Difference In Median Progression-free Survival Research Articles

Impact of beta blocker medication in patients with platinum sensitive recurrent ovarian cancer—a combined analysis of 2 prospective multicenter trials by the AGO Study Group, NCIC-CTG and EORTC-GCG

ObjectiveRetrospective analyses suggest that the treatment with beta blocker improves survival in patients with breast cancer and melanoma. The aim of this study was to investigate the impact of medication with beta blocker in patients with recurrent ovarian cancer. MethodsIncluded patients received treatment within two prospective clinical trials: AGO-OVAR 2.4 phase I trial (carboplatin/gemcitabine; N=25, protocol AGO-OVAR 2.4) and AGO led intergroup phase III trial (carboplatin vs carboplatin/gemcitabine; N=356, protocol AGO-OVAR 2.5, EORTC-GCG, NCIC CTG). Concurrent medication was documented after every cycle and thorough monitoring was conducted. ResultsDuring the studies 38 patients (9.97%) received a beta blocker as co-medication. Patients treated with beta blockers were significantly older than patients not treated with beta blockers. Response rates to chemotherapy were not different between patients treated with beta blockers and those who were not. After a median follow-up of 17months, 349 (91.6%) patients had progressive disease and 267 (70.1%) patients had died. No difference in median progression-free survival (7.79 vs 7.62months (p=0.95)) and overall survival (21.2 vs 17.3months (p=0.18)) was recorded for patients treated with and without beta blocker. In multivariate analyses including age, platinum free-interval, study treatment and ECOG performance status beta blocker treatment was not associated with a significant impact on progression-free survival (HR: 0.92; 95% CI: 0.65–1.31; p=0.65) and overall survival (HR:0.74; 95%CI: 0.49–1.11; p=0.15). ConclusionsIn this series of recurrent platinum-sensitive ovarian cancer patients it could not be confirmed whether beta blocker treatment was associated with better or worse outcome.

Correlation of progression-free and post-progression survival with overall survival in advanced colorectal cancer

Polychemotherapy and biological drugs have increased therapeutic options and outcomes of advanced colorectal cancer (CRC). We examined the relation between progression-free survival (PFS), post-progression survival (PPS) and overall survival (OS) in trials of modern (oxaliplatin- and irinotecan-based) chemotherapy alone or with targeted therapies for advanced CRC. We also evaluated surrogacy of PFS and OS. A PubMed search identified 34 randomized trials. We split the OS, PFS and PPS and evaluated the correlation between OS and either PFS or PPS. The median PPS and PFS were 10.75 and 8.4 months, respectively. For all trials, PPS was strongly associated with OS [regression coefficient (R2)=0.8; Spearman's rank correlation coefficient (r)=0.88], whereas PFS was moderately associated with OS (R2)=0.43; r=0.64). In trials with targeted therapies, the correlation of PPS with OS was 0.88. However, across all trials, correlation between differences in median PFS (ΔPFS) and median OS (ΔOS) is 0.59 (P=0.0007), confirming PFS/OS surrogacy. Our findings indicate that in recent first-line, phase III, trials, OS becomes more associated with PPS than PFS. However, improvements in PFS are strongly associated with improvements in OS. In this setting so, PFS may be an appropriate surrogate for OS.

A randomized phase II study of biweekly irinotecan monotherapy or a combination of irinotecan plus 5-fluorouracil/leucovorin (mFOLFIRI) in patients with metastatic gastric adenocarcinoma refractory to or progressive after first-line chemotherapy

The aim of this study was to evaluate the efficacy of irinotecan (CPT-11) monotherapy and CPT-11 plus 5-fluorouracil (5-FU)/leucovorin (LV) combination (mFOLFIRI) as second-line treatment in patients with advanced gastric cancer (AGC). A total of 59 patients were randomly assigned to either CPT-11 (150 mg/m(2) iv on day 1) or mFOLFIRI (CPT-11 150 mg/m(2) plus LV 20 mg/m(2) on day 1 followed by 5-FU 2,000 mg/m(2) over 48 h), every 2 weeks. The primary end point was objective response rate (ORR). Following random assignment, 29 patients received CPT-11 and 30 patients mFOLFIRI. The ORR was 17.2 % [95 % confidence interval (CI) 3.4-30.9] and 20.0 % (95 % CI 5.6-34.3) for the CPT-11 and mFOLFIRI arms, respectively (P = 0.525). There was no significant difference in median progression-free survival: 2.2 months (95 % CI 0.2-4.3) for CPT-11 versus 3.0 months (95 % CI 2.0-3.7) for mFOLFIRI (P = 0.481) or in median overall survival: 5.8 months (95 % CI 3.0-8.7), compared with 6.7 months (95 % CI 5.3-8.2) (P = 0.514). Grade 3/4 toxicity was observed in 21 and 28 events in the CPT-11 and mFOLFIRI arms, respectively. Although this study had a small sample size and limited statistical power, CPT-11 monotherapy and mFOLFIRI appear to be equally active and tolerable as second-line chemotherapy for AGC. The addition of 5-FU/LV to CPT-11 did not significantly improve efficacy.

Anti-ovarian antibodies in sera of patients with ovarian tumors

Aim of paperThe purpose of this study was to assess the presence of anti-ovarian autoantibodies in sera of patients with ovarian tumors. Materials and methodsThe study group consisted of 82 patients treated at the Division of Gynecological Surgery, Poznan University of Medical Sciences, Poland in 2007–2011. 46 patients with malignant ovarian tumors and 36 patients diagnosed with benign ovarian tumor were included into the study. Age-matched healthy control groups consisted of 15 women and 19 men. Anti-ovarian autoantibodies in serum were assessed with the use of indirect immunofluorescence. The presence of anti-ovarian autoantibodies in serum was correlated with clinical and histopathological features of the disease. ResultsSerum anti-ovarian autoantibodies were found in 59% (27/46) of patients with malignant ovarian tumors, compared to 55% (20/36) and 26% (4/15) of patients with benign ovarian tumors and healthy female controls respectively. The difference was statistically significant (P=0.04). All serum samples from the male controls were negative. Anti-ovarian antibodies occurred more often among advanced stage (III and IV stage according to FIGO, P=0.037) and grade 3 (P=0.049) ovarian cancers, however, there were no differences in median progression-free survival (P=0.388). The presence of anti-ovarian antibodies was neither influenced by histopathological type of the tumor, menopausal status, presence of ascites nor CA125 levels. Seropositivity for anti-ovarian antibodies was correlated positively with patients’ age and negatively with tumor size. ConclusionsAnti-ovarian autoantibodies develop with higher frequency in ovarian cancer comparing to healthy controls, however with similar proportion to benign ovarian tumors patients. The presence of antibodies against normal ovarian tissue correlates with ovarian cancer aggressiveness.

A Pooled Analysis of Sequential Therapies with Sorafenib and Sunitinib in Metastatic Renal Cell Carcinoma

Objective: To evaluate the optimal sequence for the receptor tyrosine kinase inhibitors (rTKIs) sorafenib and sunitinib in metastatic renal cell cancer. Methods: We performed a retrospective analysis of patients who had received sequential therapy with both rTKIs and integrated these results into a pooled analysis of available data from other publications. Differences in median progression-free survival (PFS) for first- (PFS1) and second-line treatment (PFS2), and for the combined PFS (PFS1 plus PFS2) were examined using weighted linear regression. Results: In the pooled analysis encompassing 853 patients, the median combined PFS for first-line sunitinib and 2nd-line sorafenib (SuSo) was 12.1 months compared with 15.4 months for the reverse sequence (SoSu; 95% CI for difference 1.45–5.12, p = 0.0013). Regarding first-line treatment, no significant difference in PFS1 was noted regardless of which drug was initially used (0.62 months average increase on sorafenib, 95% CI for difference –1.01 to 2.26, p = 0.43). In second-line treatment, sunitinib showed a significantly longer PFS2 than sorafenib (average increase 2.66 months, 95% CI 1.02–4.3, p = 0.003). Conclusion: The SoSu sequence translates into a longer combined PFS compared to the SuSo sequence. Predominantly the superiority of sunitinib regarding PFS2 contributed to the longer combined PFS in sequential use.

Analysis according to prognostic factors in patients (pts) treated with first-line bevacizumab (BEV) combined with paclitaxel (PAC) for HER2-negative metastatic breast cancer (mBC) in a routine oncology practice study.

1077 Background: 1st-line BEV combined with weekly PAC significantly improves progression-free survival (PFS) and response rate (RR) vs PAC alone in HER2-negative mBC, as shown in E2100. We analyzed data from a German routine oncology practice study of 1st-line BEV–PAC according to prognostic factors. Methods: Pts who had received no prior chemotherapy for mBC received BEV–PAC according to the European label. Efficacy and safety were documented for up to 1 y (or until progression, death, or BEV discontinuation if earlier) with additional long-term follow-up. Efficacy was analyzed in clinically important subgroups. Results: Efficacy data were available for 818 pts. The median duration of follow-up was 11.4 mo. The composition of the pt population with respect to the subgroups below was generally similar to the population treated in E2100, except for a higher proportion of pts with visceral disease or metastases in <3 organs. RR was very similar across all subgroups analyzed. Differences in median PFS and OS were generally in line with the differing prognoses according to clinical characteristics. Conclusions: These data suggest that 1st-line BEV–PAC is typically associated with median PFS >9 mo in the real-life setting, irrespective of baseline characteristics. [Table: see text]

Bevacizumab (BEV) plus capecitabine as maintenance therapy after initial treatment with BEV plus XELOX in previously untreated patients (pts) with metastatic colorectal cancer (mCRC): Mature data from STOP and GO, a phase III, randomized, multicenter study.

3565 Background: Colorectal cancer is one of the most frequent malignancies, second after breast cancer in women and third after lung cancer and prostate cancer in men. The aim of this study was to evaluate and compare the progression-free survival (PFS) between two arms: Arm A is a combination of BEV + XELOX; Arm B is a combination of BEV + XELOX for 6 cycles followed by maintenance BEV + capecitabine as first-line therapy in mCRC. Methods: BEV (7.5 mg/kg) + XELOX (capecitabine 1000 mg/m2 bid d1–14 + oxaliplatin 130 mg/m2 d1 q3w) were administered until progression (Arm A) or 6 cycles of BEV + XELOX followed by BEV + capecitabine were administered until progression (Arm B). PFS was the primary endpoint; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. A sample size of 118 pts was required to detect with 80% power an increase of 1.5 months in median PFS between two arms with a standard deviation of 3.9 months and significance level of 0.05 (10% drop-out rate). Results: A total of 123 pts were randomized. Demographic characteristics were balanced between the arms. Median treatment period was 7.5 (range 0.5–13.9) and 8.1 (range 0.1–20.7) months in Arms A and B, respectively. There was a statistically significant difference in median PFS between arms, although there was no significant difference in ORR and OS (see table). Tolerability was acceptable in both arms with the following grade 3/4 adverse events (AEs): Arm A 48.4%; Arm B 34.4% (p=0.116). Grade 3/4 diarrhoea occurred in 9.7% vs. 3.3%, weakness in 8.1% vs. 8.2%, hand-foot syndrome in 3.2% vs. 1.6%, and neuropathy in 4.8% vs. 3.3% of pts in Arms A and B, respectively. Conclusions: These findings suggest that maintenance therapy with BEV + capecitabine following induction with 6 cycles of BEV + XELOX may be superior to continuous BEV + XELOX until progression inpts with previously untreated mCRC. [Table: see text]

Effect of germline polymorphisms of DNA repair genes on chemotherapy outcome in advanced non-small cell lung cancer (NSCLC) patients.

e18057 Background: The identification of predictors of efficacy of chemotherapy in NSCLC could help in the selection of patients who are more likely to benefit from a particular scheme and the avoidance of undue toxicity in poor responders. We examined the role of several polymorphisms in DNA repair and DNA synthesis genes as pharmacogenetic markers in the outcome of NSCLC patients. Methods: A blood sample was collected from 117 patients with NSCLC and genomic DNA was isolated from the peripheral blood nucleated cells. Polymorphisms were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were excision repair cross-complementing-1 (ERCC1 Asn118Asn), xeroderma pigmentosum group D (XPD Lys751Gln), thymidylate synthase (TS) (VNTR/5’UTR, 2R G>C SNP, 3R G>C SNP) and Methylenetetrahydrofolate reductase (MTHFR) (C677T, A1298C). Progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. Results: 103 patients with stage III-IV NSCLC (47% adenocarcinoma, 41% squamous cell carcinoma, 12% NOS) receiving platinum-based chemotherapy were eligible (14 patients with stage I-II were excluded). The median PFS was significantly longer in patients with C/T or T/T genotypes in codon 118 in ERCC1: 13 months (m) and 10 m, respectively, as compared to 6 m for the C/C patients (p=0.034). Patients with ERCC1 C/T or T/T genotypes had a trend to longer median OS (20 m) than those C/C (10.5 m; p=0.1). Subgroup analysis revealed that ERCC1 C/T or T/T genotypes were associated with increased PFS in male (p=0.005), smokers (p=0.036) and age <70 years (p=0.012). Patients with A/A or A/C genotypes in codon 751 in XPD had a trend to longer median OS than those C/C (p=0.09). No differences in median PFS were observed. No association between TS and MTHFR polymorphisms and outcome was found in overall population. Conclusions: ERCC1 C/T or T/T genotype in codon 118 might be useful for predicting the outcome of NSCLC patients treated with platinum-based chemotherapy specially in male, smokers and age <70 subgroups.

Resection and Immunotherapy for Recurrent Grade III Glioma

Background. Despite surgery, radiotherapy, and chemotherapy, the prognosis of relapsed grade III gliomas remains poor. After promising results of immunotherapy in grade IV gliomas, we investigated its safety and efficacy in recurrent grade III gliomas. Methods. Thirty-nine patients received vaccines containing dendritic cells loaded with autologous tumor lysate after tumor resection. Progression-free survival (PFS) and overall survival (OS) were compared with those obtained after temozolomide (TMZ) treatment as found in the literature. Results. Median PFS and OS were 4.6 and 20.5, 3.4 and 18.8, 7.8 and 13.3 months in recurrent grade III astrocytoma, oligodendroglioma, and oligoastrocytoma, respectively. Compared with TMZ, no grade III/IV toxicity was reported and median OS tended to be higher although there was no difference in median PFS. The perceived benefit of immunotherapy was more pronounced in astrocytic tumors. Conclusions. We provide the first description of immunotherapy in recurrent grade III glioma as safe, promising, and feasible.

A Randomized Phase II Trial of Two Regimens of Moderate Dose Chemoradiation Therapy for Patients with Non-small Cell Lung Cancer Not Suitable for Curative Therapy: Trans Tasman Radiation Oncology Study TROG 03.07

There are patients with stage I-III non-small cell lung cancer (NSCLC) who are not suitable for curative radical chemoradiation therapy. There are patients with an isolated solitary extracranial metastasis who have improved outcomes compared with those with cranial or multiple metastases. Patients of good performance status receiving moderate dose radiation therapy have improved survival. Two regimens of moderate dose chemoradiation therapy for such patients were compared in a randomized phase II trial. Patients were eligible if they had stage I-IIIB NSCLC, unsuitable for curative therapy, or stage IV with a PET-detected extracranial solitary metastasis. Patients were randomized to the following groups-arm A: 40 Gy/20 fractions/4 weeks with concurrent weekly vinorelbine 25 mg/m + cisplatin 20 mg/m or arm B: 30 Gy/15 fractions/3 weeks with concurrent weekly gemcitabine 200 mg. Primary end points were feasibility, response rates, and toxicity. Secondary end points were progression-free survival, overall survival, and quality of life. Eighty-four patients were randomized. Compliance was above 90% for both arms. The overall response rate was 51% in arm A and 38% in arm B (p = 0.147). Grade 3/4 toxicity in both arms was acceptable. There was no difference in median progression-free survival between the two arms (5.5 versus 5.0 months, p = 0.19). Patients in arm A had longer median survival but this did not reach statistical significance (13.1 versus 8.3 months, p = 0.25). No difference in quality of life was observed. Arm A was chosen for a future phase II comparison with radiation therapy alone as it demonstrated a response rate greater than 50%, and data suggested that arm A had superior survival to arm B.

Frontline Therapy of Nodular Lymphocyte Predominant Hodgkin Lymphoma with Rituximab: The Stanford University Experience

Abstract 2686 Background:Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subtype of HL (∼5%). This unique clinical entity is characterized by an indolent clinical course and unlike classical HL late relapses may occur. Standard treatment depends on stage and includes radiation therapy (RT) and/or chemotherapy which can be associated with an increased risk of treatment related late effects warranting investigation of other active agents. The malignant cells of NLPHL universally express CD20, therefore therapy with rituximab (R), the monoclonal anti-CD20 antibody, is a targeted option. We report our experience with R as front-line treatment for patients with NLPHL. Methods:Patients with newly diagnosed NLPHL and measurable disease were treated with R at 375 mg/m2 administered weekly × 4 or, after protocol amendment (February 2003) with R followed by 4 doses of R maintenance (RM) administered every 6 months for 2 years. Restaging studies were performed at 1, 3 and 6 months and then every 6 months until progression. All pathology was centrally reviewed. Results:Nineteen patients were enrolled between May 1999 and September 2006. The median age at treatment was 45 years (range 17–63), stage I (n=6), stage II (n=7), stage III (n=6). Ten patients were treated with R alone and 9 with R+RM. The median follow-up for R patients is 8.8 years (5–11.4) and for R+RM patients is 5 years (2.5–7.6). At the end of induction therapy with R alone, the overall response rate was 100% [complete response (CR) (n=10), CR unconfirmed (n=2) and partial response (n=7)]. The median progression free survival (PFS) for patients treated with R alone and R+RM is 50 months and 67 months, respectively (p=0.7; log rank test) and median overall survival (OS) not reached. The median follow up for patients without progressive disease at the time of this analysis was 6.9 years (range 2.5–11.5). The estimated PFS at 5 years is 51.7%, [95% CI 33.2–80.4] and at 10 years 35.4% [95% CI 17.7–70.8]. There was no difference in median PFS between patients with stages I-II versus III (5.6 years and 4.15 years respectively, p=0.58 [log rank test]). The estimated OS at 5 years is 93.3%, [95% CI 81.5–100] and 10 years 76% [95% CI 55.4–100]. Ten patients progressed (5 treated with R alone, 5 treated with R+RM) of whom 6 transformed to an aggressive B cell lymphoma (biopsy proven) at a median of 4.2 years [range 0.9–8]. Five of the 6 transformed patients had abdominal disease at initial diagnosis (stage III, n=4). Three patients died (2 aggressive NHL, 1 unknown). Conclusion:Rituximab is an active single agent in the treatment of newly diagnosed NLPHL with a median PFS of 5.6 years. R+ RM resulted in a non-significant increase in PFS compared to R alone. In this series, abdominal involvement was associated with transformation to an aggressive B cell lymphoma underscoring the need for biopsy at relapse. These results demonstrate a pattern of late relapse following rituximab, at least as great as the historical data with RT or RT + CT. Although R alone achieved proof of concept for a targeted therapy, its use should remain investigational as primary therapy of NLPHL. Disclosures:Advani:Genentech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Rituximab. Anti-CD20 agent that targets CD20 on NLPHL cells. Horning:Genentech: Employment, Equity Ownership.

A Retrospective Comparison of Docetaxel and Paclitaxel for Patients with Advanced or Recurrent Esophageal Cancer Who Previously Received Platinum-Based Chemotherapy

Objective: To retrospectively compare docetaxel (DTX) with paclitaxel (PTX) with regard to efficacy and safety in advanced or recurrent esophageal cancer patients who previously received platinum-based chemotherapy. Methods: We retrospectively analyzed 124 advanced or recurrent esophageal cancer patients who had received platinum-based chemotherapy and then received DTX or PTX from April 2006 to November 2010. Results: Eighty-six patients (69.4%) received DTX and 38 patients (30.6%) received PTX monotherapy. Due to toxicity, dose reduction was needed in 36.0 and 27.8% of patients and treatment was discontinued in 10.5 and 2.6% of patients receiving DTX and PTX, respectively. The objective response (25.7 vs. 10.3%, p = 0.03) and disease control rates (60.0 vs. 34.6%, p = 0.01) were higher in the PTX group than in the DTX group, respectively. There were no significant differences in median progression-free survival (2.1 vs. 3.5 months) and overall survival (6.1 vs. 7.2 months) between the DTX and PTX groups, respectively. Grade 3–4 neutropenia (48.8 vs. 21.1%, p = 0.003) and febrile neutropenia (20.9 vs. 5.3%, p = 0.029) were more frequent in the DTX patients than in the PTX patients, respectively. Conclusion: Although the efficacy of DTX and PTX for advanced or recurrent esophageal cancer patients after platinum-based chemotherapy was not significantly different in terms of survival, PTX was a more feasible treatment. PTX provided similar efficacy to DTX with less febrile neutropenia.

A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03)

BackgroundEORTC study 08021/ILCP 01/03 evaluated the role of consolidation gefitinib, an oral tyrosine kinase inhibitor (TKI), administered in patients with advanced non-small cell lung cancer (NSCLC), not progressing following standard 1st-line chemotherapy. MethodsPatients with advanced NSCLC, not-progressing after four cycles of platinum-based chemotherapy, were randomised to receive either gefitinib 250mg/d or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival (OS). Secondary end-points were progression-free survival (PFS) and toxicity. The study was powered to detect a 28% increase in OS from a median of 11–14.1months (HR=0.78) and planned to randomise 598 patients to observe 514 deaths. ResultsAfter inclusion of 173 patients, the trial was prematurely closed due to low accrual. Baseline characteristics for gefitinib (n=86) and placebo (n=87) arms were well balanced. After a median follow up of 41months, the difference in median OS in the gefitinib and placebo arms was not statistically significant (10.9 and 9.4months, HR 0.83 [95% confidence interval (95% CI) 0.60–1.15]; p=0.2). The difference in median PFS significantly favoured gefitinib (4.1 and 2.9months, HR=0.61, [95% CI 0.45, 0.83]), p=0.0015). Adverse events reported in more than 10% of patients were rash (47% with gefitinib versus 13% with placebo) and diarrhoea (34% with gefitinib versus13% with placebo). ConclusionsDespite its premature closure, this trial confirms previous evidence that consolidation gefitinib is safe and improves PFS. However, no difference in OS was observed in this study (NCT00091156).

Bevacizumab plus capecitabine as maintenance treatment after initial treatment with bevacizumab plus XELOX in previously untreated metastatic colorectal cancer: Updated findings from a randomized, multicenter phase III trial.

3579 Background: Colorectal cancer is one of the most frequent malignancies, second to breast cancer in women and third to lung cancer and prostate cancer in men. The aim of this study in first-line metastatic colorectal cancer (mCRC) was to achieve a better progression-free survival (PFS) and less risk of toxicity by administrating bevacizumab (BEV) + capecitabine + oxaliplatin (XELOX) for 6 cycles, stop oxaliplatin and go with maintenance therapy (BEV + capecitabine) until progression. Methods: BEV (7.5 mg/kg) + XELOX (capecitabine 1000 mg/m2 bid d1–14 + oxaliplatin 130 mg/m2 d1 q3w) were administered until progression (Arm A) or 6 cycles of BEV + XELOX followed by BEV + capecitabine were administered until progression (Arm B). PFS was the primary endpoint; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. A sample size of 118 patients (pts) was calculated to achieve 80% power to detect an increase of 1.5 months in median PFS between Arm A (9.5 months) and Arm B (11.0 months) with a standard deviation of 3.9 months and significance level of 0.05 using a 10% drop-out rate. Results: A total of 122 pts were randomized. No significant differences were found in demographic characteristics between the two arms. Median treatment period was 6.1 (range 0.7–13.4) and 6.8 (range 0.7–12.4) months in Arms A and B, respectively. Interim analysis showed no statistically significant differences in median PFS and ORR between arms (Table). Tolerability was also acceptable in both arms with grade 3/4 diarrhoea in 7.7% vs. 8.2%, weakness in 15.2% vs. 8.4%, hand-foot syndrome in 6.3% vs. 9.4%, and neuropathy in 2.8% vs. 4.6% of pts in Arms A and B, respectively. Conclusions: BEV + capecitabine as maintenance therapy following induction BEV + XELOX is noninferior to continuous BEV + XELOX until progression. These interim findings suggest that maintenance therapy with BEV + capecitabine is an appropriate option following induction BEV + XELOX in pts with mCRC. Updated data will be presented. Efficacy Arm A (n=61) Arm B (n=61) P value Median PFS, months 8.3 9.9 0.064 ORR, % 57.4 69.2 0.207

The Changes in Residual Cancer Burden after Interval Debulking Surgery Are Effective in Evaluating the Response to Adjuvant Chemotherapy

Objective: To study the clinical significance of the change of residual cancer burden (RCB) of epithelial ovarian carcinoma (EOC) between primary (PDS) and interval debulking surgery (IDS) in order to evaluate the effectiveness of adjuvant chemotherapy. Methods: Thirty-eight EOC patients with suboptimal PDS with adjuvant chemotherapy were selected for this retrospective study and divided into pathologically negative (group A) and pathologically positive (group B) groups based on the histopathological examination and the change of size of residual disease after IDS. Patients in group B were further divided into groups B1 (partial remission criteria, n = 9), B2 (consistent with stable disease, n = 12) and B3 (consistent with disease progression, n = 4) based on the changes in RCB between PDS and IDS and the guidelines to evaluate the response to treatment in solid tumors (Response Evaluation Criteria in Solid Tumors, RECIST). The responses to chemotherapy evaluated by pathological examination of RCB versus by CA-125, recurrence patterns, and prognoses were analyzed. Results: The clinical benefit rates evaluated by pathological assessment for groups A, B1, B2 and B3 were 100, 100, 100 and 0%, respectively (p < 0.01), whereas the rates were not statistically different when evaluated by CA-125 (100, 100, 91.7 and 100%, respectively; p > 0.05). The median progression-free survival (PFS) for patients in groups A and B was 36 and 6 months, respectively (p < 0.05); the median overall survival (OS) was 93 and 42 months, respectively (p < 0.05). There were no significant differences in median PFS or OS among patients in groups B1, B2 and B3 (PFS: 16, 6 and 1.5 months; OS: 52, 31 and 30.5 months, respectively; all p > 0.05), but there were significant differences in median PFS or OS between B1 and B3. There was no significant difference in recurrence rates between groups A and B (53.8 vs. 72.0%, p > 0.05), but there were significant differences in the rate of drug-resistant recurrence [28.6% (2/7) vs. 72.2% (13/18), p < 0.05] and in median PFS of relapsed patients (19 vs. 4 months, p < 0.05). Conclusion: The histopathological assessment of RCB between PDS and IDS may be used to evaluate and predict the response to adjuvant chemotherapy in EOC.

Adjuvant chemotherapy no benefit in patients with rectal cancer

130 British Journal of Hospital Medicine, March 2011, Vol 72, No 3 New data from the randomized, double-blind, placebo-controlled, multicentre phase III RADIANT-2 trial has revealed that combination therapy with a rapamycinderived immunosuppressant, everolimus, and the somastatin analogue, octreotide LAR, lengthens median progressionfree survival in patients with advanced neuroendocrine tumours. Dr James Yao, Associate Professor, MD Anderson Cancer Centre, University of Texas, Houston, Texas, reported that patients who received the everolimus–octreotide LAR combination had a median progression-free survival of 16.4 months vs 11.3 months in patients assigned to placebo plus octreotide LAR. ‘Conventional chemotherapy has limited efficacy for patients with advanced neuroendocrine tumours, and there remains a significant unmet medical need in this population,’ he commented. While the everolimus and octreotide LAR combination did not achieve its primary progression-free survival end point, the 5.1-month increase in progression-free survival is a clinically meaningful improvement. Importantly, analyses that adjusted for imbalances in baseline characteristics in the two treatment groups and inconsistencies in the review of radiology scans for disease progression showed that everolimus plus octreotide LAR significantly decreased the likelihood of disease progression. A total of 429 patients with advanced lowor intermediate-grade neuroendocrine tumours and a history of symptoms attributed to carcinoid syndrome were randomized to treatment with oral everolimus (10 mg/day) plus octreotide LAR (30 mg administered by intramuscular injection every 28 days) or placebo plus octreotide LAR. Treatment continued until disease progression. Dr Yao said that octreotide LAR has been the foundation of therapy for patients with neuroendocrine tumours, but additional treatment options were needed. Everolimus, an oral inhibitor of mTOR, had demonstrated promising antitumour activity in patients with neuroendocrine tumours as a single agent and in combination with octreotide LAR in two phase II studies. The difference in median progression-free survival between the two arms of RADIANT-2 represented a 23% reduction in risk of progression (hazard ratio=0.77, P=0.026). Correcting for the informative censoring bias, further analysis showed a significant 5.5-month improvement in median progression-free survival with the combination treatment (hazard ratio=0.60, P= 0.0014). The benefit of the everolimus–octreotide LAR combination was seen across all patient sub-groups. Most frequent drug-related adverse events were stomatitis, rash, fatigue, and diarrhoea; mostly grade 1–2. Grade 3–4 adverse events reported in >5% were stomatitis, fatigue, diarrhoea, infections and hyperglycaemia. Dr Yao concluded: ‘The combination of everolimus and octreotide LAR provided a 5.1month clinically meaningful increase in median progressionfree survival – a benefit that increased to 5.5 months after correcting for reporting bias.’ Stephen Pinn Success with combination therapy for neuroendocrine cancer asCO GastrOintestinal CanCers sympOsium san FranCisCO, CaliFOrnia, 20–22 January

A randomized, multicenter phase III trial of bevacizumab plus capecitabine as maintenance treatment after initial treatment with bevacizumab plus XELOX in previously untreated metastatic colorectal cancer.

474 Background: Colorectal cancer is one of the most frequent malignancies, second to breast cancer in women and third to lung cancer and prostate cancer in men. The aim of this study in first-line metastatic colorectal cancer (mCRC) was to achieve a better progression-free survival (PFS) and less risk of toxicity by administrating bevacizumab (BEV) + capecitabine + oxaliplatin (XELOX) for 6 cycles, stop oxaliplatin and go with maintenance therapy (BEV + capecitabine) until progression. Methods: BEV (7.5 mg/kg) + XELOX (capecitabine 1,000 mg/m2 bid d1–14 + oxaliplatin 130 mg/m2 d1 q3w) were administered until progression (Arm A) or 6 cycles of BEV + XELOX followed by BEV + capecitabine were administered until progression (Arm B). PFS was the primary endpoint; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. A sample size of 118 patients (pts) was calculated to achieve 80% power to detect an increase of 1.5 months in median PFS between Arm A (9.5 months) and Arm B (11.0 months) with a standard deviation of 3.9 months and significance level of 0.05 using a 10% drop-out rate. Results: A total of 122 pts were randomized. No significant differences were found in demographic characteristics between the two arms. Median treatment period was 6.1 (range 0.7–13.4) and 6.8 (range 0.7–12.4) months in Arms A and B, respectively. Interim analysis showed no statistically significant differences in median PFS and ORR between arms (see table). Tolerability was also acceptable in both arms with grade 3/4 diarrhoea in 7.7% vs. 8.2%, weakness in 15.2% vs. 8.4%, hand-foot syndrome in 6.3% vs. 9.4%, and neuropathy in 2.8% vs. 4.6% of pts in Arms A and B, respectively. Conclusions: BEV + capecitabine as maintenance therapy following induction BEV + XELOX is non-inferior to continuous BEV + XELOX until progression. While this study is ongoing, these interim findings suggest that maintenance therapy with BEV + capecitabine is an appropriate option following induction BEV + XELOX in pts with mCRC. [Table: see text] [Table: see text]

22 Does histological subtype determine response to chemotherapy in advanced non-small cell lung cancer? A retrospective study

Introduction: Chemotherapy is the mainstay of treatment for advanced NSCLC. Recent results have focused interest on whether histological subtype is a prognostic or predictive factor for patients receiving it. The primary aim was to assess whether overall survival of patients receiving chemotherapy for NSCLC depends on histological type. Secondary endpoints were to assess the contribution of histological subtype to response rate and progression-free survival. Method: We undertook a retrospective analysis of NSCLC patients treated with a first line platinum-containing regimen at WPH between January 2004 and December 2008. Eligible patients had a pathologically confirmed diagnosis of advanced stage NSCLC. 600 patients were identified through an electronic prescribing database. Every third patient was selected to give a sample size of 200. Data were extracted from their medical notes and hospital databases. Patients with squamous and non-squamous histology were compared. Response was assessed on restaging CT scans during and after treatment. Results: 177 patients were eligible. Age, smoking status, performance status, co-morbidities and stage of disease were well balanced between the two histological groups. 79% received gemcitabine and carboplatin as first-line treatment in both groups. The overall response rate (RR) to chemotherapy was 55%. Although the RR appeared to be higher in those with squamous histology (64% vs 51%), this was not significant (p = 0.271). There was no significant difference in RR to different chemotherapy regimens (squamous p = 0.727, non-squamous p = 0.241). Similarly, there was no significant difference in median progressionfree survival (PFS) between the two groups. The median overall survival was 49 weeks for squamous and 35 weeks for non-squamous cancers but this difference was not statistically significant. Conclusion: Response and survival following chemotherapy at WPH are compatible with best international reports. In this study, histology was not predictive of response to chemotherapy, nor prognostic for survival. This is in contrast to some previously published prospective studies.

Abstract PD10-05: Do the Results of Metastatic Breast Tumour Biopsies Affect Patient Survival Outcomes? Results from a Large Prospective Trial

Abstract Background: Differences in receptor status between primary and metastatic breast cancer are well recognized. We have previous demonstrated substantial receptor discordance rates resulting in a change in management in 14% of patients. However, while retrospective studies suggest that discordance can be associated with a worse patient prognosis, there are currently no prospective data assessing the impact of such discordance on survival outcomes. Methods: A single-center prospective biopsy study was performed. Patients with either recurrent or progressive disease underwent biopsy of their metastases. Subsequent treatment choices were modified according to the results and patients were followed up for progression or death. To account for the differing times at which patients entered the study, progression-free survival (PFS) was calculated as the duration between biopsy and either progression or death. Overall survival (OS) was defined as the duration from diagnosis of metastatic disease to death. A Cox propotional hazards model accounting for duration of metastatic disease and visceral versus non-visceral metastatic disease was utilized. Results: 121 biopsies were completed and 38% of cases showed discordance between the primary and the recurrence. Survival data were available from 96 patients. After a median follow-up of 11 months, 76 patients (79%) had progressed and 38 (40%) had died. There was no difference in median PFS between concordant and discordance cases (5.9 vs. 6.5 months, HR 0.89, p=0.61). There was a non-significant trend towards worse OS in discordant cases (50.6 vs. 57.8 months, HR 0.77, p=0.47). When compared with the primary tumour a gain of HER2 was associated with a poor survival, while loss of HER2 was associated with improved outcome. Metastatic biopsies showed a trend towards better prediction of response to endocrine therapy with tumors losing progesterone receptor expression between primary and metastatic disease having worse DFS on endocrine therapy. Conclusion: We have previously shown that performing metastatic biopsies is associated with a substantial rate of receptor discordance between primary and metastatic disease. The current analysis demonstrates that this discordance is associated with a trend towards worse OS, but not PFS. Knowledge of the receptor status of metastatic disease allows better prognostication between HER2-postive and HER2-negative disease and also allows for improved prediction of response to endocrine therapy. Metastatic biopsies should therefore be considered in patients with recurrent breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD10-05.

Abstract PD05-01: CALGB 40302: Fulvestrant with or without Lapatinib as Therapy for Hormone Receptor Positive Advanced Breast Cancer: A Double-Blinded, Placebo-Controlled, Randomized Phase III Study

Abstract Background: Preclinical data suggest that inhibition of the EGFR and HER2 growth factor signaling pathways might potentiate the efficacy of endocrine treatment for ER positive breast cancer. CALGB 40302 was designed to determine whether the addition of the dual-kinase inhibitor, lapatinib, would improve progression-free survival (PFS) among women with hormone receptor positive metastatic breast cancer treated with the anti-estrogen, fulvestrant. Patients and Methods: This study was activated on 9/15/2006 for women with advanced (stage IV or stage III, not curable) breast cancer with measurable or evaluable (bone-only) disease, ECOG PS 0-2, adequate end-organ function, ER and/or PR positive tumors, and prior therapy with an aromatase inhibitor. Prior tamoxifen and up to 1 line of prior chemotherapy for advanced breast cancer were permitted. Patients were eligible regardless of HER2 status. All patients received fulvestrant 500 mg IM day 1, followed by 250 mg day 15 and day 28, and every 4 weeks thereafter. Patients were randomized 1:1 to lapatinib 1500 mg daily or placebo. Patients were restaged every 2 months, and continued on treatment until disease progression or prohibitive toxicity. The study was designed to accrue 324 patients and powered to show a 50% improvement in PFS with addition of lapatinib from 5 to 7.5 months. Results: At the 3rd planned interim analysis, 173 events were observed and the futility boundary was crossed, such that the predictive probability of concluding superiority of lapatinib over placebo if the study went to completion was 0.5%. At the recommendation of the Data Safety and Monitoring Board, the study was closed and treatment unblinded on 7/14/2010, having accrued 267 patients. The log-rank test showed no difference in PFS (hazard ratio [HR] = 0.982, 95% CI: 0.73 to 1.33; p = 0.94); median PFS was 5.2 months for fulvestrant + lapatininb vs 4.0 months for fulvestrant + placebo. There was no difference in median overall survival (22.3 vs 21.9 months for fulvestrant ± lapatinib; p= 0.64). Outcomes among HER2 normal (78%) and HER2 positive (22%) cohorts were not significantly different under an interaction model (p = 0.23). No differences in median PFS were seen in patients with HER2 normal tumors (4.1 vs 4.0 months for fulvestrant ± lapatinib, p=0.53). In patients with HER2+ tumors, a trend favored improved median PFS with addition of lapatinib (5.9 vs 2.8 months for fulvestrant ± lapatinib, p = 0.29). Treatment was generally well tolerated. The most frequent toxicities were grade 3 diarrhea (9%), fatigue (4%), and rash (4%) associated with lapatinib therapy. Conclusions: Among women with hormone receptor positive breast cancer previously treated with an AI, adding lapatinib to fulvestrant does not improve PFS or OS. Updated efficacy, response, and toxicity data will additionally be presented. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD05-01.