Cycles Of Oxaliplatin Research Articles

Adjuvant mFOLFOX6 with or without cetuxiumab (Cmab) in KRAS wild-type (WT) patients (pts) with resected stage III colon cancer (CC): Results from NCCTG Intergroup Phase III Trial N0147.

CRA3507 Background: FOLFOX is standard adjuvant therapy for stage III CC. Adding Cmab to FOLFOX benefits pts with metastatic CC WT KRAS tumors. N0147 assessed the potential benefit of Cmab added to FOLFOX. Methods: 21-56 days following resection and informed consent, KRAS status was centrally determined. Pts with wtKRAS CC were randomized to 12 biweekly cycles of oxaliplatin 85 mg/m2 d1, with leucovorin 400 mg/m2, 5FU 400 mg/m2 bolus IV, then 46-hr IV 5FU 2,400 mg/m2 on d1-2 (mFOLFOX6), without (arm A) or with Cmab (arm D) 250 mg/m2 d1&8, with Cmab at 400 mg/m2, cycle 1, d1. Primary endpoint was 3-yr disease free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. Planned accrual of 2,070 wtKRAS pts provided 90% power to detect hazard ratio (HR) of 1.33 with 2-sided α=0.05; with interim analyses after 25%, 50%, and 75% of planned events. Results: 1,760 wtKRAS pts (Arm A-858, Arm D-902) were enrolled at the time of closure; median follow-up on 1,624 pts is 15.9 months. Trial closed to accrual when preplanned interim analysis after 50% of planned events demonstrated no benefit to addition of Cmab. 3-yr DFS favored FOLFOX alone (HR 1.18, 95% CI 0.92-1.52; p=0.33). No benefit of Cmab was observed in any subgroups assessed. Any grade ≥ 3 AE, diarrhea, and failure to complete 12 cycles was significantly increased in arm D. Increased toxicity and greater differences in all outcomes were observed in pts aged ≥ 70 ( Table ). Conclusions: In this randomized phase III trial the addition of Cmab to mFOLFOX6 was of no benefit for pts with resected stage III wtKRAS CC. Supported by NIH Grant CA25224, Bristol-Myers Squibb, ImClone, Sanofi-Aventis, and Pfizer. [Table: see text] [Table: see text]

Clinical significance of bolus 5-fluorouracil for recurrent or metastatic colorectal cancer treated with FOLFOX therapy.

e14078 Background: In recurrent or metastatic colorectal cancer, a combination of leucovorin and fluorouracil with oxaliplatin (FOLFOX) is a standard first-line regimen. Although a variety of FOLFOX regimens are widely used, the neutropenia caused by FOLFOX is often problematic. The purpose of this study was to evaluate the clinical significance of bolus 5-fluorouracil for recurrent or metastatic colorectal cancer treated with FOLFOX therapy. Methods: From January 2008 to December 2009, 39 patients who had metastatic lesions from colorectal cancer treated with FOLFOX + bevacizumab at the Osaka Rosai Hospital were included. This study compared mFOLFOX6 + bevacizumab (mFF6 + BV) with mFOLFOX7 + bevacizumab (mFF7 + BV) to assess the clinical significance of bolus 5-fluorouracil. Results: Grade 3/4 neutropenia was significantly less in mFF7 + BV (58.8%: median 12 cycles) than in mFF6 + BV (22.7%: median 10 cycles) (p = 0.02). Response rates were 50% in mFF6 + BV and 57.9% in mFF7 + BV (p = N.S.). Relative dose intensities (RDI) during the first four cycles of oxaliplatin were 89% in mFF6 + BV and 94.6% in mFF7 + BV, respectively (p = N.S). Completion rates were 52.9% in mFF6 + BV and 68.2% in mFF7 + BV, respectively (p = N.S.). The main factor of RDI and completion rate decrease was hematologic toxicity. The median PFS was 12.5 months in mFF6 + BV compared with 14.8 months in mFF7 + BV (p = 0.91). Conclusions: The mFOLFOX7 + BV regimen seems beneficial as first-line therapy in recurrent or metastatic colorectal cancer, demonstrating a decreased toxicity with acceptable response rate and PFS. Bolus 5- fluorouracil may be unnecessary in a FOLFOX regimen. Further study is needed to fully evaluate bolus 5-fluorouracil. No significant financial relationships to disclose.

Montelukast prophylaxis of oxaliplatin hypersensitivity reactions.

e14046 Background: Oxaliplatin acute hypersensitivity reactions (HSRs) are typically a Type I reaction, occurring in patients (pts) with second or subsequent exposure, with an incidence of 10–20% and predominantly grade 1–2. Our institution tracks and documents all acute adverse drug HSRs using an NCI CTC 2.0 derived grading form including cardiac, dermatologic, constitutional, and pulmonary domains. A retrospective review of oxaliplatin HSRs was undertaken to access severity and outcomes depending treatment of the HSR “traditional” (corticosteroids and antihistamines) versus the LTD4 inhibitor, montelukast. Methods: All oxaliplatin related HSRs reported, since form implementation in 2002, were reviewed to determine cycle number and outcome (stopped oxaliplatin for HSR vs completed therapy to alternate endpoint). Results: 75 pts had 101 oxaliplatin HSRs. Pts were treated for metastatic disease (40 pts) or adjuvantly (35 pts). HSRs were grade 1 (42%), gr 2 (28%), gr 3 (27%) and gr 4 (3%). Dyspnea and hypoxia were the primary grade 3 and 4 symptoms. The first HSR occurred in median cycle 8 (range cycle 1–26). Timing of first HSR was similar for metastatic vs. adjuvant pts. Post-HSR, pts received a mean of 2.1 additional cycles of oxaliplatin. Montelukast-treated pts received 3.6 cycles on average vs. 1.93 cycles with traditional premedication. Of the 35 adjuvant pts, oxaliplatin was discontinued by 15 and completed by 20 (average 4.2 cycles of oxaliplatin post HSR). Of the 40 metastatic pts, 22 pts discontinued oxaliplatin due to HSR, while 18 stopped due to progressive disease or neuropathy. Of five pts receiving montelukast secondary prophylaxis (2 adjuvant, 3 metastatic), none stopped therapy due to further HSRs; both adjuvant pts completed therapy (12 cycles), 2 metastatic pts progressed (2 and 8 cycles later) while a third pt completed 3 more cycles then initiated targeted maintenance therapy. All pts treated with montelukast reported subjective improvement in their symptoms of HSR with subsequent oxaliplatin. None of the pts were retreated with a formal desensitization regimen. Conclusions: Montelukast may prevent early discontinuation of oxaliplatin following HSRs without a desensitization regimen. Further study in secondary prophylaxis is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck, sanofi-aventis sanofi-aventis

Gene expression profile (GEP) for the prediction of pathologic complete response (pCR): Preliminary data from a neoadjuvant study of capecitabine (C), oxaliplatin (OXP), and radiation (RT) for esophageal cancer (EC).

4100 Background: A pCR following chemoradiation (CRT) is associated with improved survival in EC patients (pts). Our prior study noted the safety of combination C, OXP and RT. The present phase II neoadjuvant (NA) EC trial was designed to examine the pCR rate using C, OXP and RT, correlate GEP with pCR, and assess toxicity. Methods: EC pts with stages II-IVa, adequate organ function and performance status were eligible. Treatment (Rx) consisted of OXP, 85 mg/m2 iv on days 1, 15 and 29, C (oral or enteral tube) 625 mg/m2 bid with RT, and 50.4 Gy RT (3D conformal), followed by surgery (S) 4-6 wks later. 2 cycles of OXP + C were given post-operatively. GEP using Agilent microarrays was conducted on primary tumor tissue pre-Rx, day (D) 17 of CRT and at S.More than 50% viable tumor cells were required. Results: 32 pts enrolled (27 M); median age 58.5 yrs; 25 adenocarcinomas and 7 squamous. Stage: II (9), III (19) and IVa (4). 30 pts completed NA Rx; 4 pts did not undergo S (2 disease progression, 2 declined). 21 pts have undergone S with 7 pCR (33%). 10/13 pts starting adjuvant therapy completed 2 cycles. No G4 nonhematologic toxicity during NA Rx; G3 toxicity: anorexia (1), esophagitis (1), fatigue (1), hyperbilirubinemia (2), elevated AST (6), OXP hypersensitivity (2), neutropenia (1). Post-op complications: pneumonia (2), infection (4), leak (2), esophageal fistula (1) and bowel obstruction (2). 1 pt developed acute leukemia, likely OXP-related 17 months post-Rx. Analysis on pre-Rx GEP on 22 pts via gene set analysis revealed several enriched genetic pathways comparing pCR with non-pCR pts. Specifically, the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways glutathione metabolism and base excision repair, 2 pathways that may be important for chemotherapy resistance, were found to be enriched. Conclusions: C, OXP and RT is effective and well tolerated in resectable EC. Ongoing work will further validate the noted pathways in determining chemotherapy resistance. Acknowledgement: The study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Roche Laboratories, Inc. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche

Comparative effectiveness of adjuvant oxaliplatin and irinotecan-based chemotherapy regimens among elderly stage III colon cancer patients completing 12 cycles.

e14069 Background: Randomized controlled trials and real world comparative effectiveness studies have suggested survival benefits with adjuvant oxaliplatin (OX)-based regimen in stage III colon cancer patients. However, patients in routine clinical practice may experience early discontinuation of therapy due to adverse events or other reasons. Our aim was to compare survival among colon cancer patients on OX and irinotecan (IRI)-based regimens who received at least 12 cycles of chemotherapy. Methods: The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify stage III colon cancer patients older than 65 who were diagnosed between 2002 and 2005, with follow-up through 2007. Patients who received at least 12 cycles of OX (n = 439) or IRI-based regimen (n = 142) after surgery were included. The primary outcomes were survival time from initiation of chemotherapies to all-cause death, colon cancer-specific death, and non-colon cancer death. Cox proportional hazards models, adjusting for patient and clinical characteristics, were used to comparing the survival benefit between OX and IRI- based combination therapy. Results: The crude event rates for all-cause death per 100 person years were 6.7 and 15.2 among OX and IRI-based regimen users, respectively. The crude event rates for colon cancer-specific death per 100 person years were 0.5 among OX- based and 8.4 among IRI-based regimen users. The adjusted overall survival and non-colon cancer survival between OX-based and IRI-based regimen in stage III colon cancer patients who received at least 12 cycles of chemotherapies were comparable. However, the point estimate suggests that OX-based regimen (HR, 0.31; 95% CI, 0.10-1.00; p = 0.049) had more favorable colon cancer-specific survival benefit than IRI-based regimen. Conclusions: There appears to be a comparative effectiveness benefit of OX-based versus IRI-based regimens among elderly stage III colon cancer patients who receive chemotherapy at least 12 times. The survival benefit reflects a wide range of possible magnitudes and is impacted by a variety of patient and treatment-related characteristics. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis Amgen, Bayer, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, sanofi-aventis sanofi-aventis Pfizer, sanofi-aventis GlaxoSmithKline, Novartis, Pfizer, sanofi-aventis

Characterization of innate responses elicited by neoadjuvant radio-chemotherapy for rectal cancer

e15044 Background: The neoadjuvant chemo-radiotherapy (CT-RT) has improved the treatment of locally advanced rectal cancer reducing the local recurrence. However a survival benefit has not been reached yet. In order to increase the rate of pathological complete remissions in our Institution we intensified both the CT schedule adding oxaliplatin to 5-FU and the RT program with tomotherapy. The aim of this study was to verify: whether the pattern of innate response elicited by the neoadjuvant CT-RT is heterogeneous among pts and whether this information can be used to identify which pts will benefit from the treatment. Methods: We collected samples of T3N+M0 rectal cancer pts before, during and after neoadjuvant CT-RT (3 cycles of oxaliplatin + 5-FU; 45 Gy). At each time point we characterized circulating monocytes by flow cytometry, infiltrating macrophages by immunoistochemistry (IHC) and selected inflammatatory molecules by ELISA.Results: We recruited so far 25 pts, of whom 10 have reached the surgery with three pathological complete remission and four down staging. No substantial changes were detectable in the number of circulating monocytes. In contrast we observed a clear expansion of CD14/CD86 and CD14/CD163 double positive subsets. This event was transient and apparently causally related to the treatment since it abated at the later time point. Moreover, it correlated with sensitivity to the treatment: 5/7 pts who underwent disease regression had an early and transitory increase of the number of CD14/CD86 and CD14/CD163 positive cells, which was absent or negligible in non responder pts. The IHC study revealed a massive tumoral infiltration by macrophages which displayed clear features of alternative M2 polarization as assessed by expression of the CD163 and 206 scavenger receptors. A subset of pts had elevated PTX3 and low CRP concentration at the onset of treatment. PTX3 concentration abated after the first CT cycle. Conclusions: These data suggest that neoadjuvant CT-RT modulates the cellular components of innate immune responses, that could represent valuable predictive factors. No significant financial relationships to disclose.

Preliminary results of a phase II study of oxaliplatin, docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary, peritoneum, and fallopian tube

5546 Background: Objectives are to estimate efficacy and safety of a novel taxane/platinum chemotherapy doublet in combination with bevacizumab (B), as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube (FT), after initial debulking surgery. Methods: Eligibility criteria included histological confirmation of primary disease, previous debulking surgery, and normal renal, hepatic, hematological, and neurological function. Subjects were treated with 6 cycles of oxaliplatin (85 mg/m2), docetaxel (75 mg/m2) and B (15 mg/kg) Q3W, followed by maintenance B (15 mg/kg Q3W) to complete one year of therapy. The primary endpoint is progression-free survival (PFS) of pts with measurable disease at 1 year. Results: A total of 110 subjects are included in safety and 95 in efficacy analyses (55 with measurable disease). Median age was 58 years. Tumors were mostly ovary as primary site (84%), poorly differentiated (65%), serous adenocarcinoma pathology (73%) and FIGO stage IIIC (68.2%) or IV (14.6%). 61% of subjects were optimally debulked. 95 (86%) of subjects had completed the chemotherapy cycles with 87 of the 95 having started on the B-only maintenance cycles. 85 (77%) subjects have stopped study treatment [including 33 completed study treatment, 29 disease progression, 15 adverse event (AE), 8 other reasons]. The most common grade 3–4 AEs were: neutropenia (39%), leukopenia (11%), hypertension (9%), and fatigue (7%) Grade 3–4 peripheral sensory neuropathy (PSN) occurred in 2 patients (1.3%). There was one case of colonic perforation associated with B. Investigator-determined best overall confirmed response rates were: complete response 32.8%; partial response, 29.1%; stable disease 32.7%; and progressive disease (PD), 1.8%. The 1-year PFS probability is 70.1% (95% C.I., 56.8%-83.4%) in the 55 patients with measurable disease. Conclusions: This preliminary data supports feasibility of this novel regimen, with an acceptable safety profile and a low incidence of PSN and colonic perforation. Preliminary 1-year PFS is promising. The trial completed accrual to 132 patients in August 2008. Updated results will be presented. [Table: see text]

Oxaliplatin (OXP) plus protracted infusion 5-fluorouracil (PIFU) and external beam radiation (EBRT) prior to surgery (S) for potentially curable esophageal adenocarcinoma (EA): A Southwest Oncology Group (SWOG) phase II trial with molecular correlates (S0356)

4513 Background: Although neoadjuvant combined modality therapy (NACMTX) has become a standard of care in the United States, median overall survival (OS) for patients (PTS) with EA has changed little over the past 25 years. Progression free survival (PFS) and OS after NACMTX depend on extent of primary tumor response. New regimens to increase pathologic complete response (pCR) are needed. Based on phase I data, SWOG designed a phase II trial (S0356) to test OXP with PI5FU and EBRT for PTS with EA. Objectives included pCR rate ≥ 25%, acceptable toxicity (TOX), PFS, OS and exploration of molecular parameters relevant to pCR. Methods: Eligibility: clinical stage II/III EA, ≥ 18 years, Zubrod PS ≤ 2, standard hematologic/non-hematologic values, and tumor < 2 cm into the gastric cardia. OXP 85 mg/m2 was given day (d) 1, 15 and 29; PI5FU 180 mg/m2/d was given d 8-d43. EBRT 180 cGy/d started d 8 x 25 fractions, 5 d/week to total dose 4500 cGy. S was planned 2–4 weeks after NACMTX, with a second cycle of OXP/ PI5FU after S. Central pathology review of surgical specimens was mandated. The trial used a 2-stage design; the trial was halted at 45 PTS to review pCR rate; it reopened to full accrual. Results: 98 PTS enrolled between 9/15/04 and 8/18/08. 6 PTS were ineligible; 2 PTS did not receive therapy (TX). 90 PTS, 84 men (93%), median age 61.7 years, were analyzed. 4 deaths (4.5%) were due to protocol TX; 2 due to NACMTX, 2 to S. 43% and 18% of PTS had grade 3/4 toxicity, respectively: 39% GI, 22% flu-like/fatigue, 17% pulmonary, 16% hematologic, 14% mucositis and 3% neurologic. 77 PTS (86%) underwent S. 30 PTS (33%) had pCR. 9 PTS (10%) had in-situ cancer or T1N0M0. <50% received postoperative CTX. Conclusions: OXP, PI5FU and EBRT for PTS with EA has produced the highest pCR rate reported to date for a cooperative group trial. Significant but manageable non-hematologic TOX was observed. S mortality is acceptable. Future trials built on this platform should plan to complete all TX before S. Tumor molecular profiles (analyses in progress) may predict benefit from this treatment. Data on PFS and OS will follow. [Table: see text]

Capecitabine (C), oxaliplatin (OXP), and radiation (RT) in resectable esophagus cancer (EC): A phase II trial with gene expression profiling (GEP)

e15543 Background: Novel chemotherapy regimens in combination with RT aim to improve the pathologic complete response (pCR) in EC. Following our dose-finding phase I study, the present phase II neo-adjuvant (NA) EC trial was designed to examine the pCR rate using C, OXP and RT, with secondary end-points of evaluating toxicity, quality of life, and GEP of tumor tissue for correlation to therapeutic response. Methods: EC patients (PTS) with stages II-IVa, adequate organ function and performance status (ECOG 0–1) were eligible. Treatment consisted of OXP, 85mg/m2 iv on days 1, 15 and 29, C (oral or enteral tube) 625 mg/m2 bid on days of RT, and 50.4 Gy RT (3-D conformal) in 28 fractions, followed by an esophagectomy (E) 4–6 weeks later. 2 cycles of OXP + C were administered post-operatively. GEP using Agilent microarrays was conducted on primary tumor tissue pre-treatment (Rx), day (D) 17 and at E; > 50% viable tumor cells were required. Results: 20 PTS have been enrolled (17 male, 3 female); median age 59.5 yrs; 17 adenocarcinomas & 3 squamous-cell cancers. Clinical stage: II (3), III (13) and IVa (4). 18 PTS have completed NA therapy; Grade 4 toxicity includes anemia (1), lymphopenia (2); grade 3 toxicity includes esophagitis (1), pneumonia (1), wound infection (1), anastomotic leak (2), esophageal fistula (1), bowel obstruction (1), fatigue (1), hyperbilirubinemia (1), elevated ALT, AST (1 & 2, respectively), hypoalbuminemia (3), OXP hypersensitivity (2) & leucopenia (1). One PT died > 60d post- operatively secondary to infection. 15 PTS have undergone an E with 3 pCR (20%). Analysis on pre-Rx GEP on 17 PTS revealed a distinct pattern for pCR PTS with 325 over-expressed and 79 under-expressed genes. Ongoing functional analysis will characterize GEP changes in 1) pCR PTS pre-Rx & at D17, 2) pCR & non-pCR PTS pre-Rx, and 3) by histology. Validation will be performed via RT-PCR. Accrual to the trial continues. Conclusions: C, OXP & RT appears to be a tolerable and efficacious NA regimen for EC. The exploratory GEP analysis may provide insight on predicting response to NA therapy. Acknowledgement: The study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Roche Laboratories, Inc. [Table: see text]

Capecitabine combined with oxaliplatin (XELOX) as first-line chemotherapy in colorectal cancer with liver metastases

e15146 Background: The combination of 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (I-OHP) was shown to be both more active against metastatic colorectal carcinoma and better tolerated. Methods: Chemotherapy-naive patients confirmed histologic colorectal cancer with liver metastases, adequate born morrow, renal and hepatic function, measurable diseases were considered eligible for the study. Treatment: Six cycles of oxaliplatin 85 mg/m2 day1 plus capecitabine 1250 mg/m2 twice daily days 1–14 every 21 days Results: Twenty six patients were evaluated for safety and efficacy (male/female, 12/14). Median age was 53 years (range 32–75 years). A total of 142 cycles have been administered: median per patient 4 (range 3–6 courses). In an intent-to-treat efficacy analysis, One complete and ten partial responses were achieved [overall objective response rate (ORR): 42, 3%; whereas 7 patients had stable disease and eight patients had progressive disease. Seven patients from 11 with objective response underwent major liver resection: 2 bisegmentectomy, 1 left lobectomy, 4 segmentectomy, and receive the same regimen of chemotherapy (Six cycles) as an adjuvant treatment and still alive without recurrence. The overall survival (OS) was 19, 2 months. The median response duration was 7 months. The median time to progression (TTP) was 8 months. The grade 3 toxicities were diarrhea (7%), fatigue (4%), neurotoxicity (2%), neutropenia (2%), and thrombocytopenia 4%). Conclusions: The combination of oxaliplatin and capecitabine is safe and has a promising activity in patients with liver metastatic colorectal carcinoma. No significant financial relationships to disclose.

Addition of bevacizumab to induction plus concomitant capecitabine-oxaliplatin (XELOX) chemoradiotherapy (CRT) in MRI poor prognosis locally advanced rectal cancer: Avacross study

4100 Background: Concomitant CRT with 5-FU followed 6–8 weeks later by TME surgery is well accepted standard treatment for locally advancer rectal cancer. This approach focuses only into local control. Trimodal induction approaches with chemo, radiation and anti VEGFR therapy may induce additional tumor growth delay. Methods: Eligible patients (pts) had high-risk rectal adenocarcinoma defined by MRI: distal T3 at/below levators, T3 at any other level within 2 mm of mesorectal fascia, resectable T4 and any T3 with nodal metastases. We excluded pts with any antecedent of heart disease. Treatment consisted in four 21 day cycles of oxaliplatin 130 mg/m2 d 1, bevacizumab 7.5 mg/kg d 1 and capecitabine 1000 mg/m2/12 h d 1–14. After 3–4 weeks they received concomitant RT (50.4 Gy in 28 fractions) with capecitabine 825 mg/m2/12 h plus bevacizumab 5 mg/kg, three biweekly doses. TME was planned 6–8 weeks after CRT. Primary end point was pathologic complete response rate with standarized pathology examination. Results: From July 2007 to July 2008, 47 pts were enrolled. Median age was 58 (30–78). Median KPS was 90%. Clinical stage was T3N1: 51.1%, T3N2: 25.5%, T4N0–2: 10.6%, T3N0: 8.5% of pts. 40 pts completed the induction phase: G 3–4 toxicity were diarrhea 12.7%, neutropenia 8.5%, peripheral neuropathy 6.3% and thrombocytopenia 4.2%.. 39 pts completed the CRT phase. Grade 3–4 toxicity were rectitis, linfopenia and hipertrigliceridemia in 2.5% of pts. Until now we have data on 35 resections, 2 with only one induction cycle. R0 resections were achieved in 34 pts (R1 resection in a patient with only one induction cycle). There were 7 wound complications and 10 pts required surgical reintervention. pCR were obtained in 13 pts (37,1 %, 95% CI:21.1–53.2) with 18 (51.4%) additional pts with only residual microscopic foci. There were two treatment related-deaths: one sudden death and one grade 4 diarrhea and diabetic ketoacidosis. Conclusions: Preliminary results show that our preoperative schedule appears feasible, with impressive activity level (pCR + Tmic of 88.5%), achieving downstaging in nearly all pts. Toxicity was manageable, nevertheless we stress caution with cardiac and GI events and surgical complications. No significant financial relationships to disclose.

A phase I/II trial of docetaxel and oxaliplatin in patients with advanced gastric cancer

We designed this phase I/II study of docetaxel-oxaliplatin combination chemotherapy to determine the dose-limiting toxicity (DLT), maximum tolerated dose and efficacy as a first-line treatment in patients with advanced gastric cancer. Patients with histologically proven, chemo-naive gastric adenocarcinoma were eligible. For the phase I part, three dose levels of oxaliplatin and docetaxel every 3 weeks were tested in a cohort of three patients for each level (respectively, 100 and 60 mg/m(2), 100 and 75 mg/m(2), 130 and 75 mg/m(2)). Patients were treated up to a maximum of nine cycles of oxaliplatin and docetaxel unless there was documented disease progression, an unacceptable adverse event, or withdrawal of consent. No DLT was observed at any of the three levels tested in the phase I portion. Therefore, oxaliplatin 130 mg/m(2) and docetaxel 75 mg/m(2) were recommended for the phase II study. All 47 patients were evaluable for toxicity and treatment response. The overall response rate was 55.3% (95% CI, 40.6-70.1%) and median duration of response was 4.2 months (range 0.9-9.5 months). After a median follow-up duration of 13.3 months, median overall survival was 12.7 months (95% CI: 10.4-14.9). The median time to progression was 5.0 months (95% CI, 3.4-6.5 months). The main toxicities (grade 3 or 4) were febrile neutropenia (14.9%), neutropenia (23.4%), diarrhea (10.6%) and neurotoxicity (8.5%). The combination of docetaxel and oxaliplatin was feasible with favorable toxicity profile and showed a promising anti-tumor activity in unresectable, metastatic gastric cancer patients.

A multiple-center phase II study of biweekly oxaliplatin and tegafur–uracil/leucovorin for chemonaive patients with advanced gastric cancer

The current study assessed the efficacy and safety of biweekly oxaliplatin combining oral tegafur-uracil/leucovorin in treating chemonaive patients with advanced gastric cancer. Eligible patients were 18-75 years old, had stage IV disease or post-surgery recurrence, no prior palliative chemotherapy, and an ECOG performance status of 0-2. Patients in the current study received 2-h i.v. infusion of oxaliplatin at a dose of 100 mg/m(2) after diluting in 500 mL 5% dextrose/water (dexan premedication), and 5-HT3 antagonist biweekly. Oral tegafur-uracil and leucovorin was given at a dose of 300 mg/m(2)/day and 60 mg/day three times daily from day 1 to 21, respectively, followed by a 1-week rest. Response assessment was based on the RECIST criteria and was performed every two courses. Toxicity was assessed according to NCI common toxicity criteria version 2. From October 2003 to April 2006, 57 patients were evaluated (55 eligible) with a median age of 61 years (range 31-75). According to the assessment of response in 48 evaluable patients, partial response rate was 24/48 (50.0%) (95% CI: 35.23-64.73%) and stable disease was observed in 11 patients (22.92%), and diseased progressed in 13 patients (27.08%). Mean number of oxaliplatin cycles was 3 (0.5-6.5). Median time to progression was 177 days. Median overall survival was 318 days. Major-grade (III/IV) toxicities were diarrhea 25.5%, vomiting 16.5%, anemia 10.9%, numbness 12.7%, thrombocytopenia 7.3%, neutropenia 3.6% and leucopenia 1.8%. Biweekly, oxaliplatin combining oral tegafur-uracil/leucovorin in treating patients with advanced gastric cancer showed acceptable activity and manageable toxicity.

A phase II study of oxaliplatin and pemetrexed plus bevacizumab in advanced non-squamous non-small cell lung cancer (An International Oncology Network study, #I-04–015)

19018 Background: As single agents, oxaliplatin (OX) and pemetrexed (PEM) are active in patients (pts) with non-small cell lung cancer (NSCLC) and PEMhas synergistic effectiveness when combined with platinum-based drugs. Bevacizumab (BV) has an additive effect on many chemotherapy agents in several tumor types, including NSCLC. The purpose of this Phase II study is to evaluate the efficacy and safety of the combination of BV, OX and PEMas first-line treatment for NSCLC. The primary endpoint is progression-free survival (PFS). Methods: Pts with confirmed Stage IIIB/IV non-squamous NSCLC received 6 cycles of OX (120 mg/m2), PEM(500 mg/m2) and BV (15 mg/kg) on Day 1 of each 21-day cycle. Following 6 cycles, pts received BV alone every 21 days until PD or unacceptable toxicity. Results: At the time of analysis, 69 pts have been enrolled, 67 have received study medication, and 58 are evaluable for response. Pt characteristics include: gender male/female, 44/25; median age 63 yrs (range 43–86); ECOG PS 0/1, 33/36; and race Caucasian/Black/Hispanic, 64/4/1. Median number of cycles administered is 6 (range 1–24). PFS is 7.8 months (95% CI, 5.3 to 8.4). Median survival is 16.7 months (95% CI, 10.5 to 20). Fifteen pts had a PR for an overall response rate of 26% (95% CI, 15 to 39), though 34 pts (58.6%) have SD. The most common G3 toxicities were fatigue (9%), dehydration (9%), hyperglycemia (6%), back pain (6%), neutropenia (4.5%), dyspnea (4.5%), arthralgia (4.5%), headache (4.5%) and pleuritic pain (4.5%). G4 toxicities were neutropenia (3%), dyspnea (3%), pulmonary embolism (3%), hyperglycemia (1.5%), febrile neutropenia (1.5%) and thrombocytopenia (1.5%). Nine pts remain on study. Ten pts died; 5 PD, 3 adverse events (2 hypoxia, 1 cerebral vascular accident), 1 respiratory failure and 1 pulmonary embolism. Conclusions: The median survival of 16 months is encouraging compared to expectations of <1 year in most studies in this population. Treatment led to 84% of pts having a response or SD. This may explain the higher than expected median survival for a relatively well-tolerated regimen. No significant financial relationships to disclose.

Initial safety report of NSABP C-08, a randomized phase III study of modified 5-fluorouracil (5-FU)/leucovorin (LCV) and oxaliplatin (OX) (mFOLFOX6) with or without bevacizumab (bev) in the adjuvant treatment of patients with stage II/III colon cancer

4006 Background: Bev with FOLFOX is active in advanced colorectal cancer (CRC). The C-08 trial investigates the effectiveness of adding bev to mFOLFOX6 for post-op adjuvant treatment of pts with stage II or III CRC. Methods: Pts were randomized 1:1 to receive either mFOLFOX6 q2w x 12 alone (OX 85 mg/m2, LCV 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 hours - Group A) or mFOLFOX6 plus bev (5 mg/kg q2w x 26 - Group B). The primary endpoint is disease- free survival. Results: From September 2004 to October 2006, 2,710 pts were randomized: Group A: 1,356, Group B: 1,354. Demographic factors were well balanced: 50% of pts female, 58% < age 60, and 25% stage II. 75% of pts completed at least 10 cycles of OX and 64% at least 19 doses of bev. Toxicities were well balanced in the 2 groups, overall rate of grade 4/5 toxicities 15.2% and 15.3% for groups A and B, respectively (Arm A: 13 deaths, Arm B: 17, 1.0% and 1.3%, respectively). Toxicities that occurred more often in arm B (table): sensory neuropathy (grade 2: 29 v 33%; grade 3: 14 v 16%; grade 4: < 1% each), hypertension, wound complications, pain (joint, muscle, chest and bone), proteinuria, and hand-foot syndrome. Wound complications (grade 3) were primarily the result of abdominal hernias or port dehiscence. Significantly fewer thrombocytopenia and allergic reactions were observed in arm B. Conclusions: With mean time on study of 22.4 mos, bev with mFOLFOX6 is well tolerated in the surgical adjuvant setting in pts with stage II/III CRC. Specifically, no significant increases in GI perforation, hemorrhage, arterial or venous thrombotic events or deaths with the addition of bev to mFOLFOX6 has been observed. Long-term followup for potential delayed side effects is ongoing. Supported by PHS grants U10CA-12027, -69974, -37377, and -69651 from the NCI and a grant from Genentech, Inc. Grade 3+ toxicities occurring at significantly different rates Toxicity Arm A (%) Arm B (%) P Neurosensory (grade 2+) 43.2 49.4 0.002 Hypertension 1.8 12.7 <0.001 Wound complications 0.3 1.7 <0.001 Pain (joint, muscle, chest, bone) 3.4 6.9 <0.001 Proteinuria 0.2 0.9 0.035 Hand-foot syndrome 1.4 2.5 0.047 Thrombocytopenia 3.4 1.4 0.002 Allergic reaction 4.7 3.0 0.033 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology, sanofi-aventis

Primary signet ring cell carcinoma of the appendix: A rare case report and our 18-year experience

Primary adenocarcinoma of the appendix is a rare malignancy that constitutes < 0.5% of all gastrointestinal neoplasms. Moreover, primary signet ring cell carcinoma of the appendix is an exceedingly rare entity. We have encountered 15 cases of primary appendiceal cancer among 3389 patients who underwent appendectomy over the past 18 years. In the present report, we describe a rare case of primary signet ring cell carcinoma of the appendix with ovarian metastases and unresectable peritoneal dissemination occurring in a 67-year-old female patient. She underwent appendectomy and bilateral salpingo-oophorectomy with a laparoscopy procedure. She then received palliative systemic chemotherapy with 12 cycles of oxaliplatin, 5-flurorouracil, and leucovorin (FOLFOX-4). The patient currently is well without progression of disease 12 mo after beginning chemotherapy.

A Phase II Study of Oxaliplatin with Low-dose Leucovorin and Bolus and Continuous Infusion 5-Fluorouracil (Modified FOLFOX-4) for Gastric Cancer Patients with Malignant Ascites

Clinical studies regarding chemotherapy for gastric cancer patients with malignant ascites have been classically rather limited in scope, largely because peritoneal seeding produces no measurable lesions, and patients generally exhibited poor performance status. Herein, we have evaluated the efficacy and toxicity of a fortnightly modified FOLFOX-4 (m-FOLFOX) regimen. Gastric cancer patients with cytologically confirmed malignant ascites were treated with cycles of oxaliplatin at 85 mg/m(2) plus leucovorin 20 mg/m(2) on the first day of treatment, followed by 5-fluorouracil (5-FU) via a 400 mg/m(2) bolus and a 22 h continuous infusion of 600 mg/m(2) 5-FU on Days 1-2 at 2-week intervals. Forty-eight patients participated in this study. Twenty-two patients (45.8%) were treated with m-FOLFOX-4 as a first line palliative treatment. Twenty-one patients (43.8%) were adjudged to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Thirty-six patients were assessable and exhibited measurable lesions. Twelve (33.3%) patients evidenced partial responses. Decreases or disappearances of ascites levels were observed in 17 (35.4%) patients. The median time to progression and overall survival time were 3.5 (95% CI: 2.9-4.1) months and 8.4 (95% CI: 4.9-11.9) months, respectively. Major hematologic toxicities included Grades 1-2 anemia (53.9%), neutropenia (41.6%) and, Grades 3-4 neutropenia (15.8%). The most frequently detected non-hematological toxicities were Grades 2 and 3 nausea/vomiting (17%). We noted no deaths related to treatment. The m-FOLFOX-4 regimen utilized herein was determined to be both safe and feasible even for gastric cancer patients with malignant ascites in poor performance status.

Modification of Leucovorin Dose Within a Simplified FOLFOX Regimen Improves Tolerability Without Compromising Efficacy

This analysis assesses the efficacy and safety of a modified FOLFOX (oxaliplatin/leucovorin [LV]/5-fluorouracil [5-FU]) regimen given with a low dose of LV. Forty patients with previously untreated metastatic colorectal cancer were enrolled to receive every-2-week cycles of oxaliplatin 100 mg/m(2) intravenously administered over 2 hours concurrently with LV 20 mg/m(2) bolus and 5-FU 400 mg/m(2) bolus, followed by a 46-hour infusion of 5-FU 2.4 g/m(2). Thirty-nine patients received > or = 1 oxaliplatin dose and a median of 10 treatment cycles (range, 1-13 cycles). Thirteen patients (34%) experienced grade 3/4 neutropenia, whereas 21% of patients experienced grade 3 neurotoxicity. Of 37 eligible patients, complete or partial responses were observed in 18 patients (49% [95% confidence interval (CI), 32%-66%]). The median progression-free survival was 6.2 months (95% CI, 5.5-8.7 months) with a median overall survival of 14.2 months (95% CI, 10-20.5 months). A modified schedule of FOLFOX using a lower than standard dose of LV provides good response and survival results with excellent safety. A comparison with a previous study undertaken in the same centers using identical inclusion/exclusion criteria but using higher doses of LV suggests that reducing the dose of LV improves safety without compromising efficacy.

Preliminary safety and efficacy results of a phase II study of oxaliplatin, docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary, peritoneum, and fallopian tube

5518 Background: Objectives: Determine safety and estimate efficacy of a novel taxane/platinum chemotherapy (CTX) doublet in conjunction with bevacizumab, as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube (FT), after initial debulking surgery. Methods: Treatment: 6 cycles of oxaliplatin (O) (85 mg/m2), docetaxel (D) (75 mg/m2) and bevacizumab (B) (15 mg/kg) Q3W, followed by maintenance B (15 mg/kg Q3W) to complete one year of therapy. Pts were treated until disease progression, unacceptable toxicity, prolonged treatment delay, death, or refusal to continue on study. The primary efficacy endpoint is PFS at 12 months. Results: As of 30 Nov 06, 59 pts (median age 58) were enrolled. Primary sites of disease included 47 ovary, 7 peritoneum, 4 FT. Tumors were mostly poorly differentiated (70%) with a serous adenocarcinoma initial pathology type (81%). Most pts were stage IIIC (40) or IV (17). 64% of pts. were optimally debulked. GOG PS was 0–1 in 56 pts. 58 pts were treated with at least one cycle of CTX. 22 pts. completed six cycles of CTX + B; 14 of these have begun B maintenance Rx. Safety data in available on a total of 283 patient-cycles. Of the 57 pts. with adverse event (AE) data available, 31 (54%) reported at least one grade 3–4 AE, 9 (16%) at least one serious AE (SAE), 54 at least one AE related to CTX (O or D), and 45 reported at least one AE related to B. There have been 8 SAEs related to CTX (O or D): febrile neutropenia (FN) (2), chest pain (1), dehydration (1), lymphopenia (1), neutropenia (1), peripheral sensory neuropathy (PSN) (1), palpitations (1). There have been 7 SAEs related to B: chest pain, colonic fistula, dehydration, FN, palpitations, PSN, vertigo (1 each). There were no B-associated colonic perforations. Of the 59 subjects, 31 (53%) had measurable disease at baseline. One of 31 patients has confirmed progression of disease. Conclusions: This preliminary data supports feasibility of this novel regimen, with an acceptable safety profile. As of December 2006, 75 patients have been enrolled. Updated safety and preliminary efficacy (RR) data will be presented. No significant financial relationships to disclose.

A phase II study of oxaliplatin and pemetrexed plus bevacizumab in advanced non-squamous non-small cell lung cancer

18025 Background: As single agents, oxaliplatin and pemetrexed have shown activity in patients with non-small cell lung cancer (NSCLC) and pemetrexed has demonstrated synergistic effectiveness when combined with platinum-based drugs. Moreover, bevacizumab has an additive effect on many chemotherapy agents in several tumor types, including NSCLC. The purpose of this phase II, open-label, non- randomized study is to evaluate the efficacy and safety of the combination of bevacizumab, oxaliplatin, and pemetrexed as first-line treatment for NSCLC. This report presents preliminary safety information demonstrating the safety and tolerability of this combination. Methods: Patients = 18 years with histologically/pathologically confirmed Stage IIIB/IV non-squamous NSCLC received 6 cycles of oxaliplatin (120 mg/m2), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle. Following 6 cycles, patients received bevacizumab alone every 21 days until disease progression or unacceptable toxicity. Results: At the time of analysis, 53 subjects received study medication and are evaluable for safety. Patient characteristics include: gender male/female/unknown, 16/34/3; median age 62.0 years (range 43–86); and ECOG performance status 0/1/unknown, 24/25/4. The median number of cycles administered is 4 (range 1–11). Fifty patients are still on study. The most common Grade 3 toxicities were neutropenia (10.4%), dyspnea (6.0%), fatigue (4.5%), thrombocytopenia (4.5%), hyperglycemia (4.5%), nausea (3.0%), and vomiting (3.0%). Grade 4 toxicities were dyspnea (1.5%), hyperglycemia (1.5%), asthenia (1.5%), thrombocytopenia (3.0%), neutropenia (3.0%), and pulmonary embolism (1.5%). Three patients died; 2 of progressive disease and 1 of hypoxia (not likely related to study drugs). Conclusions: These preliminary results suggest that the combination of oxaliplatin, pemetrexed, and bevacizumab demonstrates an acceptable safety profile for first-line treatment of stage IIIB/IV NSCLC. Conclusions concerning the efficacy of this combination await further treatment information. Supported by Genentech, Inc., Sanofi-Aventis, and Eli Lilly and Company. [Table: see text]