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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.  Ovarian cancer (advanced) 
Clinical Evidence  2009;2009:0816.
Introduction
Ovarian cancer is the fourth most common cause of cancer deaths in the UK. The 5-year relative survival rate in the UK at diagnosis for women aged 15-39 years is nearly 70%. In comparison, it is only 12% for women diagnosed aged over 80 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of surgical treatments for ovarian cancer that is advanced at first presentation? What are the effects of platinum-based chemotherapy for ovarian cancer that is advanced at first presentation? What are the effects of taxane-based chemotherapy for ovarian cancer that is advanced at first presentation? What are the effects of intraperitoneal chemotherapy for ovarian cancer that is advanced at first presentation? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 31 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding taxanes to platinum-based chemotherapy, carboplatin plus a taxane, cisplatin plus a taxane, combination or single-agent platinum-based chemotherapy, docetaxel, intravenous and intraperitoneal chemotherapy, interval debulking, paclitaxel, primary surgery, and second-look surgery.
Key Points
Ovarian cancer is the fourth most common cause of cancer deaths in the UK. Incidence rises with age, and peaks in the seventh and eighth decades of life.Risk factors include family history of ovarian cancer, increasing age, and low parity. Risks are reduced by using the oral contraceptive pill for more than 5 years, tubal ligation, hysterectomy, breastfeeding, increased age at menarche, decreased age at menopause, and use of NSAIDs.In the UK, the 5-year relative survival rate at diagnosis for women aged 15-39 years is nearly 70%. In comparison, it is only 12% for women diagnosed over 80 years of age.
Standard treatment for advanced ovarian cancer is primary surgical debulking, followed by chemotherapy. We found no direct evidence on the effects of primary surgery versus no surgery, or primary surgery plus chemotherapy versus surgery or chemotherapy alone.Although we found no direct evidence, subgroup analysis comparing groups by the degree to which maximal surgical debulking was acheived or not, suggests that maximal surgical cytoreduction at primary surgery is strongly associated with improved survival in advanced ovarian cancer.Subsequent debulking and second-look surgery seem unlikely to improve survival, especially if initial surgery achieved optimal cytoreduction.
Platinum-based regimens are now standard first-line chemotherapy and have been shown to be beneficial in prolonging survival compared with non-platinum-based regimens. Platinum compounds seem to be the main beneficial agent, with little additional survival benefit from adding non-platinum (excluding taxanes) chemotherapeutic agents to platinum. Carboplatin is as effective as cisplatin in prolonging survival, but with less-severe adverse effects.
Taxanes may increase survival if added to platinum chemotherapy compared with platinum-based regimens alone, but studies have given conflicting results. One RCT suggests paclitaxel is as effective at prolonging survival as docetaxel when combined with a platinum drug.
Platinum-based chemotherapy can also be delivered directly into the intraperitoneal cavity, as well as by the intravenous route.
We found limited evidence that intraperitoneal platinum-based chemotherapy may increase survival compared with intravenous administration but at the cost of increased adverse effects, both those associated with the use of an intraperitoneal catheter and from increased doses of chemotherapy. Any benefit seen with intraperitoneal rather than intravenous administration may be due to different chemotherapy doses, rather than the route of administration.
Limited evidence suggests that consolidation treatment given intraperitoneally does not confer any survival benefit compared with no further treatment in women who have undergone primary surgery and chemotherapy and who have no disease at second-look laparotomy. However, consolidation treatment may be associated with increased adverse effects.
PMCID: PMC2907795  PMID: 19445772
3.  Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. Advanced Ovarian Cancer Trialists Group. 
BMJ : British Medical Journal  1991;303(6807):884-893.
OBJECTIVES--To consider the role of platinum and the relative merits of single agent and combination chemotherapy in the treatment of advanced ovarian cancer. DESIGN--Formal quantitative overview using updated individual patient data from all available randomised trials (published and unpublished). SUBJECTS--8139 patients (6408 deaths) included in 45 different trials. RESULTS--No firm conclusions could be reached. Nevertheless, the results suggest that in terms of survival immediate platinum based treatment was better than non-platinum regimens (overall relative risk 0.93; 95% confidence interval 0.83 to 1.05); platinum in combination was better than single agent platinum when used in the same dose (overall relative risk 0.85; 0.72 to 1.00); and cisplatin and carboplatin were equally effective (overall relative risk 1.05; 0.94 to 1.18). CONCLUSIONS--In the past, randomised clinical trials of chemotherapy in advanced ovarian cancer have been much too small to detect the degree of benefit which this overview suggests is realistic for currently available chemotherapeutic regimens. Hence a new trial comparing cisplatin, doxorubicin, and cyclophosphamide (CAP) with carboplatin has been launched and plans to accrue 2000 patients.
PMCID: PMC1671193  PMID: 1834291
4.  Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer 
Current Oncology  2010;17(3):37-48.
Question
What are the benefits associated with the use of anti–epidermal growth factor receptor (anti-egfr) therapies in squamous cell carcinoma of the head and neck (hnscc)? Anti-egfr therapies of interest included cetuximab, gefitinib, lapatinib, zalutumumab, erlotinib, and panitumumab.
Perspectives
Head-and-neck cancer includes malignant tumours arising from a variety of sites in the upper aerodigestive tract. The most common histologic type is squamous cell carcinoma, and most common sites are the oral cavity, the oropharynx, the hypopharynx, and the larynx. Worldwide, hnscc is the sixth most common neoplasm, and despite advances in therapy, long-term survival in hnscc patients is poor. Primary surgery followed by chemoradiation, or primary chemoradiation, are the standard treatment options for patients with locally advanced (stages iii–ivb) hnscc; however, meta-analytic data indicate that the benefit of concurrent platinum-based chemotherapy disappears in patients over the age of 70 years.
Cetuximab is a monoclonal antibody approved for use in combination with radiation in the treatment of patients with untreated locally advanced hnscc and as monotherapy for patients with recurrent or metastatic (stage ivc) hnscc who have progressed on platinum-based therapy.
Given the interest in anti-egfr agents in advanced hnscc, the Head and Neck Cancer Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) chose to systematically review the literature pertaining to this topic so as to develop evidence-based recommendations for treatment.
Outcomes
Outcomes of interest included overall and progression-free survival, quality of life, tumour response rate and duration, and the toxicity associated with the use of anti-egfr therapies.
Methodology
The medline, embase, and Cochrane Library databases, the American Society of Clinical Oncology online conference proceedings, the Canadian Medical Association InfoBase, and the National Guidelines Clearinghouse were systematically searched to locate primary articles and practice guidelines. The reference lists from relevant review articles were searched for additional trials. All evidence was reviewed, and that evidence informed the development of the clinical practice guideline. The resulting recommendations were approved by the Report Approval Panel of the pebc, and by the Head and Neck Cancer dsg. An external review by Ontario practitioners completed the final phase of the review process. Feedback from all parties was incorporated to create the final practice guideline.
Results
The electronic search identified seventy-four references that were reviewed for inclusion. Only four phase iii trials met the inclusion criteria for the present guideline. No practice guidelines, systematic reviews, or meta-analyses were found during the course of the literature search.
The randomized controlled trials (rcts) involved three distinct patient populations: those with locally advanced hnscc being treated for cure, those with incurable advanced recurrent or metastatic hnscc being treated with first-line platinum-based chemotherapy, and those with incurable advanced recurrent or metastatic hnscc who had disease progression despite, or who were unsuitable for, first-line platinum-based chemotherapy.
Practice Guideline
These recommendations apply to adult patients with locally advanced (nonmetastatic stages iii–ivb) or recurrent or metastatic (stage ivc) hnscc.
Platinum-based chemoradiation remains the current standard of care for treatment of locally advanced hnscc.
In patients with locally advanced hnscc who are medically unsuitable for concurrent platinumbased chemotherapy or who are over the age of 70 years (because concurrent chemotherapy does not appear to improve overall survival in this patient population), the addition of cetuximab to radical radiotherapy should be considered to improve overall survival, progression-free survival, and time to local recurrence.
Cetuximab in combination with platinum-based combination chemotherapy is superior to chemotherapy alone in patients with recurrent or metastatic hnscc, and is recommended to improve overall survival, progression-free survival, and response rate.
The role of anti-egfr therapies in the treatment of locally advanced hnscc is currently under study in large randomized trials, and patients with hnscc should continue to be offered clinical trials of novel agents aimed at improving outcomes.
Qualifying Statements
Chemoradiation is the current standard of care for patients with locally advanced hnscc, and to date, there is no evidence that compares cetuximab plus radiotherapy with chemoradiation, or that examines whether the addition of cetuximab to chemoradiation is of benefit in these patients. However, five ongoing trials are investigating the effect of the addition of egfr inhibitors concurrently with, before, or after chemoradiotherapy; those trials should provide direction about the best integration of cetuximab into standard treatment.
In patients with recurrent or metastatic hnscc who experience progressive disease despite, or who are unsuitable for, first-line platinum-based chemotherapy, gefitinib at doses of 250 mg or 500 mg daily, compared with weekly methotrexate, did not increase median overall survival [hazard ratio (hr): 1.22; 96% confidence interval (ci): 0.95 to 1.57; p = 0.12 (for 250 mg daily vs. weekly methotrexate); hr: 1.12; 95% ci: 0.87 to 1.43; p = 0.39 (for 500 mg daily vs. weekly methotrexate)] or objective response rate (2.7% for 250 mg and 7.6% for 500 mg daily vs. 3.9% for weekly methotrexate, p > 0.05). As compared with methotrexate, gefitinib was associated with an increased incidence of tumour hemorrhage (8.9% for 250 mg and 11.4% for 500 mg daily vs. 1.9% for weekly methotrexate).
PMCID: PMC2880902  PMID: 20567625
Head-and-neck cancer; epidermal growth factor receptor; egfr inhibitors; overall survival; progression-free survival; tumour response rate
5.  TP53 status and taxane-platinum versus platinum-based therapy in ovarian cancer patients: A non-randomized retrospective study 
BMC Cancer  2008;8:27.
Background
Taxane-platinum therapy (TP) has replaced platinum-based therapy (PC or PAC, DNA damaging chemotherapy) in the postoperative treatment of ovarian cancer patients; however, it is not always effective. TP53 protein plays a differential role in response to DNA-damaging agents and taxanes. We sought to define profiles of patients who benefit the most from TP and also of those who can be treated with PC.
Methods
We compared the effectiveness of PC/PAC (n = 253) and TP (n = 199) with respect to tumor TP53 accumulation in ovarian cancer patients with FIGO stage IIB-IV disease; this was a non-randomized retrospective study. Immunohistochemical analysis was performed on 452 archival tumors; univariate and multivariate analysis by the Cox's and logistic regression models was performed in all patients and in subgroups with [TP53(+)] and without TP53 accumulation [TP53(-)].
Results
The advantage of taxane-platinum therapy over platinum-based therapy was seen in the TP53(+), and not in the TP53(-) group. In the TP53(+) group taxane-platinum therapy enhanced the probability of complete remission (p = .018), platinum sensitivity (p = .014), platinum highly sensitive response (p = .038) and longer survival (OS, p = .008). Poor tumor differentiation diminished the advantage from taxane-platinum therapy in the TP53(+) group. In the TP53(-) group PC/PAC was at least equally efficient as taxane-platinum therapy and it enhanced the chance of platinum highly sensitive response (p = .010). However, in the TP53(-) group taxane-platinum therapy possibly diminished the risk of death in patients over 53 yrs (p = .077). Among factors that positively interacted with taxane-platinum therapy in some analyses were endometrioid and clear cell type, FIGO III stage, bulky residual tumor, more advanced age of patient and moderate tumor differentiation.
Conclusion
Our results suggest that taxane-platinum therapy is particularly justified in patients with TP53(+) tumors or older than 53 years. In the group of patients ≤53 yrs and with TP53(-) tumors platinum-based therapy is possibly equally efficient. We provide hints for planning randomized trials to verify these observations.
doi:10.1186/1471-2407-8-27
PMCID: PMC2268700  PMID: 18230133
6.  A Medical Research Council randomized trial of single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma 
British Journal of Cancer  2000;83(12):1623-1629.
The UK Medical Research Council conducted this trial of carboplatin chemotherapy in advanced seminoma to compare single agent carboplatin with a standard combination of etoposide with cisplatin. The use of single agent carboplatin was expected to be associated with reduced toxicity. A total of 130 patients with advanced seminoma were randomly assigned to treatment with either single agent carboplatin (C) at a dose of 400 mg/m2 to be corrected for glomerular filtration rate outside the range 81–120 ml min–1 and to be administered on day 1 of a 21 day cycle to a total of 4 cycles or to etoposide + platinum (EP). The trial was designed as an equivalence study aiming to exclude a reduction in the 3-year progression-free survival in patients allocated to carboplatin of between 10 and 15%, requiring initially a target accrual of 250 patients (90% power significance level 5% (one-sided)). The trial closed after 130 patients had been randomized following recommendation by an independent data monitoring committee. At a median follow-up time of 4.5 years, 81% of patients had been followed up for at least 3 years and 19 patients have died. The estimated PFS rate (95% Confidence Intervals (CI)) at 3 years was 71% (60–82%) in patients allocated C and 81% (71–90%) in those allocated EP; the 95% CI for the difference in 3 year PFS was – 6% to +19%. The hazard ratio of 0.64 (95% CI 0.32–1.28) favoured EP but the difference was not statistically significant (log rank chi-squared = 1.59 P = 0.21). The 3-year survival rate was 84% (75–92%) in those allocated C, and 89% (81–96%) in those allocated EP. The hazard ratio for survival was 0.85 with 95% CI, 0.35–2.10, log rank chi-squared = 0.12, P = 0.73. The trial has not demonstrated statistically significant differences in the major survival endpoints comparing single agent carboplatin with a combination of etoposide + cisplatin. This cannot be taken as an indication of equivalence since the limited size of this trial rendered it unable to exclude a 19% lower progression-free survival and survival in those treated with single agent carboplatin which would be important clinically. Standard initial chemotherapy for advanced seminoma should be based on cisplatin combinations and the role of carboplatin awaits the outcome of further studies. © 2000 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2000.1498
PMCID: PMC2363456  PMID: 11104556
seminoma; germ cell tumour; chemotherapy; cisplatin; carboplatin; randomized control trial
7.  The Role of Pegylated Liposomal Doxorubicin in Ovarian Cancer: A Meta-Analysis of Randomized Clinical Trials 
The Oncologist  2013;18(9):1022-1031.
A meta-analysis of randomized trials showed that carboplatin and pegylated liposomal doxorubicin (PLD) had better progression-free survival and similar overall survival compared with carboplatin and paclitaxel and had a very different toxicity profile. Therapy selection could be based on patient risks for side effects. Single-agent PLD is as efficacious as other monotherapies and is more tolerable.
Learning Objectives
Determine circumstances under which ovarian cancer patients would benefit from carboplatin plus pegylated liposomal doxorubicin rather than carboplatin plus paclitaxel.Compare and contrast efficacy and toxicity profiles of carboplatin plus pegylated liposomal doxorubicin versus carboplatin plus paclitaxel.Compare and contrast efficacy and toxicity profiles of single agent pegylated liposomal doxorubicin versus topotecan, gemcitabine, olaparib, patupilone, and canfosfamide.
Background.
Recent studies suggest that carboplatin with pegylated liposomal doxorubicin (C+PLD) is as efficacious as carboplatin with paclitaxel (C+P) and possibly is more tolerable for ovarian cancer therapy. Pegylated liposomal doxorubicin (PLD) may also be efficacious and tolerable as monotherapy in recurrent or platinum-resistant disease. We performed a meta-analysis of randomized trials in order to elucidate the role of PLD in ovarian cancer.
Methods.
We searched PubMed, Scopus, and ISI Web of Knowledge for studies comparing C+PLD with C+P and comparing PLD with another monotherapy. Summary hazard ratios (HRs) and relative risks with their corresponding 95% confidence intervals (CIs) were calculated using a fixed-effects model.
Results.
Three trials were included in the doublet regimen analysis, and five trials were included in the monotherapy regimen analysis. C+PLD provided superior progression-free survival (PFS) (HR, 0.87; 95% CI, 0.78–0.96) and similar overall survival (OS; HR, 0.95; 95% CI, 0.84–1.07) compared with C+P. There was no evidence of improved tolerability: C+PLD had more gastrointestinal toxicity, anemia, thrombocytopenia, cutaneous toxicity, and mucositis/stomatitis, although there was less neutropenia, neuropathy, and alopecia. PLD monotherapy had similar PFS (HR, 0.99; 95% CI, 0.89–1.11) and OS (HR, 0.99; 95% CI, 0.88–1.11) to other monotherapies, but it was more tolerable. There was less neutropenia, anemia, thrombocytopenia, and gastrointestinal toxicity, although cutaneous toxicity was increased.
Conclusion.
C+PLD had better PFS and similar OS compared with C+P and had a very different toxicity profile. Therapy selection could be based on patient risks for side effects. PLD is as efficacious as other monotherapies and is more tolerable.
doi:10.1634/theoncologist.2013-0126
PMCID: PMC3780634  PMID: 23881990
Pegylated liposomal doxorubicin; Ovarian cancer; Meta-analysis; Carboplatin; Paclitaxel
8.  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
9.  Adjuvant Therapy Choices in Patients With Resected Non-Small-Cell Lung Cancer: Correlation of Doctors' Treatment Plans and Relevant Phase III Trial Data 
Journal of Oncology Practice  2005;1(2):37-42.
Purpose
To evaluate case-based choices selected from among preselected options for adjuvant therapy management in patients with completely resected non-small-cell lung cancer (NSCLC).
Methods
In a series of meetings in which US oncologists participated in case-based discussions, market research data were acquired using audience response keypad technology. Participant's anonymous responses to specific case-based questions were recorded electronically and tabulated.
Results
Core behaviors among the majority of physician participants are driven by emerging level 1 evidence. However, a “more aggressive than literature-supported treatment posture” is frequently selected. For the scenario involving a patient with completely resected pT1N0 disease, approximately 60% recommended observation but one third of respondents indicated they would propose three to four cycles of platinum-based adjuvant chemotherapy. Twenty-three percent would recommend adjuvant radiation following adjuvant chemotherapy for a patient with completely resected pT2N1 (stage IIB) disease. In the stage IIB setting, when cisplatin or carboplatin chemotherapy choices were specified, carboplatin-based combinations were selected by 43.6% compared with 30% for cisplatin regimens. Eight respondents (3.5%) favored observation for the stage IIB setting. This is consistent with the preponderance of level 1 evidence for adjuvant management. Carboplatin combinations are also recommended despite the availability of only abstract data and a meeting report for a single phase III trial showing a survival benefit for carboplatin based management in stage IB disease. The use of radiation as an element in adjuvant therapy in the settings assessed in this research is not supported by prospective data.
Conclusions
Treatment plans that include adjuvant platinum-based chemotherapy have been widely adopted by US oncologists for a large fraction of patients with completely resected NSCLC. Recommendations for adjuvant chemotherapy for the patient described here with stage IA disease, or for adjuvant radiation alone or after adjuvant chemotherapy, for the stage IIB disease patient presented are overly aggressive, not evidence based, and carry potential harm. In settings in which level 1 evidence for a survival benefit from adjuvant chemotherapy does exist, some of the specific adjuvant chemotherapy regimens selected, while widely used in NSCLC patients with more advanced disease, have not yet been demonstrated to provide improved disease-free or overall survival as adjuvant treatment. Individualized adjuvant treatment recommendations not specifically grounded in level 1 evidence appear to be widely recommended by US medical oncologists for patients with completely resected NSCLC.
PMCID: PMC2793579  PMID: 20871677
10.  Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer 
Background
Epithelial ovarian cancer is diagnosed in 4500 women in the UK each year of whom 1700 will ultimately die of their disease.Of all cases 10% to 15% are diagnosed early when there is still a good possibility of cure. The treatment of early stage disease involves surgery to remove disease often followed by chemotherapy. The largest clinical trials of this adjuvant therapy show an overall survival (OS) advantage with adjuvant platinum-based chemotherapy but the precise role of this treatment in subgroups of women with differing prognoses needs to be defined.
Objectives
To systematically review the evidence for adjuvant chemotherapy in early stage epithelial ovarian cancer to determine firstly whether there is a survival advantage of this treatment over the policy of observation following surgery with chemotherapy reserved for treatment of disease recurrence, and secondly to determine if clinical subgroups of differing prognosis based on histological sub-type, or completeness of surgical staging, have more or less to gain from chemotherapy following initial surgery.
Search methods
We performed an electronic search using the Cochrane Gynaecological Cancer Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL 2011, Issue 3), MEDLINE (1948 to Aug week 5, 2011) and EMBASE (1980 to week 36, 2011). We developed the search strategy using free-text and medical subject headings (MESH).
Selection criteria
We selected randomised clinical trials that met the inclusion criteria set out based on the populations, interventions, comparisons and outcome measures.
Data collection and analysis
Two review authors independently extracted data and assessed trial quality. Disagreements were resolved by discussion with a third review author. We performed random-effects meta-analyses and subgroup analyses.
Main results
Five randomised controlled trials (RCTs), enrolling 1277 women, with a median follow-up of 46 to 121 months, met the inclusion criteria. Four trials were included in the meta-analyses and we considered them to be at a low risk of bias. Meta-analysis of five-year data from three trials indicated that women who received adjuvant platinum-based chemotherapy had better overall survival (OS) than those who did not (1008 women; hazard ratio (HR) 0.71; 95% confidence interval (CI) 0.53 to 0.93). Likewise, meta-analysis of five-year data from four trials indicated that women who received adjuvant chemotherapy had better progression-free survival (PFS) than those who did not (1170 women; HR 0.67; 95% CI 0.53 to 0.84). The trials included in these meta-analyses gave consistent estimates of the effects of chemotherapy. In addition, these findings were robust over time (10-year PFS: two trials, 925 women; HR 0.67; 95% CI 0.54 to 0.84).
Subgroup analysis suggested that women who had optimal surgical staging of their disease were unlikely to benefit from adjuvant chemotherapy (HR for OS 1.22; 95% CI 0.63 to 2.37; two trials, 234 women) whereas those who had sub-optimal staging did (HR for OS 0.63; 95% CI 0.46 to 0.85; two trials, 772 women). One trial showed a benefit from adjuvant chemotherapy among women at high risk (HR for OS 0.48; 95% CI 0.32 to 0.72) but not among those at low/medium risk (HR for OS 0.95; 95% CI 0.54 to 1.66). However, these subgroup findings could be due to chance and should be interpreted with caution.
Authors’ conclusions
Adjuvant platinum-based chemotherapy is effective in prolonging the survival of the majority of patients who are assessed as having early (FIGO stage I/IIa) epithelial ovarian cancer. However, it may be withheld from women in whom there is well-differentiated encapsulated unilateral disease (stage 1a grade 1) or those with comprehensively staged Ib, well or moderately differentiated (grade 1/2) disease. Others with unstaged early disease or those with poorly differentiated tumours should be offered chemotherapy. A pragmatic approach may be necessary in clinical settings where optimal staging is not normally performed/achieved. In such settings, adjuvant chemotherapy may be withheld from those with encapsulated stage Ia grade 1 serous and endometrioid carcinoma and offered to all others with early stage disease.
doi:10.1002/14651858.CD004706.pub4
PMCID: PMC4164914  PMID: 22419298
Antineoplastic Agents [*therapeutic use]; Carboplatin [therapeutic use]; Chemotherapy, Adjuvant [methods]; Cisplatin [therapeutic use]; Disease-Free Survival; Early Detection of Cancer; Melphalan [therapeutic use]; Neoplasm Staging; Ovarian Neoplasms [*drug therapy; pathology; surgery]; Randomized Controlled Trials as Topic; Female; Humans
11.  Platinum drugs in the treatment of non-small-cell lung cancer 
British Journal of Cancer  2002;87(8):825-833.
The use of chemotherapy is considered standard therapy in patients with locally advanced non-small-cell lung cancer that cannot be treated with radiotherapy and in those with metastatic non-small-cell lung cancer and good performance status. This approach is also accepted in patients with earlier stage disease, when combined with radiotherapy in those with non-resectable locally advanced disease, or in the preoperative setting. Randomised clinical studies and meta-analyses of the literature have confirmed the beneficial survival effect of platinum-based chemotherapy. Cisplatin and carboplatin have been successfully used with other drugs in a wide variety of well-established two-drug combinations while three-drug combinations are still under investigation. Cisplatin and carboplatin use is limited by toxicity and inherent resistance. These considerations have prompted research into new platinum agents, such as the trinuclear platinum agent BBR3464, the platinum complex ZD0473 and oxaliplatin. These compounds could be developed in combination with agents such as paclitaxel, gemcitabine or vinorelbine in patients with advanced and/or refractory solid tumours.
British Journal of Cancer (2002) 87, 825–833. doi:10.1038/sj.bjc.6600540 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600540
PMCID: PMC2376170  PMID: 12373594
cisplatin; carboplatin; ZD0473; BBR3464; oxaliplatin; non-small-cell lung cancer
12.  Targeted treatment of folate receptor-positive platinum-resistant ovarian cancer and companion diagnostics, with specific focus on vintafolide and etarfolatide 
Among the gynecological malignancies, ovarian cancer is the leading cause of mortality in developed countries. Treatment of ovarian cancer is based on surgery integrated with chemotherapy. Platinum-based drugs (cisplatin and carboplatin) comprise the core of first-line chemotherapy for patients with advanced ovarian cancer. Platinum-resistant ovarian cancer can be treated with cytotoxic chemotherapeutics such as paclitaxel, topotecan, PEGylated liposomal doxorubicin, or gemcitabine, but many patients eventually relapse on treatment. Targeted therapies based on agents specifically directed to overexpressed receptors, or to selected molecular targets, may be the future of clinical treatment. In this regard, overexpression of folate receptor-α on the surface of almost all epithelial ovarian cancers makes this receptor an excellent “tumor-associated antigen”. With appropriate use of spacers/linkers, folate-targeted drugs can be distributed within the body, where they preferentially bind to ovarian cancer cells and are released inside their target cells. Here they can exert their desired cytotoxic function. Based on this strategy, 12 years after it was first described, a folate-targeted vinblastine derivative has now reached Phase III clinical trials in ovarian cancer. This review examines the importance of folate targeting, the state of the art of a vinblastine folate-targeted agent (vintafolide) for treating platinum-resistant ovarian cancer, and its diagnostic companion (etarfolatide) as a prognostic agent. Etarfolatide is a valuable noninvasive diagnostic imaging agent with which to select ovarian cancer patient populations that may benefit from this specific targeted therapy.
doi:10.2147/PGPM.S58374
PMCID: PMC3917542  PMID: 24516337
vintafolide; etarfolatide; platinum-resistant ovarian cancer; targeted therapy; biomarkers; folate receptor
13.  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
14.  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
15.  Imaging VCAM-1 as an indicator of treatment efficacy in metastatic ovarian cancer 
The inability to successfully treat women with ovarian cancer is due in large part to the advanced stage of disease at diagnosis, the development of platinum resistance, and the lack of sensitive methods to monitor tumor progression and response to treatment. Vascular cell adhesion molecule-1 (VCAM-1) is expressed on the mesothelium of ovarian cancer patients. We investigated VCAM-1 expression as a marker of peritoneal metastasis and tumor response to platinum-based chemotherapy.
Methods
Peritoneal or omental biopsies obtained from women diagnosed with Stage I, Stage II or Stage III/IV ovarian cancer were evaluated by immunohistochemistry. The effects of carboplatin on mesothelial VCAM-1 expression were determined in cultured cells by Western blot. Radiolabeled VCAM-1-specific peptide imaging probes and single photon emission computed tomography (SPECT) were employed in a mouse model of ovarian cancer peritoneal metastasis to identify VCAM-1 as a viable imaging target.
Results
VCAM-1 expression correlated with tumor stage. All specimens from Stage I patients were negative, while 29% of Stage II patients and the 73% of Stage III/IV patients were positive. While the majority of women with advanced stage disease expressed VCAM-1, the incidence of expression was reduced among women who received neoadjuvant chemotherapy, suggesting a role for chemotherapy in regulating VCAM-1 expression. Treatment of mesothelial cells in culture with carboplatin resulted in a transient decrease in VCAM-1 expression 4 hours after treatment that returned to baseline within 16 to 24 hours. In vivo imaging of VCAM-1 also demonstrated an acute decrease in expression 4 hours after carboplatin administration that recovered within 48 hours in mice harboring platinum-resistant tumors. Chronic VCAM-1 expression reflected the effect of platinum-based treatment on tumor burden. Specifically, carboplatin treatment of mice with platinum-sensitive tumors showed reduced VCAM-1 expression, which correlated with reduced tumor burden; mice with platinum-resistant tumors retained elevated VCAM-1 expression and tumor burden following treatment.
Conclusions
Clinically relevant VCAM-1-specific imaging probes identify VCAM-1 expression as an indicator of ovarian cancer peritoneal metastasis and therapeutic response to platinum-based agents. These observations support testing the utility of VCAM-1 imaging probes to monitor treatment response in ovarian cancer patients, thus providing the potential to improve management of women with this disease.
doi:10.2967/jnumed.112.117796
PMCID: PMC3992874  PMID: 24029657
VCAM-1; ovarian cancer; metastasis; SPECT/CT imaging
16.  Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer delays third-line chemotherapy and prolongs the platinum-free interval 
Annals of Oncology  2010;22(1):49-58.
Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD; CentoCor Ortho Biotech Products L.P., Raritan, NJ, USA). over single-agent PLD in 672 patients with relapsed ovarian cancer, particularly in the partially platinum-sensitive subgroup [platinum-free interval (PFI) of 6–12 months]. This superiority has been suggested to be due to the differential impact of subsequent (platinum) therapy.
Patients and methods: A detailed analysis of subsequent therapies and survival outcomes in the overall population and in the subsets according to platinum sensitivity was therefore conducted.
Results: Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), including further platinum-based regimens (49% versus 55%). Patients in the trabectedin/PLD arm received subsequent chemotherapy at a later time (median delay 2.5 months versus PLD arm). Overall survival from subsequent platinum was significantly prolonged in the partially platinum-sensitive disease subset (hazard ratio = 0.63; P = 0.0357).
Conclusion: The superiority of trabectedin/PLD over single-agent PLD in OVA-301 cannot be explained by differences in the extent or nature of subsequent therapies administered to these patients. On the other hand, these exploratory analyses support the hypothesis that the enhanced survival benefits in the partially platinum-sensitive subset might be due to an extended PFI leading to longer survival with subsequent platinum.
doi:10.1093/annonc/mdq353
PMCID: PMC3003617  PMID: 20643863
pegylated liposomal doxorubicin; platinum-free interval; relapsed ovarian cancer; trabectedin
17.  Bevacizumab in combination with chemotherapy for the treatment of advanced ovarian cancer: a systematic review 
As increased angiogenesis has been linked with the progression of ovarian cancer, a number of anti-angiogenic agents have been investigated, or are currently in development, as potential treatment options for patients with advanced disease. Bevacizumab, a recombinant monoclonal antibody against vascular endothelial growth factor, has gained European Medicines Agency approval for the front-line treatment of advanced epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer in combination with carboplatin and paclitaxel, and for the treatment of first recurrence of platinum-sensitive ovarian cancer in combination with carboplatin and gemcitabine. We conducted a systematic literature review to identify available efficacy and safety data for bevacizumab in ovarian cancer as well as for newer anti-angiogenic agents in development. We analyzed published data from randomized, controlled phase II/III clinical trials enrolling women with ovarian cancer to receive treatment with bevacizumab. We also reviewed available data for emerging anti-angiogenic agents currently in phase II/III development, including trebananib, aflibercept, nintedanib, cediranib, imatinib, pazopanib, sorafenib and sunitinib. Significant efficacy gains were achieved with the addition of bevacizumab to standard chemotherapy in four randomized, double-blind, phase III trials, both as front-line treatment (GOG-0218 and ICON7) and in patients with recurrent disease (OCEANS and AURELIA). The type and frequency of bevacizumab-related adverse events was as expected in these studies based on published data. Promising efficacy data have been published for a number of emerging anti-angiogenic agents in phase III development for advanced ovarian cancer. Further research is needed to identify predictive or prognostic markers of response to bevacizumab in order to optimize patient selection and treatment benefit. Data from phase III trials of newer anti-angiogenic agents in ovarian cancer are awaited.
doi:10.1186/1757-2215-7-57
PMCID: PMC4033616  PMID: 24864163
Angiogenesis; Bevacizumab; Fallopian tube cancer; Ovarian cancer; Primary peritoneal cancer; Targeted therapies
18.  Platinum-Based Versus Non-Platinum-Based Chemotherapy as First Line Treatment of Inoperable, Advanced Gastric Adenocarcinoma: A Meta-Analysis 
PLoS ONE  2013;8(7):e68974.
Background
Although the platinum regimen is adopted widely nowadays in spite of the excessive side effects, there is still no international standard for palliative chemotherapy of advanced gastric cancer. This meta-analysis assessed the efficacy and tolerability of platinum versus non–platinum chemotherapy as first-line palliative treatment in patients with inoperable, advanced gastric cancer.
Methods
Randomized phase II and III clinical trials on first-line palliative chemotherapy in inoperable, advanced gastric cancer were identified by electronic searches of PubMed, Embase, and the Cochrane Controlled Trial Register, and hand searches of relevant abstract books and reference lists. Response rates, overall survival, and toxicity were analyzed. Depending on whether new-generation agents (S-1, taxanes and irinotecan) were utilized, the non–platinum regimens were divided into two subgroup.
Results
Compared to non-platinum regimens containing new-generation agents, the use of platinum-based regimens was associated with better response (risk ratio (RR) = 1.94, 95%CI[1.48, 2.55], p<0.001), an increase of overall survival (hazard ratio (HR) = 0.85, 95%CI[0.78, 0.92], p<0.001), a higher risk of hematological and non-hematological toxicity. No statistically significant increase in response (RR = 1.03, 95%CI [0.85, 1.24], p = 0.76) or overall survival (HR = 1.07, 95%CI [0.88, 1.30], p = 0.49) was found when platinum therapies were compared to new-generation agent based combination regimens. The toxicity of platinum-based regimens was significantly higher for hematologic toxicity, nausea and vomiting, and neurotoxicity, but not for diarrhea and toxic death rate.
Conclusion
New-generation agent based combination regimens achieved similar response rate and overall survival as platinum-based therapy that had generally higher side effects. S-1, taxanes and irinotecan seemed to be valid options for patients with inoperable, advanced gastric cancer as first-line chemotherapy.
doi:10.1371/journal.pone.0068974
PMCID: PMC3708886  PMID: 23874831
19.  Combination chemotherapy with carboplatin, capecitabine and epirubicin (ECarboX) as second- or third-line treatment in patients with relapsed ovarian cancer: a phase I/II trial 
British Journal of Cancer  2006;94(1):74-78.
Platinum-based combination chemotherapy has been proven to be superior to single-agent platinum in the treatment of relapsed ovarian cancer after a treatment-free interval of more than 6 months. A response rate of 41% was previously reported by our group using a combination of epirubicin, cisplatin and 5-FU in patients who relapsed within 12 months, we therefore assessed a similar, but more convenient combination of epirubicin, carboplatin and capecitabine in this phase-I/II trial. In total, 18 patients with recurrent epithelial ovarian carcinoma, who had not received more than two lines of chemotherapy and the treatment-free interval exceeded 6 months were treated with carboplatin AUC5, epirubicin 50 mg m−2 and capecitabine at several dose levels on continuous 21 day cycles and 14 of 21 day cycles. Patients were assessed for toxicity and by CT and CA-125 for response. The overall response rate was 61.1%, with three complete and eight partial responses. Grade 3/4 haematological toxicity was seen in 10 out of 18 patients and caused dose reductions and treatment delays. The combination of epirubicin, carboplatin and capecitabine showed good activity but caused excessive toxicity. A phase-II trial using carboplatin and capecitabine is underway.
doi:10.1038/sj.bjc.6602879
PMCID: PMC2361084  PMID: 16306873
capecitabine; carboplatin; epirubicin; ovarian cancer; relapse
20.  Platinum Neurotoxicity Pharmacogenetics 
Molecular cancer therapeutics  2009;8(1):10-16.
Cisplatin, carboplatin, and oxaliplatin anticancer drugs are commonly used to treat lung, colorectal, ovarian, breast, head/neck, and genitourinary cancers. However, the efficacy of platinum-based drugs is often compromised because of the substantial risk for severe toxicities, including neurotoxicity. Neurotoxicity can result in both acute and chronic debilitation. Moreover, colorectal cancer patients treated with oxaliplatin more often discontinue therapy due to peripheral neuropathy than for tumor progression, potentially compromising patient benefit. Numerous methods to prevent neurotoxicity have so far proven unsuccessful. In order to circumvent this life-altering side effect, while taking advantage of the antitumor activities of the platinum agents, efforts to identify mechanism-based biomarkers are underway. In this review, we detail findings from the current literature for genetic markers associated with neurotoxicity induced by single agent and combination platinum chemotherapy. These data have the potential for broad clinical implications if mechanistic associations lead to the development of toxicity modulators to minimize the noxious sequelae of platinum chemotherapy.
doi:10.1158/1535-7163.MCT-08-0840
PMCID: PMC2651829  PMID: 19139108
21.  Activity of chemotherapy in mucinous ovarian cancer with a recurrence free interval of more than 6 months: results from the SOCRATES retrospective study 
BMC Cancer  2008;8:252.
Background
Mucinous ovarian carcinoma have a poorer prognosis compared with other histological subtypes. The aim of this study was to evaluate, retrospectively, the activity of chemotherapy in patients with platinum sensitive recurrent mucinous ovarian cancer.
Methods
The SOCRATES study retrospectively assessed the pattern of care of a cohort of patients with recurrent platinum-sensitive ovarian cancer observed in the years 2000–2002 in 37 Italian centres. Data were collected between April and September 2005. Patients with recurrent ovarian cancer with > 6 months of platinum free interval were considered eligible.
Results
Twenty patients with mucinous histotype and 388 patients with other histotypes were analyzed. At baseline, mucinous tumours differed from the others for an higher number of patients with lower tumor grading (p = 0.0056) and less advanced FIGO stage (p = 0.025). At time of recurrence, a statistically significant difference was found in performance status (worse in mucinous, p = 0.024). About 20% of patients underwent secondary cytoreduction in both groups, but a lower number of patients were optimally debulked in the mucinous group (p = 0.03). Patients with mucinous cancer received more frequently single agent platinum than platinum based-combination therapy or other non-platinum schedules as second line therapy (p = 0.026), with a response rate lower than in non-mucinous group (36.4% vs 62.6%, respectively, p = 0.04). Median time to progression and overall survival were worse for mucinous ovarian cancer. Finally, mucinous cancer received a lower number of chemotherapy lines (p = 0.0023).
Conclusion
This analysis shows that platinum sensitive mucinous ovarian cancer has a poor response to chemotherapy. Studies dedicated to this histological subgroup are needed.
doi:10.1186/1471-2407-8-252
PMCID: PMC2538544  PMID: 18761742
22.  First-line treatment for advanced ovarian cancer: paclitaxel, platinum and the evidence 
British Journal of Cancer  2002;87(8):815-824.
Four large randomised trials of paclitaxel in combination with platinum against a platinum-based control treatment have now been published in full, representing around 88% (3588 out of 4057) of patients randomised into the eight known trials of this question. There is substantial heterogeneity in the results of these four trials. Four main explanations for this heterogeneity have been proposed: differences in the extent and timing of ‘crossover’ to taxanes in the control groups; differences in the types of patient included; differences in the effectiveness of the research regimens used; differences in the effectiveness of the control regimens used. In this study we examine whether any of these explanations is consistent with the pattern of results seen in these trials. Each explanation suggests that a particular characteristic of each trial was responsible for the results observed. For each explanation the trials were split into groups according to that characteristic, in order to partition the total heterogeneity into that seen ‘within’ and ‘between’ groups of trials. If a particular explanation was consistent with the pattern of results, we would expect to see relatively little heterogeneity within each group of trial results viewed in this way, with most of the heterogeneity being between groups which are dissimilar with respect to the key characteristic. Heterogeneity ‘within’ and ‘between’ groups was formally compared using the F-ratio. If any explanation appeared to be consistent with the results of the trials, it was considered whether the explanation was also consistent with other evidence available about these regimens. Only one explanation appeared to be consistent with the pattern of results seen in these trials, and that was differences in effectiveness of the control arms used in these trials. This suggests that the very positive results in favour of paclitaxel/cisplatin seen in two of the trials may have been due to the use of a suboptimal control arm. There is no direct evidence about the relative effectiveness of the control arms used in these trials, but indirect evidence is consistent with the conclusion that the cyclophosphamide/cisplatin regimen used in two of the trials may be less effective than the control regimens used in the other trials. Specific concerns about the choice of a cyclophosphamide/cisplatin control arm in the first of these trials to report were raised before the results of the other trials were known, i.e. before any heterogeneity had been observed. Further investigation of this question would be useful. In the meantime, given all of the randomised evidence on the efficacy and toxicity associated with the regimens used in these trials, we conclude that single agent carboplatin is a safe and effective first-line treatment for women with advanced ovarian cancer.
British Journal of Cancer (2002) 87, 815–824. doi:10.1038/sj.bjc.6600567 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600567
PMCID: PMC2376171  PMID: 12373593
ovarian cancer; platinum; paclitaxel; heterogeneity
23.  Shenqi fuzheng, an injection concocted from chinese medicinal herbs, combined with platinum-based chemotherapy for advanced non-small cell lung cancer: a systematic review 
Background
Platinum-based chemotherapy has been a standard therapy for advanced non-small cell lung cancer (NSCLC), but it has high toxicity. In China, Shenqi Fuzheng, a newly developed injection concocted from Chinese medicinal herbs has been reported that may increase efficacy and reduce toxicity when combined with platinum-based chemotherapy, but little is known about it outside of China. The aim of this study was to systematically review the existing clinical evidence on Shenqi Fuzheng Injection(SFI) combined with platinum-based chemotherapy for advanced NSCLC.
Methods
Pubmed, Cochrane Library, EMBASE, CNKI, and CBM search were organized for all documents published, in English and Chinese, until April 2010. The randomized controlled clinical trials were selected based on specific criteria, in which a SFI plus platinum-based chemotherapy treatment group was compared with a platinum-based chemotherapy control group for patients with advanced NSCLC. The quality of studies was assessed by modified Jadad's scale, and Revman 4.2 software was used for data syntheses and analyses.
Results
Twenty nine studies were included in this review based on our selection criteria. Of them, ten studies were of high quality and the rest were of low quality, according to the modified Jadad scale. The meta-analysis showed there was a statistically significant higher tumor response (RR, 1.19; 95% CI, 1.07 to 1.32; P = 0.001) and performance status ((RR, 1.57; 95% CI, 1.45 to 1.70; P < 0.00001); but lower severe toxicity for WBC (RR, 0.37; 95% CI, 0.29 to 0.47; P < 0.00001), PLT (RR, 0.33; 95% CI, 0.21 to 0.52; P < 0.00001), HB (RR, 0.44; 95% CI, 0.30 to 0.66; P < 0.0001) and nausea and vomiting (RR, 0.32; 95% CI, 0.22 to 0.47; P < 0.00001), when the SFI plus platinum-based chemotherapy treatment group was compared with the platinum-based chemotherapy control group. Sensitivity analysis was restricted to studies with the high quality, and the result was similar when the studies with low quality were excluded. Asymmetry was observed in a funnel plot analysis, and Egger's test also indicated an evidence of publication bias (P = 0.016).
Conclusions
SFI intervention appears to be useful to increase efficacy and reduce toxicity when combined with platinum-based chemotherapy for advanced NSCLC, although this result needs to be further verified by more high-quality trials.
doi:10.1186/1756-9966-29-137
PMCID: PMC2972256  PMID: 20969765
24.  Phase ii/iii study of intraperitoneal chemotherapy after neoadjuvant chemotherapy for ovarian cancer: ncic ctg ov.21 
Current Oncology  2011;18(2):84-90.
Three large randomized clinical trials have shown a survival benefit in women with stage iii epithelial ovarian cancer (eoc) who receive intraperitoneal (IP) chemotherapy after optimal primary debulking surgery. The most recent Gynecologic Oncology Group study, gog 172, showed an improvement in median overall survival of approximately 17 months. That result led to a U.S. National Cancer Institute (nci) clinical announcement recommending that IP chemotherapy be considered for this group of women with eoc. However, IP chemotherapy is associated with increased toxicity, and rates for completion of treatment are low (42% in gog 172). The optimal IP regimen and duration of treatment has yet to be defined. Women undergoing chemotherapy before optimal debulking surgery were not included in the studies or in the nci clinical announcement. The National Cancer Institute of Canada Clinical Trials Group has developed a protocol for a randomized phase ii/iii study which will examine whether IP platinum–taxane-based chemotherapy benefits women who have received neoadjuvant chemotherapy before optimal surgical debulking. To address whether the less systemically toxic carboplatin can be substituted for cisplatin IP, the first phase of the study will have 3 arms: 1 intravenous-only, and 2 IP-containing regimens. At the end of the first stage, and provided that IP therapy is feasible to administer in this patient population, one of the IP regimens, either IP carboplatin or IP cisplatin, will proceed into a phase iii comparison with the intravenous arm. This exciting new study has gathered international support.
PMCID: PMC3070707  PMID: 21505599
Intraperitoneal chemotherapy; epithelial ovarian cancer; neoadjuvant chemotherapy; ncic ctg ov.21
25.  Cytoreductive surgery followed by chemotherapy versus chemotherapy alone for recurrent platinum-sensitive epithelial ovarian cancer (SOCceR trial): a multicenter randomised controlled study 
BMC Cancer  2014;14:22.
Background
Improvement in treatment for patients with recurrent ovarian cancer is needed. Standard therapy in patients with platinum-sensitive recurrent ovarian cancer consists of platinum-based chemotherapy. Median overall survival is reported between 18 and 35 months. Currently, the role of surgery in recurrent ovarian cancer is not clear. In selective patients a survival benefit up to 62 months is reported for patients undergoing complete secondary cytoreductive surgery. Whether cytoreductive surgery in recurrent platinum-sensitive ovarian cancer is beneficial remains questionable due to the lack of level I-II evidence.
Methods/Design
Multicentre randomized controlled trial, including all nine gynecologic oncologic centres in the Netherlands and their affiliated hospitals. Eligible patients are women, with first recurrence of FIGO stage Ic-IV platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, who meet the inclusion criteria. Participants are randomized between the standard treatment consisting of at least six cycles of intravenous platinum based chemotherapy and the experimental treatment which consists of secondary cytoreductive surgery followed by at least six cycles of intravenous platinum based chemotherapy. Primary outcome measure is progression free survival. In total 230 patients will be randomized. Data will be analysed according to intention to treat.
Discussion
Where the role of cytoreductive surgery is widely accepted in the initial treatment of ovarian cancer, its value in recurrent platinum-sensitive epithelial ovarian cancer has not been established so far. A better understanding of the benefits and patients selection criteria for secondary cytoreductive surgery has to be obtained. Therefore the 4th ovarian cancer consensus conference in 2010 stated that randomized controlled phase 3 trials evaluating the role of surgery in platinum-sensitive recurrent epithelial ovarian cancer are urgently needed. We present a recently started multicentre randomized controlled trial that will investigate the role of secondary cytoreductive surgery followed by chemotherapy will improve progression free survival in selected patients with first recurrence of platinum-sensitive epithelial ovarian cancer.
Trial registration
Netherlands Trial Register number: NTR3337.
doi:10.1186/1471-2407-14-22
PMCID: PMC3897943  PMID: 24422892
Secondary cytoreductive surgery; Recurrent; Platinum-sensitive; Ovarian cancer

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