID: 19343150
23.  Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS) 
BMC Cancer  2011;11:329.
Background
Radical surgery is the cornerstone in the treatment of resectable gastric cancer. The Intergroup 0116 and MAGIC trials have shown benefit of postoperative chemoradiation and perioperative chemotherapy, respectively. Since these trials cannot be compared directly, both regimens are evaluated prospectively in the CRITICS trial. This study aims to obtain an improved overall survival for patients treated with preoperative chemotherapy and surgery by incorporating radiotherapy concurrently with chemotherapy postoperatively.
Methods/design
In this phase III multicentre study, patients with resectable gastric cancer are treated with three cycles of preoperative ECC (epirubicin, cisplatin and capecitabine), followed by surgery with adequate lymph node dissection, and then either another three cycles of ECC or concurrent chemoradiation (45 Gy, cisplatin and capecitabine). Surgical, pathological, and radiotherapeutic quality control is performed. The primary endpoint is overall survival, secondary endpoints are disease-free survival (DFS), toxicity, health-related quality of life (HRQL), prediction of response, and recurrence risk assessed by genomic and expression profiling. Accrual for the CRITICS trial is from the Netherlands, Sweden, and Denmark, and more countries are invited to participate.
Conclusion
Results of this study will demonstrate whether the combination of preoperative chemotherapy and postoperative chemoradiotherapy will improve the clinical outcome of the current European standard of perioperative chemotherapy, and will therefore play a key role in the future management of patients with resectable gastric cancer.
Trial registration
clinicaltrials.gov NCT00407186
doi:10.1186/1471-2407-11-329
PMCID: PMC3175221  PMID: 21810227
24.  Phase 2 Trial of Paclitaxel Polyglumex with Capecitabine for Metastatic Breast Cancer 
American journal of clinical oncology  2012;10.1097/COC.0b013e31826e0550.
Background
Capecitabine and paclitaxel are established effective treatments, alone and combined with other cytotoxic and targeted agents, for metastatic breast cancer (MBC). Paclitaxel polyglumex (a macromolecular conjugate of paclitaxel bound to poly-L-glutamic acid) has potential advantages over conventional paclitaxel, including little alopecia, short infusion time with no premedication, enhanced tumor permeability/retention effect, and improved tolerability. We therefore examined tolerability & efficacy of paclitaxel polyglumex with capecitabine in patients with MBC.
Patients and Methods
This was a single stage phase 2 study, with interim analysis conducted with endpoints of tumor response, adverse events (toxicities), time to progression & overall survival. The main eligibility criteria were: age >18, no prior MBC chemotherapy, ECOG performance score <2, disease measurable by RECIST criteria, no HER2 overexpression or amplification, no brain metastases or peripheral sensory neuropathy. Treatment consisted of paclitaxel polyglumex 135 mg/m2 by intravenous infusion on day 1 + capecitabine 825 mg/m2 orally twice daily days 1 - 14, repeated on a 3-week cycle. Forty one (41) evaluable patients were required to test null hypothesis that complete and partial tumor response rate (CR + PR) was at most 40% against the alternative of at least 60%. Paclitaxel polyglumex + capecitabine would be considered promising in this population if ≥21 responses were observed among first 41 evaluable patients.
Results
48 patients were enrolled between April 2006 - April 2007; all patients were evaluable. The median cycles administered was 6. Eighteen (18) patients (38%; 95% CI: 24-53%) had a confirmed tumor response (2 CR, 16 PR) by RECIST criteria. Fifteen (15; 38%, 95% CI: 23%-53%) responses occurred in first 41 patients, falling short of prespecified goal of 21 responses. Median duration of tumor response was 13.2 months. Three of the responders were progression free at last follow-up with a median follow-up of 43 months. Median progression-free survival was 5.1 months (95% CI: 4.0-7.6 months). Six-month progression free survival was 42% (95% CI: 30-58%). Median dose level administered = 135 mg/m2 paclitaxel polyglumex, 825 mg/m2 capecitabine for cycles 1-7. Most common severe (grade 3/4) toxicities (at least possibly related to study drug) were: leukopenia 9 (19%), neutropenia 8 (17%), neuro-sensory 4 (8%), skin reaction-hand/foot 4 (8%), dyspnea 2 (4%). Forrty-six% (22/47) of patients experienced a grade ≥3 toxicity and 8% (4/48) experienced a grade ≥4 toxicity. No alopecia was reported.
Conclusions
Although the trial failed to reach goal of 21 confirmed tumor responses among the first 41 evaluable patients, paclitaxel polyglumex and capecitabine is well tolerated and effective in MBC.
doi:10.1097/COC.0b013e31826e0550
PMCID: PMC3593738  PMID: 23211220
25.  A phase II study of biweekly dose-intensified oral capecitabine plus irinotecan (bXELIRI) for patients with advanced or metastatic gastric cancer 
British Journal of Cancer  2007;96(10):1514-1519.
Capecitabine, a prodrug of 5-FU, has been reported to generate maximal tumour activity at tumour sites and/or to improve drug tolerability as compared with 5-FU infusion, and it has also been demonstrated to act synergistically with irinotecan against some solid cancers. A previous study concluded that dose-intensified biweekly capecitabine seems to be more effective at increasing both response rate and progression-free survival time than conventional dose and schedule of capecitabine in colon cancer. We conducted this study to ascertain the efficacy and toxicity of dose-intensified biweekly capecitabine and irinotecan combination chemotherapy in chemotherapy-naïve advanced or metastatic gastric cancer patients. Patients were treated with irinotecan 130 mg m−2 intravenously for 90 min on days 1 and 15. Capecitabine at 3500 mg m−2 day−1, divided into two sessions per day, was administered for seven consecutive days from days 1 and 15, and followed by a 7-day drug-free period, respectively. Fifty-five eligible patients were enrolled in this study from November 2003 to April 2006. There were 22 women and 33 men: median patient age was 54 years (range: 27–81). A total of 200 treatment cycles were administered at a median number of four per patient (range: 1–9). Intent-to-treatment analysis showed that one patient achieved complete response (1.8%), 23 partial response (41.8%), 15 stable disease (27.3%), 10 progressive disease (18.2%) and 6 were non-evaluable (10.9%). The overall response rate was 43.6% (95% confidence interval: 30.2–56.9). The common grade 3–4 toxicities were neutropenia in 12 (21.8%), nausea/vomiting in 3 (5.4%) and diarrhea in 4 (7.2%) patients. Median time to progression was 5 months (range: 0.5–11 months), median survival duration was 11 months (range: 0.5–45 months) and median response duration was 6 months (range: 0.5–9 months). Biweekly dose-intensified capecitabine and irinotecan combination chemotherapy was active for the treatment of advanced or metastatic gastric cancers with a tolerable safety profile.
doi:10.1038/sj.bjc.6603752
PMCID: PMC2359951  PMID: 17473829
irinotecan; capecitabine; stomach neoplasms

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