bluuebunny/crossref_metadata_2025 huggingface dataset:
Late psychosocial sequelae in Hodgkin's disease survivors: a French population-based case-control study.
Authors: Joly F , Henry-Amar M , Arveux P , Reman O , Tanguy A , Peny A M , Lebailly P , Macé-Lesec'h J , Vié B , Génot J Y , Busson A , Troussard X , Leporrier M
Published: February 2017

PURPOSE

To evaluate late psychosocial sequelae in long-term survivors of Hodgkin's disease (HD) in the population of Calvados, France.

PATIENTS AND METHODS

Ninety-three patients issued from the Calvados General Tumor Registry, treated from 1978 to 1990, free of relapse and second malignancy since January 1991, were enrolled onto cross-sectional case-control study. One hundred eighty-six healthy controls, matched for sex, age, and residency, were selected at random from electoral rolls. Two self-administered questionnaires were mailed in the spring of 1995.

RESULTS

Compared with controls, HD patients reported (1) more physical (P < .001), role (P < .001), and cognitive (P = .015) functioning impairments, as well as dyspnea (P < .001) and chronic fatigue (P = .025), while no statistical difference was found in global health status; (2) to be more often childless (P = .04), fewer divorces or separations (P = .013), fewer changes in relationships with friends (P = .012), similar proportions at work but less ambitious professional plans (P < .001), and greater difficulties in borrowing from banks (P < .001); (3) a slight increase in the number of visits to a general practitioner (P = .05) and greater consumption of medical resources (mainly thyroid extracts, P = .05).

CONCLUSION

The study demonstrated that French long-term HD survivors have good global health status and good psychologic, familial, and professional status, although difficulties in borrowing from banks remain a major limitation in daily life. Although physical, role, and cognitive functioning impairments persist that might limit their activities, HD survivors seem to have learned to cope with problems related to their disease and its treatment.
Cytarabine with high-dose mitoxantrone induces rapid complete remissions in adult acute lymphoblastic leukemia without the use of vincristine or prednisone.
Authors: Weiss M , Maslak P , Feldman E , Berman E , Bertino J , Gee T , Megherian L , Seiter K , Scheinberg D , Golde D
Published: February 2017

PURPOSE

To evaluate the efficacy and safety of a new induction regimen for adult acute lymphoblastic leukemia (ALL) that does not contain vincristine or corticosteroids.

PATIENTS AND METHODS

Thirty-seven adult patients with newly diagnosed ALL and lymphoblastic lymphoma were treated with a dose-intense induction regimen. This regimen was designed to increase the fraction of patients achieving an early complete remission (CR) in an attempt to increase long-term disease-free survival. The induction regimen was cytarabine (Ara-C) 3 g/m2/d for 5 days and mitoxantrone 80 mg/m2 as a single dose on day 3. Granulocyte colony-stimulating factor (G-CSF) 200 micrograms/ m2/d beginning on day 7 was used to promote early myeloid recovery.

RESULTS

There were 31 CRs (84%). Median time to CR was 34 days, median hospital stay was 28 days, and the median number of days with a neutrophil count less than 500/microL was 18. There were three patients with resistant disease who experienced treatment failure and three early deaths from sepsis. Four patients with Philadelphia chromosome-positive (Ph+) ALL achieved hematologic and cytogenetic CRs.

CONCLUSION

This dose-intense induction regimen produced a high incidence of CRs with acceptable toxicity without the use of vincristine or corticosteroids. Comparisons with our prior vincristine/prednisone-based induction regimen (the L-20 protocol) suggest that patients treated on the current study were more likely to achieve a CR and that they achieved this remission earlier than patients treated with a traditional four-drug (vincristine, prednisone, doxorubicin, and cyclophosphamide) induction regimen.
Phase I Trial of Adenovirus-Mediated p53 Gene Therapy for Recurrent Glioma: Biological and Clinical Results
Authors: Lang Frederick F. , Bruner Janet M. , Fuller Gregory N. , Aldape Kenneth , Prados Michael D. , Chang Susan , Berger Mitchel S. , McDermott Michael W. , Kunwar Sandeep M. , Junck Larry R. , Chandler William , Zwiebel James A. , Kaplan Richard S. , Yung W.K. Alfred
Published: February 2017

Purpose: Advances in brain tumor biology indicate that transfer of p53 is an alternative therapy for human gliomas. Consequently, we undertook a phase I clinical trial of p53 gene therapy using an adenovirus vector (Ad-p53, INGN 201).

Materials and Methods: To obtain molecular information regarding the transfer and distribution of exogenous p53 into gliomas after intratumoral injection and to determine the toxicity of intracerebrally injected Ad-p53, patients underwent a two-stage approach. In stage 1, Ad-p53 was stereotactically injected intratumorally via an implanted catheter. In stage 2, the tumor-catheter was resected en bloc, and the postresection cavity was treated with Ad-p53. This protocol provided intact Ad-p53–treated biologic specimens that could be analyzed for molecular end points, and because the resection cavity itself was injected with Ad-p53, patients could be observed for clinical toxicity.

Results: Of fifteen patients enrolled, twelve underwent both treatment stages. In all patients, exogenous p53 protein was detected within the nuclei of astrocytic tumor cells. Exogenous p53 transactivated p21CIP/WAF and induced apoptosis. However, transfected cells resided on average within 5 mm of the injection site. Clinical toxicity was minimal and a maximum-tolerated dose was not reached. Although anti-adenovirus type 5 (Ad5) titers increased in most patients, there was no evidence of systemic viral dissemination.

Conclusion: Intratumoral injection of Ad-p53 allowed for exogenous transfer of the p53 gene and expression of functional p53 protein. However, at the dose and schedule evaluated, transduced cells were only found within a short distance of the injection site. Although toxicity was minimal, widespread distribution of this agent remains a significant goal.
A randomized trial in ovarian cancer (OC) of early treatment of relapse based on CA125 level alone versus delayed treatment based on conventional clinical indicators (MRC OV05/EORTC 55955 trials)
Authors: Rustin G. J. , van der Burg M. E.
Published: February 2017

1

Background: Serum CA125 often rises several months before women with OC have symptoms or clinical signs of relapse. OV05/55955 was designed to determine whether there were benefits from early treatment based on a confirmed elevation of CA125 levels versus delaying treatment until clinically indicated. Methods: Women with OC in clinical complete remission after first-line platinum-based chemotherapy and a normal CA125 were registered. CA125 was measured every 3 months but patients and investigators were blinded to the results, which were only monitored by the trials units. If CA125 levels exceeded twice the upper limit of normal, patients were randomized to either immediate treatment or to remain having blinded CA125 measurements with treatment commencing when clinical or symptomatic recurrence appeared. Patients in both arms were treated according to standard local practice. The primary outcome measure was overall survival. The study was designed to detect a 10% improvement in 2-year overall survival in the immediate treatment arm with at least 85% power and 5% significance level (2-sided). Results: 1,442 patients were registered from 59 sites in 10 countries between 1996 and 2005. Randomization closed on March 31, 2008 with 527 patients (264 immediate and 263 delayed) randomized and when the targeted number of events (deaths) were reached. 915 patients have not been randomized due to: no CA125 rise and no relapse (48%); relapse with or without CA125 rise (30%); death (6%); patient withdrawal (14%); or other reasons (2%). For randomized patients baseline characteristics were well balanced between the groups. Median age at registration was 61 years; 81% were FIGO stage III/IV. Second-line chemotherapy started a median of 5 months earlier in the immediate arm. With a median follow-up of 49 months from randomization and a total of 351 deaths, there was no evidence of a difference in overall survival between the immediate and delayed arms, hazard ratio 1.01, 95% CI 0.82–1.25, p = 0.91. Conclusions: There is no survival benefit from early treatment based on a raised serum marker level alone, and therefore no value in the routine measurement of CA125 in the follow-up of ovarian cancer patients.

No significant financial relationships to disclose.
Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer
Authors: Tutt A. , Robson M. , Garber J. E. , Domchek S. , Audeh M. W. , Weitzel J. N. , Friedlander M. , Carmichael J.
Published: February 2017

CRA501

Background: Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. A phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal of efficacy in BRCA-deficient ovarian cancers (ASCO 2008; abst 5510). The primary aim of this study was to test the efficacy of olaparib in confirmed BRCA1/BRCA2 carriers with advanced refractory breast cancer. The secondary aim was to assess safety and tolerability in this population. Methods: In an international, multicenter, proof-of-concept, single-arm, phase II study, two sequential patient (pt) cohorts received continuous oral olaparib in 28-day cycles initially at the MTD, 400 mg bd (27 pts), and subsequently at 100 mg bd, a previously identified PARP inhibitory dose (27 pts). Eligibility criteria included confirmed BRCA1/BRCA2 mutation and recurrent, measurable chemotherapy-refractory breast cancer. The primary efficacy endpoint was best objective response rate (ORR; RECIST) post baseline. Progression-free survival (PFS) and clinical benefit rate were secondary endpoints. All adverse events were reported using CTCAE v3. Results: On November 20, 2008, 54 pts exposed to a median of three prior lines of chemotherapy had been enrolled. 27 pts were dosed at 400 mg bd (18 BRCA1 deficient and 9 BRCA2 deficient), and 24 of these had databased RECIST assessments. The ORR (currently based on unconfirmed responses) was 38% (9/24) (400 mg bd). Causally-related toxicity was mainly mild (grade 1–2) in severity; 9/27 pts (33%) had fatigue; 7/27 (26%) had nausea; 4/27 (15%) had vomiting; and 1/27 (4%) had anemia. Causally-related grade 3 or higher toxicities were seen in 5 pts (19%) with fatigue (3 pts), nausea (2 pts), and anemia (1 pt). 27 pts were treated in the subsequent 100 mg bd cohort where no data are currently available. Conclusions: Olaparib at 400 mg bd is well tolerated and highly active in advanced chemotherapy-refractory BRCA-deficient breast cancer. Toxicity in BRCA1/BRCA2 carriers was similar to that reported previously in non-carriers. This first study with olaparib in BRCA-deficient breast cancers provides positive proof of concept for high activity and tolerability of a genetically defined targeted therapy.

[Table: see text]
Impact of omission of completion axillary lymph node dissection (cALND) or axillary radiotherapy (ax RT) in breast cancer patients with micrometastases (pN1mi) or isolated tumor cells (pN0[i+]) in the sentinel lymph node (SN): Results from the MIRROR study
Authors: Tjan-Heijnen V. C. , Pepels M. J. , de Boer M. , Borm G. F. , van Dijck J. A. , van Deurzen C. H. , Adang E. M. , Menke-Pluymers M. B. , van Diest P. J. , Bult P.
Published: February 2017

CRA506

Background: The Dutch MIRROR study is the largest cohort study on pN1mi and pN0(i+) in the SN era with long-term follow-up, central pathology review (6th AJCC-classification), and separate analyses on the use of adjuvant systemic therapy (AST). In patients not receiving AST, pN1mi and pN0(i+) as final N-stage were shown to be independent prognosticators for disease-free survival (SABCS 2008, #23, oral). As a substantial number of patients in the MIRROR study did not undergo cALND or ax RT, we questioned whether this policy was safe in patients with pN1mi(sn) or pN0(i+)(sn). Methods: Patients operated for breast cancer in all Dutch hospitals in the years 1998–2005, having favorable primary tumor characteristics, and having undergone an SN biopsy without macrometastases as final N-stage were included. For this present research question, patients were categorized by their SN-stage. Median follow-up was 4.7 years. The Kaplan-Meier method was used to estimate 5-year axillary recurrence (AR) rates, and Cox regression was used to estimate the hazard ratios (HR). In the analyses, the effect of AST was taken into account. Results: In total, 835 patients with pN0(i-)(sn), 799 patients with pN0(i+)(sn), and 958 patients with pN1mi(sn) were included. AR rates, and HRs on AR are displayed below. Conclusions: Omission of cALND or ax RT in patients with pN1mi(sn) resulted in a significantly higher 5-year AR rate, even after correction for AST, and other patient and tumor characteristics. This indicates that patients with pN1mi(sn) should undergo cALND or ax RT to prevent AR. Support: The Netherlands Organization for Health Research and Development (ZonMw) and the Dutch Breast Cancer Trialists’ Group (BOOG).

[Table: see text]

No significant financial relationships to disclose.
Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early-stage breast cancer: A pharmacoepidemiologic study
Authors: Dezentje V. , Van Blijderveen N. J. , Gelderblom H. , Putter H. , Van Herk-Sukel M. P. , Casparie M. K. , Egberts A. C. , Nortier J. W. , Guchelaar H. J.
Published: February 2017

CRA509

Background: The use of cytochrome P450 2D6 inhibiting drugs (CYP2D6 inhibitors) during tamoxifen treatment leads to a decrease in plasma concentration of endoxifen, the major active tamoxifen metabolite. Concomitant use of CYP2D6 inhibitors, such as the commonly prescribed selective serotonin reuptake inhibitors, as well as low tamoxifen adherence may negatively impact tamoxifen efficacy in breast cancer. The objectives were to relate concomitant CYP2D6 inhibitor use and tamoxifen adherence to breast cancer event free time (EFT). Methods: Data were used from PHARMO, a pharmacy database, PALGA, a nationwide pathology database and the Dutch Medical Register in the Netherlands. Breast cancer patients who were treated with tamoxifen as adjuvant therapy between 1994 and 2006 were included. A Cox proportional hazards model with a time-dependent definition for the CYP2D6 inhibitor exposure was used. Results: 1,990 breast cancer patients using tamoxifen were included, among whom 215 (10.8%) used a CYP2D6 inhibitor during tamoxifen treatment. No association between concomitant CYP2D6 inhibitor use and breast cancer recurrence was observed. Poor tamoxifen adherence was associated with lower EFT. Conclusions: This observational study did not show an association between concomitant CYP2D6 inhibitor use and breast cancer recurrence among patients treated with adjuvant tamoxifen. However, this study shows for the first time that poor tamoxifen adherence is associated with lower EFT.

No significant financial relationships to disclose.
A sense of urgency: Evaluating the link between clinical trial development time and the accrual performance of CTEP-sponsored studies
Authors: Cheng S. , Dietrich M. , Finnigan S. , Sandler A. , Crites J. , Ferranti L. , Wu A. , Dilts D.
Published: February 2017

CRA6509

Background: Post-activation barriers to oncology clinical trial accruals are well documented; however, potential barriers prior to trial opening are not. We investigate one such barrier: trial development time. Methods: National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) sponsored trials for all therapeutic, non-pediatric phase I,I/II, II, and III studies activated in an eight year period (2000–2007) were investigated (n=553). Successful trials were those achieving 100% of minimum accrual goal. Time to open a study was the calendar time from initial CTEP submission to trialactivation. Multivariable logistic regression analysis was used tocalculate unadjusted and adjusted odds ratios, controlling for study phase and size of expected accruals. Results: 40.0 percent (n=221) of CTEP-approved oncology trials failed to achieve minimum accrual goals, with 49.2 percent (n=30) of phase III trials failing to achieve at least 25 percent of accrual goals. A total of 8,723 patients (17.0% of accruals) accrued to those studies that were unable to achieve the projected minimum accrual goal. Trials requiring 9–12 months development were significantly more likely to achieve accrual goals (odds ratio, 1.94; 95% CI, 1.06 to 3.52, P=0.031) than trials requiring the median time (15–18 months); trials that exceeded 27 months of development time were significantly less likely of achieving accrual goals (odds ratio, 0.14; 95% CI, 0.04 to 0.54, P=0.004). Conclusions: A large percentage of oncology clinical trials do not achieve minimum projected accruals. Trial development time appears to be one important predictor of the likelihood of successfully achieving the minimum accrual goals.

[Table: see text]

No significant financial relationships to disclose.
A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): Results of the CONKO 004 trial
Authors: Riess H. , Pelzer U. , Deutschinoff G. , Opitz B. , Stauch M. , Reitzig P. , Hahnfeld S. , Hilbig A. , Stieler J. , Oettle H.
Published: February 2017

LBA4506

Background: The course of pts with APC is often complicated by venous thromboembolic events (VTE). Anticoagulation therapy with LMWH may prevent VTE and is under discussion to improve overall survival (OS) in cancer. Based on our previous pilot study (Hilbig et al, Onkologie 2005;28(suppl 3)) indicating the safety and feasibility to the addition of the LMWH enoxaparin to chemotherapy in pts with APC we started the open, prospective, randomized, multicenter study to investigate the role of enoxaparin in these pts. Methods: Primary endpoint was the reduction of symptomatic VTE (sVTE) from an expected 10% to 3% within the first 12 weeks of treatment. The occurrence of sVTE (secured by an independent, blinded event review board) in 24 pts was calculated to be necessary in order to define the role of enoxaparin in decreasing the risk of VTE. Toxicity, time to progression (TTP), and OS were among the secondary endpoints of the study approved by the ethics committees of the participating centers. VTE-naive and chemotherapy-naive pts with histologically or cytologically confirmed APC were randomized to receive or not to receive additional LMWH (enoxaparin 1mg/kg once daily) starting in parallel to palliative systemic chemotherapy. Results: In January 2009 after recruitment of 312 pts the study was closed. There were 22 sVTE in 152 pts of the observation group (O) and 8 in 160 pts of the enoxaparin group (E). ITT and PP analyses demonstrated significant risk reductions from 14.5% to 5.0% (65% RRR) and 14.5% to 3.8% (74% RRR) for E, respectively. Major bleeding events were 9.9% for O and 6.3% for E (ITT; n.s.). In each group there was one tumor-related fatal hemorrhage. Preliminary data show no difference in TTP (O:19 vs. E:22 w) and OS (O:29 vs. E:31 w). Conclusions: Enoxaparin is effective and safe in the primary prevention of sVTE applied in parallel with cytotoxic chemotherapy in pts with APC. Final results on TTP and OS are pending.

No significant financial relationships to disclose.
A randomized, phase III study (AGO-OVAR-9, GINECO-TCG, NSGO-OC-0102): Gemcitabine-paclitaxel-carboplatin (TCG) versus paclitaxel-carboplatin (TC) as first-line treatment of ovarian cancer (OC): Survival of FIGO stage I-IIA patients
Authors: Herrstedt J. , Huober J. , Priou F. , Müller H. , Baekelandt M. , Kurzeder C. , Pfisterer J. , Stähle A. , Ray-Coquard I. , du Bois A.
Published: February 2017

LBA5510

Background: One option to increase the efficacy of TC in pts with first diagnosis of ovarian cancer is to add a not cross-resistant drug. Methods: We conducted a randomized, prospective, stratified, phase III study comparing therapy with TC to TC plus gemcitabine. From 7/02 to 4/04, pts with a histological verified first diagnosis of epithelial OC, FIGO IC-IV were randomized to either TC (paclitaxel [T] 175 mg/m2 3h iv d1 + carboplatin [C] AUC 5 iv d1) or TCG (TC + gemcitabine [G] 800 mg/m2 iv d1+8) for at least 6 cycles every 21 days starting within 6 weeks post-operatively. The randomization was balanced within three strata: 1) FIGO I-IIA, 2) FIGO IIB-IIIC with residual tumor ≤ 10mm, 3) FIGO IIB-IIIC with residual tumor > 10 mm or FIGO IV. Primary endpoint is overall survival. Results: We enrolled 1,742 pts and administered 5,268 cycles TC and 5,129 cycles TCG. All baseline characteristics of the patients in both arms were well balanced. Most pts received 6+ cycles (87.2% TC, 86.2% TCG). Previous interim analyses has shown that TCG was tolerable but induced more hematological toxicity and final analysis has shown that addition of gemcitabine did not improve overall survival in patients with FIGO stage IIB-IV disease. Approximately 11% of the patients (n = 175) had FIGO stage I-IIA disease (stratum I). Most patients received 6+ cycles (93.3% TC, 86.9% TCG). With a median follow-up of 53.8 (range 0 –75) months, and using the log rank test and Cox regression analysis, no relevant differences in progression free survival (first quartile about 57 months and median ≥ 75 months in both groups, HR = 0.90 [95% CI: 0.47–1.72], p = 0.7500) and a negative trend in overall survival (first quartile ≥ 75 months in both groups, HR = 2.19 [95% CI: 0.75–6.41], p = 0.1419) were seen. Conclusions: Addition of G to TC did not improve efficacy in patients with stage I-IIA ovarian cancer. This was also the case for stratum II-III patients (previously reported). The addition of G to TC in patients with first diagnosis of ovarian cancer cannot be recommended.

[Table: see text]
Should liver metastases of breast cancer be biopsied to improve treatment choice?
Authors: Locatelli M. A. , Curigliano G. , Fumagalli L. , Bagnardi V. , Aurilio G. , Della Vigna P. , Monfardini L. , Giudici S. , Viale G. , Goldhirsch A.
Published: February 2017

CRA1008

Background: Decision making on systemic treatment of women with metastatic breast cancer is based on features like estrogen receptor (ER), progesterone receptor (PgR), and HER2 status assessed on the primary tumor. We evaluated the concordance of receptor status between primary tumor and liver metastases (mts) and its impact on treatment choice.

Methods: We retrospectively analyzed a database including ultrasound guided liver biopsies performed from 1995 to 2008. All tissue samples, both from primary tumor and liver mts, were analyzed for ER, PgR and HER2 status. Clinical and biological data were obtained from medical charts. Differences between proportions were evaluated using the Pearson chi-square test.

Results: We identified 255 consecutive patients (pts) with matched primary and liver tissue samples. Median time from primary diagnosis to liver biopsy was 3.4 years (range 0-18.3 years). Changes in ER status were observed in 41/255 pts (16.0%). 16/58 pts (27.6%) changed from ER-negative to ER-positive and 25/197 pts (12.7%) changed from ER-positive to ER-negative (p=0.0066). Changes in PgR status were observed in 76/255 pts (29.8%). 18/91 pts (19.8%) changed from PgR-negative to -positive and 58/164 pts (64.6%) from PgR-positive to PgR-negative (p <0.0001). 12/52 pts (23.1%) changed from ER- and PgR-negative to ER- or PgR-positive (group A) and 27/203 pts (13.3%) changed from ER- or PgR-positive to ER- and PgR-negative (group B) (p=0.087). In the group A the treatment of 4/12 pts (33.3%) was changed after biopsy: 2/4 started endocrine treatment (HT) and 2/4 stopped it. In group B the treatment of 18/27 pts (66.6%) was changed after biopsy: 17/18 stopped HT. Changes in HER2 status were observed in 22/167 pts (13.1%): 6/116 pts (5.1%) changed from HER2-negative to HER2-positive and 16/51 pts (31.4%) changed from HER2-positive to negative (p≤0.0001). In this group pts started and/or stopped a trastuzumab containing treatment after biopsy.

Conclusions: There was a discordance in receptor status between primary tumor and liver mts, which led to change in therapy for 48/255 of pts (18.8%). Biopsy of metastases for reassessment of biological features should be considered in all pts when safe and easy to perform, since it is likely to impact treatment choice.

No significant financial relationships to disclose.
NOA-08 randomized phase III trial of 1-week-on/1-week-off temozolomide versus involved-field radiotherapy in elderly (older than age 65) patients with newly diagnosed anaplastic astrocytoma or glioblastoma (Methusalem).
Authors: Wick W. , Engel C. , Combs S. E. , Nikkhah G. , Steinbach J. , Kortmann R. , Simon M. , Wille C. , Reifenberger G. , Weller M.
Published: February 2017

LBA2001

Background: The median survival time for elderly patients (pts) with malignant gliomas is in the range of a few months. Radiotherapy (RT) is the standard treatment and superior to best supportive care both with respect to progression-free and overall survival. The benefit derived from surgery and RT is modest, and both treatments are less well tolerated in elderly pts than in the young. The availability of a potentially effective pharmacological agent, temozolomide (TMZ), for malignant glioma, which exhibits a favorable safety profile, necessitated a reconsideration of the widespread therapeutic nihilism with malignant glioma in the elderly.

Methods: The NOA-08 trial of the Neurooncology Working Group (NOA) of the German Cancer Society compared standard postsurgical involved-field RT to a dose of 54-60 Gy, in pts with anaplastic astrocytoma or glioblastoma > 65 ys with a Karnofsky performance score ≥ 60, to TMZ in an one week on/one week off schedule at 100 mg/m2 with dose modification in 25 mg steps in both directions. The primary endpoint was the median survival time (OS) during the follow-up in the 12 months after date of operation. The trial sought to demonstrate the non-inferiority of TMZ compared with RT. Regarding a maximal difference of 25% between both treatment arms in OS as being equivalent, 2 x 206 pts were randomized between May 15, 2005 and Nov 2, 2009 in 22 German and one Suisse sites to provide 80% power to achieve significance at a one-sided level of 0.05. Thirty-nine patients were excluded from the intention-to-treat (ITT) population because no therapy was applied (n=22) or withdrawal of informed consent (n=17).

Results: All histological diagnoses were centrally confirmed. Pts characteristics were balanced between arms in the ITT population (n=373) except for more resections and more anaplastic astrocytomas in the RT arm. The non-inferiority of TMZ was not shown. In contrast, pts in the TMZ arm had an increased risk of death (HR=1.24 [95% CI: 0.94-1.63]) compared to pts in the RT arm. The rate of adverse and serious adverse events was higher in the TMZ arm.

Conclusions: This trial fails to show the non-inferiority of dose-intensified TMZ alone compared with RT alone in the primary treatment of older pts with malignant glioma. Unlike anaplastic glioma in the younger patient population, RT cannot be safely deferred in the treatment of elderly patients with anaplastic astrocytoma or glioblastoma. Whether RT plus TMZ is superior to RT alone, is addressed in the ongoing companion trial conducted by NCIC, EORTC and TROG.

[Table: see text]

[Table: see text]
Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436).
Authors: Infante J. R. , Falchook G. S. , Lawrence D. P. , Weber J. S. , Kefford R. F. , Bendell J. C. , Kurzrock R. , Shapiro G. , Kudchadkar R. R. , Long G. V. , Burris H. A. , Kim K. B. , Clements A. , Peng S. , Yi B. , Allred A. J. , Ouellet D. , Patel K. , Lebowitz P. F. , Flaherty K. T.
Published: February 2017

CRA8503

Background: In preclinical models, the BRAF/MEK inhibitor (i) combination GSK436/GSK212 has demonstrated enhanced activity against BRAF-mutant cancer cells compared to either drug alone, delayed emergence of GSK436 resistance, and prevented proliferative skin lesions attributable to BRAFi exposure. Methods: Eligible patients (pts) had BRAF V600 mutation positive solid tumors. Part 1: pharmacokinetic (PK) drug-drug interaction (DDI) study. Part 2: Dose escalation of continuous daily dosing of the combination followed by expansion cohorts; Part 3: Randomized phase II trial in untreated stage IV melanoma. Results: 45 pts have received ≥ 1 dose of GSK212 + GSK436, including 43 melanoma (all BRAFi naïve), 1 NSCLC and 1 salivary duct carcinoma. PK results of 7 pts in Part 1 showed no effect of GSK212 on single dose of GSK436. There was no clinically meaningful DDI between GSK436 and GSK212 after repeat dosing of the combination (Part 2). GSK436 was dosed 75-150 mg BID in combination with GSK212 1.0, 1.5, 2.0 mg QD. The recommended dose was 2 mg QD GSK212 in combination with 150 mg BID GSK436. At 1.5 mg GSK212, there was one DLT, a recurrent grade (G) 2 neutrophilic panniculitis. The only G4 adverse event (AE) was a sepsis-like syndrome with fever/hypotension. G3 AEs included generalized rash (n=2, 4%) and neutropenia (n=2, 4%). Skin toxicity ≥ G2 occurred in 9 (20%) pts; of these, G2 rash (n=4, 8%) and G2 macular rash (n=1, 2%). No cutaneous squamous cell carcinoma (SCC) or hyperproliferative skin lesions have occurred at any dose level. Other common G2 toxicities were pyrexia (n=5, 11%), vomiting (n=2, 4%) and fatigue (n=2, 4%). Of 16 evaluable pts in Part 2, 13 pts had PR and 3 SD for an ORR of 81% (95% CI 54.4%-96.0%) and all but 2 pts remain on study. In 10 evaluable pts who received 150 mg BID GSK436 + ≥1 mg QD GSK212, 9 pts had PR and 1 SD. Conclusions: GSK212 at 2 mg QD combines safely with GSK436 150 mg BID, no SCC thus far and decreased frequency of rash compared to previous trials of single agent GSK436 and GSK212, respectively. The preliminary anti-tumor activity warrants further investigation; the randomized phase II trial (Part 3) is accruing.
Ampullary cancer ESPAC-3 (v2) trial: A multicenter, international, open-label, randomized controlled phase III trial of adjuvant chemotherapy versus observation in patients with adenocarcinoma of the ampulla of vater.
Authors: Neoptolemos J. P. , Moore M. J. , Cox T. F. , Valle J. W. , Palmer D. H. , Mcdonald A. , Carter R. , Tebbutt N. C. , Dervenis C. , Smith D. , Glimelius B. , Coxon F. Y. , Lacaine F. , Middleton M. R. , Ghaneh P. , Bassi C. , Halloran C. , Olah A. , Rawcliffe C. L. , Büchler M. W. ,   European Study Group for Pancreatic Cancer
Published: February 2017

LBA4006

Background: The effect of adjuvant treatment on overall survival (OS) of resected ampullary adenocarcinoma is not known. The aim was to compare the survival effect of adjuvant chemotherapy compared to observation (OBS) after resection and within the chemotherapy group to compare 5-fluorouracil/folinic acid (5-FU/FA) against gemcitabine (GEM). Methods: Patients were stratified by R0/R1 margins, randomised into three arms: (1) 5-FU/FA (FA, 20 mg/m2 iv bolus then 5-FU, 425 mg/m2, iv bolus, 1-5d every 28 days); (2) GEM (100mg/m2 iv infusion 1d, 8d and 15d every 4 weeks); (3) observation. The primary outcome measure was OS of chemotherapy versus no chemotherapy. 300 patients (200 chemotherapy and 100 observation) would provide 80% power to detect a 15% 5y survival difference, p<0.05. Results: 304 patients were randomised (July 2000 to April 2008), 199 to chemotherapy (101 5FU, 98 GEM) and 105 to observation. Median (range) age was 62 (35 – 81) years; 187 (61.5%) were men. Median (IQR) maximum tumour diameter was 20.0 (15.0 – 28.0) mm, 186 (63%) were moderately differentiated tumours, 174 (57%) had involved lymph nodes and 276 (91%) were R0 resections. Independent prognostic factors were tumour diameter and grade, lymph node status and R0/R1 status. Median (95% CI) OS for chemotherapy [57.1 (41.7 – 73.8) months] versus no chemotherapy [43.0 (27.6 - ) months] gave an HR (95% CI) of 0.85 (0.61 – 1.18), p=0.323. For R0 patients median (95% CI) OS for chemotherapy [58.4 (45.4 – 84.0) months] versus no chemotherapy [45.1 (26.7 - ) months] gave an HR (95% CI) of 0.78 (0.55 – 1.11), p=0.173. Cox proportional hazards modelling for all 304 patients p=0.161 and for 276 R0 patients p=0.057. Conclusions: This is the only large adjuvant trial ever conducted for ampullary adenocarcinoma. The results suggest a benefit for adjuvant monochemotherapy in patients with clear resection margins.
Result of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer.
Authors: Kristensen G. , Perren T. , Qian W. , Pfisterer J. , Ledermann J. A. , Joly F. , Carey M. S. , Beale P. J. , Cervantes A. , Oza A. M. ,   GCIG
Published: February 2017

LBA5006

Background: ICON7 was designed to investigate safety and efficacy of adding bevacizumab to standard chemotherapy in women with newly diagnosed ovarian cancer. Analyses of mature progression-free survival (PFS) data suggest a PFS benefit from bevacizumab (p=0.0041, a 15% improvement at 12 months and 1.5 months overall), and a trend for overall survival (OS) improvement, hazard ratio (HR)=0.81, 95%CI=0.63 to 1.04, p =0.098. The final analysis of OS will be performed when 715 deaths have occurred. An interim analysis with at least 365 deaths was requested by regulatory authorities considering licensing. This was approved by the independent data monitoring and steering committees. A subgroup analysis for poor prognosis patients (FIGO III debulked to >1.0cm or FIGO IV with debulking) was performed in an exploratory manner. Methods: Eligible women with high-risk early (FIGO stage I or IIa (grade 3 or clear cell), capped ≤10%) or advanced (stage IIb-IV) epithelial ovarian, primary peritoneal or fallopian tube cancer were randomised (1:1) to 6 cycles of 3 weekly chemotherapy (carboplatin AUC 5 or 6 and paclitaxel 175mg/m2) alone, or the same chemotherapy given concurrently with bevacizumab (7.5mg/kg) for 5 or 6 cycles followed by continued 3-weekly single-agent bevacizumab for 12 additional cycles or until progression whichever was the earlier. Results: From December 2006 to February 2009, 1,528 women were randomised from 263 centres in 7 GCIG groups. Baseline characteristics were balanced between arms: median age (57 years); ECOG PS 0-1 (47%); high-risk early-stage disease (9%); poor prognosis patients (30%); histology (69% serous, 8% endometrioid, 8% clear cell). Overall OS analysis: median follow-up 28 months, 377 deaths (200 standard, 177 bevacizumab), HR=0.84, 95%CI=0.69 to 1.03, p=0.099. Exploratory subgroup analysis of poor prognosis patients: 188 deaths (109 standard, 79 bevacizumab), HR=0.64, 95%CI=0.48 to 0.85, p=0.0022 with p=0.015 for test for interaction (treatment/risk group). Conclusions: The overall trend for improvement in OS from bevacizumab continues with a numerically larger benefit in poor prognosis patients.
OCEANS: A randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC).
Authors: Aghajanian C. , Finkler N. J. , Rutherford T. , Smith D. A. , Yi J. , Parmar H. , Nycum L. R. , Sovak M. A.
Published: February 2017

LBA5007

Background: BEV, a humanized anti-VEGF monoclonal antibody, has shown a progression-free survival (PFS) benefit in 2 frontline phase III trials in patients with EOC, PPC and FTC. The therapeutic impact of BEV in combination with carboplatin (C) and gemcitabine (G) followed by single agent BEV to disease progression (PD) was evaluated in this phase III trial in the platinum-sensitive recurrent setting. Methods: Patients had recurrent, platinum-sensitive EOC, PPC or FTC, 1 prior regimen, no prior BEV, ECOG performance status 0-1, measurable disease. Subjects were randomized to: Arm A: [IV C (AUC 4, Day (D) 1) + G (1,000 mg/m2 D1 and 8) + placebo (PL) D1] q21D x 6 cycles (c) → PL q21D until PD or unacceptable toxicity (tox) Arm B: [CG + BEV (15 mg/kg) D1] q21D x 6 c → BEV q21D until PD or tox primary endpoint was investigator assessed PFS (RECIST). Secondary endpoints included objective response (OR), overall survival (OS), duration of response and safety. The design provided 80% power to detect a 27% reduction in the hazard of progression or death in Arm B vs A, limiting the overall type I error of 5%. Results: OCEANS enrolled 484 patients (242 per arm) from 4/07 - 1/10, median follow up of 24 months. BEV plus CG followed by single agent BEV to PD significantly increased PFS compared to CG alone (HR=0.484, p<0.0001). OR increased by 21% (p<0.0001). OS data is immature with only 29% of patients having had an event. The safety profile was consistent with other BEV trials. Conclusions: Results show a statistically significant and clinically relevant benefit when bevacizumab is added to chemotherapy in patients with recurrent, platinum sensitive EOC, PPC, and FTC. This is the first phase III trial of an antiangiogenic to demonstrate a clinical benefit to these patients.

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Bevacizumab (BEV) plus second-line taxane (TAX) or other chemotherapy (CT) for triple-negative breast cancer (TNBC): Subgroup analysis of RIBBON-2.
Authors: Brufsky A. , Valero V. , Tiangco B. , Dakhil S. R. , Brize A. , Duenne A. A. , Bousfoul N. , Rugo H. S. , Yardley D. A.
Published: February 2017

290

Background: In three randomized trials in the first-line metastatic breast cancer (MBC) setting, combining BEV with CT significantly improved progression-free survival (PFS; primary endpoint) and objective response rate (ORR) vs. CT alone. BEV also showed a significant PFS benefit in the second-line MBC setting (RIBBON-2) when combined with TAX or other CT. We analyzed data from the subgroup of patients (pts) with TNBC in RIBBON-2.

Methods: Eligible pts had MBC that had progressed on first-line CT without BEV. Second-line CT (TAX, gemcitabine, capecitabine, or vinorelbine) was chosen before 2:1 randomization to CT with either BEV (10 mg/kg q2w or 15 mg/kg q3w) or placebo (PLA). All pts could receive BEV at progression. The primary endpoint was PFS.

Results: RIBBON-2 included 684 pts; 159 (23%) had TNBC and of these, 67 (42%) received TAX with BEV/PLA. Baseline characteristics were broadly similar in the two treatment arms. In an exploratory analysis of pts with TNBC, BEV + CT led to significantly improved PFS and ORR vs. CT alone, and a trend toward improved overall survival (OS). The magnitude of the effect was particularly pronounced in pts receiving TAX CT.

Conclusions: Pts with TNBC derive significant ORR and PFS benefit from BEV combined with second-line CT. Despite the small sample size, there was a trend (HR 0.624; p = 0.0534) toward OS benefit in pts treated with BEV, especially with TAX CT.

[Table: see text]
A phase I/II study of S-1 plus cisplatin alternating with S-1 plus docetaxel in patients with advanced gastric cancer (AGC).
Authors: Hosokawa A. , Ogawa K. , Kajiura S. , Tsukioka Y. , Kobayashi T. , Horikawa N. , Kobayashi Y. , Yoshioka A. , Sumi S. , Sugiyama T.
Published: February 2017

101

Background: S-1 plus cisplatin has been regarded as standard first-line chemotherapy for patients with AGC in Japan, and S- 1 plus docetaxel showed promising results for AGC in clinical trials. To investigate the usefulness of S-1 plus cisplatin alternating with S-1 plus docetaxel as first-line treatment in patients with AGC, we conducted a phase I/II study to determine the maximum tolerated dose (MTD), the recommended dose (RD), preliminary efficacy and toxicity.

Methods: Eligibility criteria included pathologically confirmed AGC; no prior chemotherapy; Age 20 to 74, ECOG performance status (PS) of 0 to 2; adequate organ function; and written informed consent. Cisplatin was administered on day1 and the dose was escalated by 10 mg/m2 from starting dose of 40 mg/m2 in phase I part. S-1 was given orally at 80 mg/m2 on day1-14. Docetaxel was administered at 40 mg/m2 on day 22 in combination with S-1 80 mg/m2 on days 22-35. The treatment was repeated every 6 weeks. The RD was studied in every 3-6 patients cohort and determined according to the pre-defined DLTs. Primary endpoint of phase II was the response rate (RR).

Results: Between Aug 2006 and Jul 2010, 33 pts were enrolled. Nine patients entered the phase I part and 24 enrolled in phase II part. In the phase I part, the MTD of cisplatin was presumed to be 50 mg/m2, because 50% of patients (3/6) developed DLTs. Therefore, the RD of cisplatin was estimated as 40 mg/m2, and the 27 patients received the treatment at RD level. Patients characteristics were as follows: median age=65 years (range 48-74), Male: female=21:6, PS 0:1:2=11:16:0, diffuse: intestinal=19:8, initially unresectable: recurrent=24:3. The RR was 59.2% (95% CI, 40.7-77.7). Median follow-up period was 14.6 months, median PFS was 7.9 months, and median survival time was 17.2 months, although survival data remain to be confirmed. Major grade 3/4 toxicities were neutropenia (63%), leucopenia (41%), and anemia (33%). These toxicities were tolerable and manageable. No treatment-related death was observed. The updated analysis will be presented at the meeting.

Conclusions: This alternating treatment seems to be effective and well tolerated in the first-line treatments in patients with AGC.

No significant financial relationships to disclose.
Induction cisplatin, paclitaxel, and 5FU (PTF) before definitive local therapy for locally advanced esophageal squamous cell carcinoma (SCC).
Authors: Fernandez R. , Lopez de Argumedo G. , Fuente N. , Ferreiro J. , Martinez M. , Azkona E. , Gutierrez E. , Iza E. , Casas R. , Mane J.
Published: February 2017

115

Background: Induction chemotherapy for locally advanced oesophageal SCC is controversial. Triple combination is under study with promising results. We analyse induction therapy with PTF before local definitive therapy in terms of response, resectability, toxicity and survival.

Methods: Pts diagnosed of locally advanced oesophageal SCC have been included. Treatment schedule: paclitaxel 175 mg/m2 and CDDP 75 mg/m2 on day 1 and 5FU 800 mg/m2/day days 1-4, every 28 days. After 2-3 cycles surgery is considered. If unresectable, radical radiotherapy (64 Gy) and concomitant carboplatin (60 mg/m2, d 1–5 during 1st, 4th and, if feasible, 7th week of RT) are administered.

Results: From May-02 to Feb-10 48 pts have been treated (44M, 4F). Age: 56,7 (32–70). PS 0-1: 8-40. Location: Upper: 14, Middle: 25, Distal: 8, Whole: 1. T2/3/4:1/26/21, N0/1: 12/36. M1a: 6. Weight loss over 10 kg: 11 pts. Cycles delivered: 140; median 3. Toxicity (episodes): Anemia 3: 1. Emesis 3: 2. Mucositis 3: 2. Asthenia 2-3: 8. Two pts died in remission (one of them with a pCR at necropsy) due to gastrostomy complications and oesophagus-tracheal fistula, treatment related. Two pts developed oesophagus-tracheal fistula as a late event after response to therapy. Response rates: CR 7 (14.6%), PR 16 (33.3%), SD 18 (37.5%), PD 7 (14.6%). Treatment after PTF: Surgery 14 pts (1 upper, 9 middle, 4 distal). One (distal) unresectable at surgery, one (middle) not resected because of liver cirrhosis, two not resected because of liver metastases, unexpected findings at surgery. pCR: 2. pPR 8 (R0: 7, R1: 1). Chemoradiation: 25, improving 2 SD to PR, 4 PR to CR and 3 SD to CR. One PR and 4 SD progressed immediately after chemoradiation. Progression: 33 (local 14, systemic 11, both 8); died: 34. Median progression free survival: 35.7 weeks (95% CI 30.2-41.2). Median overall survival: 50.7 weeks (95% CI 35.2-66.1).

Conclusions: Induction PTF has a good toxicity profile with a high response rate and disease control during therapy. Surgical rescue is possible in middle and distal tumours. Local definitive therapy with chemoradiation is the best approach for unresectable or upper third tumours.

No significant financial relationships to disclose.
Multicenter feasibility study of 5-FU, leucovorin, plus paclitaxel (FLTAX) for peritoneal disseminated gastric cancer with massive ascites or inadequate oral intake.
Authors: Takiuchi H. , Yasui H. , Nishina T. , Takahari D. , Nakayama N. , Taira K. , Kusaba H. , Fuse N. , Hironaka S. , Nakajima T. E.
Published: February 2017

119

Background: Oral fluoropyrimidine plus cisplatin is widely used as a standard treatment for advanced gastric cancer, but patients (pts) with severe peritoneal metastasis often cannot tolerate this regimen. The aim of this study was to assess the feasibility of fluorouracil (5-FU), leucovorin (LV), plus paclitaxel (PTX) for peritoneal disseminated gastric cancer with massive ascites or inadequate oral intake.

Methods: Peritoneal disseminated gastric cancer with massive ascites or inadequate oral intake were enrolled in Part I (Level 1 (n=6): 5-FU bolus/l- LV div 2hr/PTX div 1hr = 500/250/60, Level 2 (n=6): 600/250/80 mg/m2 (day1, 8, 15, q4w) to determine dose-limiting toxicity (DLT) and recommended dose (RD). In Part II (n=19), primary endpoint was completion rate of 2 cycles to evaluate the feasibility of this regimen at RD level.

Results: One of Level 1 pts had DLT with grade 4 gastrointestinal perforation. Two of Level 2 pts had DLT (grade 3 febrile neutropenia and grade 3 infection with normal neutrophils) and treatment-related death (TRD) was observed in one patient due to pneumonia with grade 4 neutropenia. The RD was determined to be Level 1. Twenty-five patients were enrolled at RD level: first-line/second-line=18/7, performance status 0/1/2=1/19/5. The completion rate of 2 cycles was 92% and objective response rate of ascites was 45%. Grade 3 or 4 neutropenia was observed in 12% (febrile neutropenia in 8%). Five patients out of 7 second-line patients died within 30 days after last administration of FLTAX (TRD: 1 and disease progression: 4).

Conclusions: RD of FLTAX regimen was 5-FU/l-LV/PTX=500/250/60 mg/m2. This regimen was feasible as the first-line treatment against peritoneal disseminated gastric cancer patients with massive ascites or inadequate oral intake.

[Table: see text]