***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVES Approximately 50 % of ovarian cancers have elevated levels of epidermal growth factor receptor ( EGFR ) which correlates with a poor prognosis . Pre clinical evidence suggests that EGFR tyrosine kinase inhibitors ( TKIs ) , such as erlotinib ( OSI-774 ) , may potentiate the anti-tumour effects of cytotoxic agents , including carboplatin . Blocking EGFR could thus potentially reverse drug resistance . The primary objective of the study was to assess the response rate to the addition of erlotinib in patients with recurrent ovarian cancer who were receiving carboplatin .  METHODS Patients enrolled on this study had either local or advanced recurrent ovarian cancer with measurable disease . They may have had up to 2 prior chemotherapy regimens , one of which must have contained  platinum  , and they must have responded to prior platinum therapy . Patients were stratified by platinum sensitivity and were treated with erlotinib 150 mg daily on a continuous dosing schedule , and carboplatin at an AUC of 5 every 21 days . RESULTS Fifty patients with recurrent ovarian cancer entered the study , 33 in the platinum-sensitive arm and 17 in the platinum-resistant arm . Of patients evaluable for response , there were 14 partial responses ( PR ) of 30 evaluable for response ( 57 % objective response rate ( ORR ) ) in the platinum-sensitive arm , and 1 PR of 14 evaluable for response ( 7 % ORR ) in the platinum-resistant arm . CONCLUSIONS The combination of erlotinib and carboplatin was active in patients with platinum-sensitive disease , but not in platinum-resistant disease . The toxicities seen were those expected with carboplatin and erlotinib Introduction The epidermal growth factor receptor ( EGFR ) is a vali date d target in malignancy ; however , patients with wild type EGFR obtain little sustained benefit from anti-EGFR monotherapy . Epigenetic therapy to reactivate tumor suppressor genes may enhance the anti-proliferative effect of erlotinib . This phase I study evaluated the combination of erlotinib and 5-azacytidine for safety and maximal tolerated dose ( MTD ) . Methods Thirty patients with advanced solid tumors were treated in a st and ard 3 + 3 cohort design .  Erlotinib was dosed at 150 mg daily , and 5-azacytidine was escalated by increasing the number of daily doses of 75 mg/m2 per cycle . Patients were followed for dose-limiting toxicity ( DLT ) . Efficacy was assessed by RECIST criteria . Results Common non-hematologic toxicities included rash , diarrhea , nausea , and fatigue ; the majority was ≤ Grade 2 . DLTs included conjunctivitis in cohort 1 and infusion reaction in cohort 2 . No DLTs occurred in cohorts 3 , 4 , or 5 ; however , 2 serious neutropenic infections arose in cohort 5 after cycle 1 . Cohort 4 was exp and ed to 6 patients and was the MTD . Partial response ( lung , ovarian ) and stable disease occurred in 2 and 11 patients , respectively . Median progression-free survival was 2 months . Two patients with lung and larynx cancer had prolonged stable disease . Conclusion The combination of erlotinib and 5-azacytidine was well tolerated with interesting clinical activity in lung , head and neck , and ovarian cancer . The recommended dose for phase II study is erlotinib 150 mg daily and 5-azacytidine 75 mg/m2 daily on days 1–4 and 15–18 of a 28-day cycle BACKGROUND Tamoxifen and gefitinib ( IRESSA ) combination therapy was studied in patients with ovarian cancer refractory or resistant to platinum- and taxane-based therapy . PATIENTS AND METHODS In this phase II study , 56 patients with epithelial ovarian carcinoma or cancer of the fallopian tube or peritoneum received oral tamoxifen 40 mg/day and gefitinib 500 mg/day until progression or unacceptable toxicity . RESULTS Seventeen patients ( mean age : 59.6 years ) had previously received first-line platinum/taxane treatment only , while 39 had received 2 - 8 ( median 2 ) prior chemotherapy regimens .  Gefitinib dose reduction to 250 mg/day was performed in 10 patients ( 14.9 % ) , predominantly due to diarrhea ( 6 patients [ 10.7 % ] ) . Trial medication was discontinued in 6 patients ( 10.7 % ) due to adverse events ( AEs ) . The most frequent drug-related AEs were diarrhea and acne-like skin rash . There were no tumor responses , but 16 patients had stable disease . Median time-to-progression was 58 days ( 95 % CI , 55 - 71 days ) and median survival was 253 days ( 95 % CI , 137 - 355 days ) . CONCLUSION Gefitinib plus tamoxifen did not appear to be efficacious in the treatment of patients with refractory/resistant ovarian cancer . The addition of tamoxifen did not worsen the known side effects of gefitinib , or induce additional side effects PURPOSE To establish the safety and tolerability of ZD1839 ( Iressa ) , a selective epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor , and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types . PATIENTS AND METHODS This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days . Patients with either advanced non-small-cell lung , ovarian , head and neck , prostate , or colorectal cancer were recruited . RESULTS Eighty-eight patients received ZD1839  ( 150 to 1,000 mg/d ) . At 1,000 mg/d , five of 12 patients experienced dose-limiting toxicity ( grade 3 diarrhea [ four patients ] and grade 3 somnolence [ one patient ] ) . The most frequent drug-related adverse events ( AEs ) were acne-like rash ( 64 % ) and diarrhea ( 47 % ) , which were generally mild ( grade 1/2 ) and reversible on cessation of treatment . No change in  ZD1839 safety profile was observed with prolonged administration . Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98 % of patients by day 7 . Nineteen patients had stable disease and received ZD1839 for > or= 3 months ; seven of these patients remained on study drug for > or= 6 months . Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway . CONCLUSION ZD1839 was generally well tolerated , with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d . ZD1839 treatment result ed in clinical ly meaningful disease stabilization across a range of tumor types and doses . Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling , which was predicted from the mode of action of ZD1839 BACKGROUND Pertuzumab , a humanized monoclonal antibody targeting human epidermal growth factor receptor (HER)-mediated signalling , has shown activity in ovarian cancer in pre clinical models and in the clinic . This r and omized phase II study evaluated efficacy and safety of pertuzumab in combination with carboplatin-based chemotherapy in patients with platinum-sensitive , recurrent advanced ovarian cancer . PATIENTS AND METHODS Patients were r and omized to receive six cycles of chemotherapy ( carboplatin and either paclitaxel ( Taxol ) or gemcitabine ) with or without pertuzumab . The primary end point was progression-free survival ( PFS ) as determined by Response Evaluation Criteria in Solid Tumors and /or by CA 125 measurements . Secondary end points evaluated the response rate , safety profile , duration of response , time to progression and overall survival for both treatment arms . RESULTS A total of 149 patients received either chemotherapy with pertuzumab ( arm A , n=74 ) or chemotherapy alone ( arm B , n=75 ) . There was no significant difference either in median PFS or in the secondary end points between the two arms . No differences were seen in an exploratory biomarker analysis of HER3 mRNA expression between the two arms . Pertuzumab was well tolerated , with no increase in cardiac adverse events compared with chemotherapy alone . CONCLUSIONS The addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive ovarian cancer In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if a body of evidence is associated with a high risk of publication bias . Even when individual studies included in best- evidence summaries have a low risk of bias , publication bias can result in substantial overestimates of effect . Authors should suspect publication bias when available evidence comes from a number of small studies , most of which have been commercially funded . A number of approaches based on examination of the pattern of data are available to help assess publication bias . The most popular of these is the funnel plot ; all , however , have substantial limitations . Publication bias is likely frequent , and caution in the face of early results , particularly with small sample size and number of events , is warranted OBJECTIVES To determine the maximum tolerated dose ( MTD ) , spectrum of toxicities , clinical activity , and pharmacokinetics of carboplatin given in combination with lapatinib in women with a first recurrence of platinum sensitive epithelial ovarian carcinoma . METHODS Patients with measurable , platinum sensitive recurrent epithelial ovarian carcinoma were eligible . Cohorts of 3 - 6 patients were to receive up to 6 cycles of intravenous carboplatin AUC of 6 every 21 days in combination with escalating dosages of oral lapatinib ( starting at a dose of 750 mg daily ) .  Toxicity was assessed using NCI CTC for Adverse Events . Clinical response was monitored using RECIST criteria . Pharmacokinetic ( PK ) analysis was performed for the second cohort of patients . RESULTS Twelve patients were enrolled . No dose limiting toxicity was noted . Two of 6 patients in the first cohort had unanticipated excessive delays in treatment due to non-dose limiting G3 neutropenia . Therefore , the study was modified to reduce the carboplatin dose in the second cohort . The median number of courses administered to the 11 evaluable patients in these two cohorts was 2.8 ( range 1 - 6 ) . Drug-related grade 3 or 4 toxicities included non-dose limiting G4 thrombocytopenia ( n=1 ) , and non-dose limiting G3 neutropenia ( n=3 ) . Of the 11 patients who received > or=1 course of therapy , 3 ( 27 % ) had a partial response , and 3 ( 27 % ) had stable disease . The pharmacokinetics of carboplatin were not significantly altered by concomitant administration of lapatinib . CONCLUSIONS This regimen of lapatinib and carboplatin was associated with unacceptable non-dose limiting toxicities , excessive treatment delays and limited clinical responses Purpose : To evaluate clinical activity and target modulation of v and etanib in women with recurrent ovarian cancer . Experimental Design : A phase II trial of orally administered v and etanib 300 mg daily was design ed to include analyses of target inhibition through paired biopsies and dynamic imaging . Core 18-gauge needle biopsies and dynamic contrast-enhanced magnetic resonance imaging were obtained before initiation of therapy and 6 weeks into therapy . Biopsy sample s were subjected to reverse-phase protein lysate array endpoint analysis . Cytokine concentrations were measured by enzyme-linked immunosorbent assay in serially collected plasma sample s. Results : Twelve patients entered the study , and accrual was terminated in the first stage because of lack of response or disease stabilization beyond 6 months . Adverse events included rash , diarrhea , and prolonged QT interval corrected for heart rate , but not hypertension . Exploratory analyses showed that epidermal growth factor receptor ( EGFR ) phosphorylation was reduced in the eight paired biopsy sets obtained ; vascular endothelial growth factor ( VEGF ) receptor-2 phosphorylation was not consistently affected nor were dynamic contrast-enhanced MRI permeability and flow parameters . Serial plasma VEGF concentrations were variable and did not significantly change in the 11 patients assessed . Conclusions : V and etanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting . Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGF receptor-2 in ovarian tumor tissue , but only phosphorylated-EGFR was measurably inhibited by v and etanib . Clin Cancer Res ; 16(2 ) ; The primary objective of this study 
    Output:
    
EGFR inhibitors , including pertuzumab , may add activity to conventional chemotherapy for treatment of platinum-resistant ovarian cancer .
Certain subsets of women with particularly aggressive tumours resistant to conventional chemotherapy may benefit from EGFR inhibitor treatment .