Non-neutropenic Sepsis Research Articles

Audit of In-Hospital Mortality from a Medical Oncology and Hemato-Oncology Center with the Emphasis on Best Supportive Care.

Deepak SundriyalBackground and Objectives The newly established medical oncology and hemato-oncology center at the All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand, India, provided us an opportunity to audit in-hospital mortalities with a vision that the audit will serve as a standard for ceaseless improvement. Aim of the study was to initiate a vigorous process for the evaluation of all-cause mortality in patients suffering from cancer. Methods An audit of all in-hospital deaths that occurred during the year 2019 was performed, and comprehensive scrutiny of various parameters (demographic, clinico-pathological, therapeutic, causes of death) was done. Reviews from two independent observers sharpened the infallibility of the audit. The lacunae in the existing practices and the scope for further improvement were noted. Results Forty-five in-hospital deaths were registered during the study period (January-December 2019). The majority of the deaths occurred in patients with advanced stage of malignancy ([ n = 31] 68.8%). Most common causes of death were progressive disease, neutropenic, and non-neutropenic sepsis. Chemotherapeutic agents, growth factors, blood components, and antibiotics were found to be used judiciously as per institutional policy. The reviewers emphasized on the use of comorbidity indexes in the treatment planning and avoiding intensive care unit referrals for patients receiving best supportive care (BSC). Emphasis was put on providing only BSC to the patients with a very limited life expectancy. Emphasis was also laid down on record of out of the hospital deaths. Interpretation and Conclusion The audit disclosed areas of care which require further improvement. The mortality audit exercise should become a regular part of evaluation and training for the ongoing and future quality commitment. This should impact the clinical decision making in an oncology center providing quality care to the terminally ill patients.

Intensive Care Antifungal Stewardship Programme Based on T2Candida PCR and Candida Mannan Antigen: A Prospective Study.

Non-culture-based biomarkers may improve diagnosis and antifungal treatment (AFT) of invasive candidiasis (IC). We evaluated an antifungal stewardship programme (AFSP) in a prospective intensive care unit (ICU) study, which included T2Candida and Candida mannan antigen (MAg) screening of patients with sepsis and a high risk of IC. Patients with non-neutropenic sepsis and a high risk of IC from two large tertiary ICUs were prospectively included, during a one-year period. IC was classified as proven, likely, possible or unlikely. The AFSP, diagnostic values of T2Candida and MAg, and the consumption of antifungals were evaluated. An amount of 219 patients with 504 T2Candida/MAg samples were included. IC was classified as proven in 29 (13.2%), likely in 7 (3.2%) and possible in 10 (5.5%) patients. Sensitivity/specificity/PPV/NPV values, comparing proven/likely versus unlikely IC, were 47%/100%/94%/90% for BC alone, 50%/97%/75%/90% for T2Candida alone, and 39%/96%/67%/88% for MAg alone. For the combination of T2Candida/MAg taken ≤3 days after AFT initiation, sensitivity/specificity/PPV/NPV was 70%/90%/63%/93%. T2Candida/MAg contributed to early (<3 days) AFT initiation in 13%, early AFT discontinuation in 25% and abstaining from AFT in 24% of patients. No reduction in overall use of AFT during the study period compared with the previous year was observed. An AFSP based on T2Candida and MAg screening contributed to a reduction of unnecessary treatment, but not overall AFT use. The diagnostic performance of T2Candida was lower than previously reported, but increased if T2Candida was combined with MAg.

The Cambridge University Hospitals and Anglia Regional Experience of Using PEP-C As Palliative Chemotherapy in Lymphoma

PEP-C (prednisolone, etoposide, procarbazine, and cyclophosphamide) is an orally administered chemotherapy regimen used with palliative intent in relapsed or refractory lymphoma. To our knowledge no data on PEP-C have been reported since the original group described the regimen (Coleman et al., (2008) Leuk & Lymph 49, 447). Here we present a cohort from 3 centres describing our use of PEP-C over an 8 year period. Within the limitations of a retrospective cohort we find that PEP-C can give sustained responses and is well tolerated.PEP-C is usually administered as daily oral medication in three phases (Coleman et al., as above). Firstly, there is an induction phase where PEP-C is given daily until the white cell count falls below 3.0x109/L; then there is a break in treatment whilst the marrow recovers; and finally, PEP-C is re-started with the number of days per week on which it is given being titrated to keep the white cell count above 3.0x109/L. Variations to this schedule are possible.We identified 70 patients who received PEP-C at our centres and data from all is included. To achieve meaningful group sizes for analysis we classified patients as having high grade (43/70 (61%), mainly diffuse large B-cell) or low grade (27/70 (39%), mainly mantle cell) lymphoma.The median age when starting PEP-C was 74 years. Ninety three percent of patients had stage 3 or 4 disease, and 26% had a performance status of 3 or 4. Our cohort was therefore relatively frail.Of the 70 patients treated, 39% had a complete or partial response, and 44% had stable or progressive disease. In the remainder of cases there was no suitably objective measure by which to assess response. We assessed predictors of response by multivariate logistic regression and found the significant predictors to be whether disease was low or high grade, and whether or not a patient had responded to the line of chemotherapy prior to PEP-C (chemosensitive versus chemoresistant). Eleven out of 43 patients (26%) with high grade disease responded to PEP-C compared to 16 out of 27 (59%) with low grade disease (odds ratio=0.15 [95% CI 0.04 to 0.61]; p=0.008). Similarly, 5 out of 26 patients (19%) with chemoresistant disease responded to PEP-C compared to 19 out of 38 (50%) with chemosensitive disease (odds ratio=0.15 [95% CI 0.03 to 0.69]; p=0.014). There was no interaction between the predictors.As might be expected, whether or not a patient responded to PEP-C translated into a difference in overall survival. Patients who did not respond to PEP-C had a median overall survival from starting PEP-C of 70 days versus 599 days in patients who did respond (hazard ratio 4.9 [95% CI 2.4 to 9.9]; log rank p<0.001).Whether or not a patient responds to PEP-C cannot, however, be used a priori to make a decision about whether a patient might benefit from treatment. We therefore built Cox regression models to find other predictors of overall survival and found the significant predictor to be whether or not a patient was ‘chemosensitive’ as defined above. Chemosensitive patients had a median overall survival of 465 days compared to 77 days for chemoresistant patients (hazard ratio 0.47 [95%CI 0.26 to 0.85]; log rank p=0.011). For high versus low grade lymphoma the overall survivals were 116 and 411 days respectively but this trend did not reach statistical significance (p=0.050). For all patients the median overall survival was 167 days.The median time spent on treatment with PEP-C was 62 days, but there was considerable variation (range 4 to 1237 days). Interestingly, whilst chemosensitive patients had a median overall survival of 465 days from starting PEP-C (see above), they only spent a median of 90 days on treatment. This suggests that the optimum duration of treatment needs to be better defined as a shorter course may confer some ongoing benefit.Twenty two out of 70 patients (31%) discontinued PEP-C due to toxicity (uncomplicated marrow suppression in 10, non-neutropenic sepsis in 5, and neutropenic sepsis in 4). Thirteen patients (19%) died whilst on treatment with PEP-C but it is not clear that these deaths were a direct result of the treatment.In summary we suggest that PEP-C can be an effective palliative treatment for lymphoma, particularly but not exclusively where the lymphoma is known to be chemosensitive. The regimen has a tolerable side effect profile, and also has the advantage of being cheap. The cost of the ‘median’ course of treatment with PEP-C in our cohort was a little over £500 (BNF 73, 2017). DisclosuresFollows:Janssen: Other: advisory board and lecturing; Gilead: Other: advisory board and lecturing; Roche: Other: advisory board and lecturing; Abbvie: Other: advisory board and lecturing.

Diagnostic and prognostic value of peripheral lymphocyte subtyping for invasive candidiasis infection in critically ill patients with non-neutropenic sepsis

Objective: To assess the diagnostic and prognostic value of lymphocyte subtyping for invasive candidiasis infection (ICI) in critically ill patients with non-neutropenic sepsis. Methods: A prospective observational cohort study was performed at Peking Union Medical College Hospital (PUMCH), 377 patients with non-neutropenic sepsis admitted to Department of Critical Care Medicine from January 2017 to November 2019 were enrolled. There were 9.0% (34/377) patients diagnosed as ICI. Vital signs, supportive care therapy and microbiological specimens were collected. Peripheral blood lymphocyte subtypes, serum globulin, complements, inflammatory factors such as interleukin(IL)-6, IL-8, IL-10 and tumor necrosis factor were detected within 24 hours after sepsis was diagnosed. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value and prognostic significance of immunological indicators for ICI. Multiple logistic regression was used to analyze the independent risk factors for ICI. Kaplan-Meier analysis was used to analyze survival. Results: The acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score was 17.0 (13.0, 21.0) in all 377 patients. The sequential organ failure score (SOFA) was 11.0 (8.0, 13.0), and the 28-day mortality rate was 27.6% (104/377). Peripheral blood CD8+absolute T lymphocyte count≤177 cells/μl, CD28+CD8+T-cell count≤81 cells/μl and 1, 3-β-D-glucan (BDG) ≥88.20 ng/L were closely correlated with the diagnosis of ICI (AUC=0.793,95%CI 0.749-0.833,P<0.000 1;AUC=0.892,95%CI 0.856-0.921, P<0.000 1;AUC=0.761, 95%CI 0.715-0.803,P<0.000 1, respectively), with sensitivity of diagnosis 94.12%, 100.00%, and 88.24%; the specificity of diagnosis 81.34%, 62.39%, 63.56% respectively. Multivariate logistic regression analysis identified CD8+T-cell count≤139 cells/μl (OR=7.463, 95%CI 1.300-42.831, P=0.024) and CD28+CD8+T-cell counts≤52 cells/μl (OR=57.494, 95%CI 3.986-829.359, P=0.003) as independent risk factors for higher mortality. Kaplan-Meier survival analysis suggested that CD8+T-cell count ≤139 cells/μl (P=0.0159) and CD28+CD8+T-cell count≤52 cells/μl (P=0.000 1) were associated with higher mortality within 28 days (68.8%, 91.7%). Conclusions: Low CD28+CD8+T cell count in peripheral blood is closely related to the development and clinical outcome of ICI in sepsis patients, which could be used as an effective indicator for the diagnosis and prognosis prediction of ICI.

Non-Neutropenic Sepsis in Cancer Patients: The Luminal Obstruction Syndrome

Background: Neutropenic sepsis is a frequent complication of cytotoxic chemotherapy delivered for cancer patients. Its management is well determined by clinical guidelines. Non-neutropenic sepsis is another potential complication in cancer patients. Its management is less established in the medical literature. Materials and Methods: Three cases are presented to illustrate favourable evolution of non-neutropenic biliary-, uro- and bronchogenic-sepsis in cancer patients with poor prognosis. Results: All three patients had a survival over six months after the management of the septic complication. Two of them received subsequent systemic anticancer treatment. Conclusions: Survival benefit offered by the management of cancer-related non-neutropenic sepsis may be comparable to the benefit obtained by systemic anticancer treatments. Cost-effectiveness of sepsis management may be better than that of anticancer treatments.

Ectopic ACTH Production: Diagnosis, Treatment and Prognosis

Cushing’s syndrome due to ectopic ACTH as a result of metastatic malignancy invariably has a poor prognosis. In addition to tumour growth, diabetic and infective complications are causes of death. A multidisciplinary approach is needed with the focus of care being on management of endocrine abnormalities, control of symptoms and optimising quality of life. The adverse prognosis associated with these cancers should be taken into account when deciding on whether or not to pursue active oncological treatment with chemotherapy. In this case report, a 69-year-old patient presented with symptoms and signs of Cushing’s syndrome, which on further investigation was shown to be due to an ectopic ACTH-secreting metastatic small cell cancer of unknown primary. Treatment with palliative carboplatin etoposide chemotherapy and metyrapone was started, but unfortunately after one cycle of chemotherapy the patient died following hospital admission with poor diabetic control and non-neutropenic sepsis. We discuss the key issues in the diagnosis and management of this condition.

Gastrointestinal Leakage Detected by Serum (1→3)-β-D-Glucan in Mouse Models and a Pilot Study in Patients with Sepsis.

Gastrointestinal (GI) leakage is believed to exacerbate sepsis and new, validated markers of GI barrier performance might benefit clinical decision-making. Serum (1→3)-β-D-glucan (BG) was evaluated as a potential GI leakage marker. Serum BG was tested in several mouse models of GI leakage, including dextran sulfate solution (DSS) administration, endotoxin (LPS) injection, and cecal ligation and puncture sepsis (CLP). Serum BG titer was also evaluated in patients with sepsis and septic shock, for comparison.With 0.75% DSS administration, BG increased only after oral administration of heat-killed C. albicans, but increased spontaneously with 1.5% DSS. In the LPS and CLP models, BG increased as early as 1 h and at 12 h after LPS administration and surgery, respectively. GI leakage was confirmed by orthogonal validation methods including FITC-dextran oral administration in the DSS, LPS, and CLP models and, in the DSS model, with urine sucralose after oral administration and serum endotoxemia. IL-6 increased in parallel with serum BG. Serum BG or IL-6, at 18 h, anticipated sepsis mortality in the CLP model.Analysis of serum BG from patients with febrile neutropenic sepsis (N = 49) and febrile non-neutropenic sepsis (N = 39) demonstrated BG elevation. Patients with bacterial septic shock had serum BG titers similar to levels observed in invasive fungal disease, regardless of febrile neutropenia. Serum BG was lower in less severe cases of bacterial sepsis. Elevated serum IL-6 was associated with GI leakage and elevated serum BG.Serum BG may have potential as a sepsis/septic shock biomarker and further study in this context is warranted.

PWE-145 Contemporary uk experience with preoperative chemoradiotherapy and surgery for oesophageal cancer

Introduction The optimal neoadjuvant therapy regime for cancers of the oesophagus and OGJ remains controversial. In the UK preoperative chemotherapy is the standard of care, and we have been slow to adopt chemoradiotherapy (CRT) fearing increased surgical morbidity and under-treatment of systemic disease. The CROSS trial has led to a renewed interest in the use of CRT in the UK. We present our recent experience of patients treated with CRT and surgery for oesophageal carcinoma. Method All patients planned for CRT and surgery in a single UK institution were included. CRT consisted of carboplatin (AUC2) and paclitaxel (50 mg/m 2 ) weekly x 5 with concurrent radiotherapy (41.4Gray in 23 fractions, n = 25 (CROSS regime); 45Gray in 25 fractions, n = 4) for 29 patients and 2 patients had Oxaliplatin, Capecitabine (OxCap) and RT (45Gray in 25 fractions). In 5 CRT was preceded by 2 cycles of OxCap chemotherapy. Results Radiotherapy 31 patients (median age 66 years; male 21 (68%): female 10 (22%)) with 13 adenocarcinomas (AC) and with 17 squamous cell carcinomas (SCC) underwent CRT. One patient (3%) died during CRT after oesophageal perforation at OGD. 3 patients (9.7%) were admitted to hospital (neutropenic sepsis 1; non-neutropenic sepsis 2). The median time between CRT and surgery was 10 weeks (range 5.7–14.1). 8 patients are awaiting resection. Surgery 22 patients have completed CRT and surgery. All patients underwent an oesophagectomy (minimally invasive: 15 (62.2%); Ivor Lewis: 7 (30.4%); Mckeown: 1 (4.3%)) with median length of stay: 10 days (range 6–45). There were no deaths. Complications according to Clavien-Dindo were Grade 1: 1 (4.5%); Grade 2: 10 (45.5%); Grade 3: 1 (4.5%); Grade 4: 1 (4.5%) with no complications in 9 (40.9%) patients. One (4.5%) patient had an anastomotic leak and this required reoperation and oesophageal exteriorisation with subsequent colonic interposition. 6 (27%) patients experienced a post-operative cardiac arrhythmia. There were 6 (27%) respiratory complications and no chyle leaks. Pathology 21 pathology reports were available with one under analysis. Complete pathological response (47.6%) was observed in 8 (72.7%) SCCs and 2 (20%) ACs (Tumour regression grade (TRG)1: 10 (47.6%); 2: 6 (28:6%); 3: 3 (14.3%); 4: 2 (9.5%); 5: 0). 20 (95.2%) patients had complete (R0) resection. Median nodal yield was 22 (range 8–65). Conclusion In a single centre UK series, CRT and surgery for oesophageal cancer is safe and effective in the short term. This may in part be explained by increasing the time between the CRT and surgery from 6 to 10 weeks without compromising tumour pathology. Disclosure of interest None Declared.

Association between early peak temperature and mortality in neutropenic sepsis.

Fever is often the first sign of neutropenic infection, but its prognostic impact has not been established. We aimed to determine whether early peak temperature is associated with mortality in patients with neutropenic sepsis admitted to intensive care units (ICUs). We used a database of admissions to 157 ICUs in Australia and New Zealand between 2005 and 2013 to seek an association between peak temperature within the first 24 h in ICU and in-hospital mortality in neutropenic and non-neutropenic sepsis. Odds ratios for in-hospital death were calculated for four temperature bands, adjusting for illness severity. Two patient cohorts were identified: neutropenic sepsis (N = 4027) and non-neutropenic sepsis (N = 114,040). In-hospital mortality was higher in neutropenic sepsis than non-neutropenic sepsis. In both cohorts, early peak temperature below 36.5 °C was associated with significantly increased mortality compared to normothermia. Among non-neutropenic patients, an early peak temperature of 37.5 °C or higher was associated with reduced mortality compared to normothermia. In contrast, in patients with neutropenic sepsis, fever was not associated with reduced mortality compared to normothermia. Similar findings were seen in a subgroup of the neutropenic sepsis cohort with a documented haematological malignancy. In neutropenic sepsis patients admitted to ICU, a temperature below 36.5 °C is associated with increased mortality compared with normothermia. In contrast to non-neutropenic sepsis, fever was not associated with a significant reduction in mortality in neutropenic patients. Interventional studies are needed to determine whether physical or pharmacological measures to reduce fever influence outcomes during neutropenic infections.

Appropriate vancomycin use in a Malaysian tertiary hospital based on current HICPAC recommendations.

Antibiotic resistance is a rapidly emerging problem. A major concern is methicillin-resistant Staphylococcus aureus (MRSA), especially in developing countries where cost-effectiveness is imperative. Restriction of vancomycin usage is necessary to reduce the emergence of vancomycin-resistant organisms. The aim of this study was to look into the appropriate use of vancomycin based on the Healthcare Infection Control Practices Advisory Committee (HICPAC) guidelines and to investigate serum levels of vancomycin. The study was performed retrospectively. Medical records of patients treated with vancomycin for the past year were identified and selected. Overall, 118 patients were treated with vancomycin. Appropriate use of vancomycin was significantly higher than inappropriate use (p = 0.001). Approximately 85% (n = 100) of patients were given vancomycin for treatment, whereas the rest were given it for prophylaxis. Appropriate use of vancomycin was observed in 67% (n = 79) of patients. However, there was still a high rate of inappropriate vancomycin use for prophylaxis and treatment (n = 39, 33.1%). The most common reason for inappropriate use was non-neutropenic and non-line related sepsis (n = 36, 30.8%). Therapeutic drug monitoring of vancomycin was performed in 79 patients (67%). Most patients (n = 53, 67%) demonstrated sub-therapeutic levels during the first measurement. There was no significant difference between trough levels achieved with a higher (> 15 mg/kg) versus a lower dose (< 15 mg/kg). This study demonstrates that there was still a high level of inappropriate vancomycin use, which could potentially contribute to vancomycin resistance.

Perioperative epirubicin, oxaliplatin, and capectabine (EOX) in locally advanced resectable gastroesophageal junction and gastric adenocarcinoma.

e15142 Background: Perioperative chemotherapy with epirubicin, cisplatin and fluorouracil (ECF) confers a 13% absolute 5-year survival benefit over surgery alone in resectable gastroesophageal cancer. In the metastatic setting, the EOX regimen is at least as effective as ECF, with a favourable toxicity profile. This retrospective analysis presents the experience of a high-volume tertiary referral center with perioperative EOX in patients with resectable GEJ and gastric adenocarcinoma. Methods: Patients with cTxN+/cT3N0 gastroesophageal adenocarcinoma treated between 2006-2012 with perioperative EOX (epirubicin 50mg/m2 d1 q22d, oxaliplatin 130mg/m2 d1 q22d and capecitabine 625 mg/m2 bd d1-21 q22d), given as three neoadjuvant and three adjuvant cycles, were retrospectively identified from a prospectively recorded upper gastrointestinal cancer database. Efficacy and toxicity data were assessed. Results: 52 patients, including 41 (82%) males, with a median age of 62 (range 35-79) received perioperative EOX with curative intent. GEJ tumours represented 39 (75%) of cases, and the others were gastric cancers. 47 patients (90%) completed 3 cycles of neoadjuvant EOX. One patient died of non-neutropenic sepsis after cycle 2. 44 (85%) of patients progressed to surgery, 5 of whom were deemed unresectable. 28 (71%) surgeries were D2 resections, and the R0 resection rate was 67%. There was one postoperative death, due to pancreatitis. 28 (54%) of patients commenced adjuvant EOX, and 25 (48%) completed the planned treatment. Grade 3-4 toxicities were observed in 17% of patients, with the commonest being fatigue (8%) and nausea (4%). Pathological response rate, as defined by Mandard Tumour Regression Grade 1-3, was seen in 26%, with 3 (6%) pathological complete response. The median progression-free survival was 7 months, with a median overall survival of 22 months, and a 2-year survival rate of 45%. Conclusions: In our institution, perioperative EOX in gastroesophageal cancer is associated with a reasonable safety profile, and efficacy consistent with that reported in the MAGIC trial.

A phase I study of the CDK inhibitor dinaciclib (SCH 727965) administered every 3 weeks in patients (pts) with advanced malignancies: Final results.

3080 Background: Dinaciclib is a potent and selective inhibitor of CDKs 1, 2, 5, and 9 with anti-tumor activity in multiple tumor cell lines and xenograft models. Methods: Dinaciclib is administered every 3 weeks in pts with advanced malignancies. Part 1: accelerated titration design to establish the RP2D of a 2-hr IV infusion. Part 2: 8 and 24-hr continuous IV infusions. Part 3: determined effect of the CYP3A4 inhibitor aprepitant on PK. PD assessments: ex vivo lymphocyte proliferation assay; FDG-PET/CT scans; and skin and/or tumor biopsies for IHC of cdk targets. Results: 81 pts treated. Part 1: Doses 1.85 to 58 mg/m2. RP2D 50 mg/m2. DLTs: non-neutropenic sepsis (1), neutropenic fever (2), neutropenia with pneumonia (1), hypotension (1), and rise in transaminases (3). Part 2: 7.4 and 10.4 mg/m2 well tolerated as 8- and 24-hr infusions, respectively. DLTs seen at lower doses with 8-hr and 24-hr vs 2-hr infusions. 8-hr DLTs: neutropenia with or without fever (5), hypotension (1), syncope (1), and elevated transaminases (2). 24-hr DLTs: rise in bilirubin (1) and delirium (1). Part 3: pts received dinaciclib 29.6 mg/m2 by 2-hr infusion +/- aprepitant. Among all pts, the most common treatment-related adverse events were nausea, vomiting, diarrhea, neutropenia, and fatigue. Dinaciclib was rapidly eliminated with a t1/2 of 1.4-3.3 hrs. Coadministration of aprepitant had no significant effect on PK. PD: Dose and infusion time correlated with degree and durability of suppression of lymphocyte proliferation. Tumor metabolic changes occurred in some pts by FDG-PET at day 8 but were not predictive of response. No objective responses by RECIST; SD ≥6 cycles (range 6-30) achieved in 10 pts. Pre/post tumor biopsies from 2 pts with melanoma show reduced phospho-Rb [pT356] post-treatment; total Rb was preserved. In 1 pt, p27 and p53 increased post-treatment, consistent with cdk2 and cdk9 inhibition. Analysis of skin biopsies ongoing. Conclusions: Dinaciclib has an acceptable safety profile at 50, 7.4 and 10.4 mg/m2 for 2-, 8- and 24-hr infusions, respectively, without PK interaction with aprepitant. Prolonged SD was achieved in some pts. Trials are ongoing in hematologic malignancies and melanoma.

19 A Kent and Medway Cancer Network (KMCN) audit of first-line treatment with cisplatin/pemetrexed (CisPem) in non squamous non-small cell lung cancer (NSCLC)

Introduction: NICE approved CisPem for first-line treatment of advanced large cell or adenocarcinoma NSCLC patients in September 2009. We reviewed outcomes for this regimen within KMCN, a large cancer network of 1.8 million population. Therapy was given at 7 sites within a nurse led model incorporating close clinical oversight. Methods: A retrospective analysis of patients receiving CisPem as first-line treatment for NSCLC (September 2009 August 2010) was undertaken. Results: 39 chemotherapy-naive patients with locally advanced or metastatic non-squamous NSCLC were identified; 37 were treated with CisPem. Baseline demographics are shown below: 59% male; median age 63 years; smoking status 27% current, 32% previous, 38% unknown, 2.7% never-smokers; stage at presentation III = 22%, IV = 70%; performance status PS = 0 8%, PS = 1 84%, PS = 2 5%. Five patients did not receive treatment due to rapid progression. A median of 4 cycles of chemotherapy was delivered: 67% completed 4 cycles, 5.4% received 6 cycles, 13% only completed 1 2 cycles. Of 109 cycles of chemotherapy, just 0.9% of cycles were delayed. Cisplatin dose was reduced or omitted in 7% and 5% of cycles respectively. Pemetrexed doses were reduced or omitted in 4% and 5% of cycles respectively. 25% of patients were admitted at some point during their chemotherapy. The reasons for admission were non-neutropenic sepsis (12%), thromboembolic phenomena (24%) and progressive disease (64%). There were no deaths within 30 days of CisPem administration. Partial responses were documented in 62.5% of cases. Stable disease was seen in 12.5% and progressive disease in 25%. As of August 2010, 12 patients had died (median overall survival of 6.5 months and median progression-free survival 6.0 months). Conclusions: First line CisPem delivered within a community/nurseled setting provides similar efficacy outcomes to published trial data. The high rate of hospital admission and thromboembolic complications warrants further investigation.

Docetaxel and imatinib every 21 days for castration resistant prostate cancer: A phase II trial

e16086 Background: Docetaxel (D) IV every 21 days, is the only cytotoxic agent that prolongs survival in men with castrate resistant prostate cancer (CRPC). Imatinib (I), a tyrosine kinase inhibitor, modulates PDGFR-ß in tumor vasculature. Based on phase I data from our institution, we hypothesized that D plus I would prolong time to progression (TTP) in patients (pts) with CRPC. Methods: Subjects with CRPC received D 60 mg/m2 IV every 21 days plus I 400 mg PO daily. After 10 pts, the study treatment was modified due to toxicity so that pts received I 400 mg on 10 of 21 days/cycle. The primary endpoint was TTP. Secondary endpoints were rate of PSA response and overall survival (OS). The sample size of 43 pts was designed to provide 90% power to detect an increase in TTP from 5 to 8 months. Results: 43 pts enrolled from 8/05 to 9/08. Age at enrollment ranged from 54–86 years (median 69 years). 14 pts received &lt;1 cycle of D plus I and were unevaluable: 10 had significant toxicity, 4 due to non-treatment related reasons. Primary toxicities were hematologic: 21% G4 neutropenia, 5% G4 anemia, and no G4 thrombocytopenia. Fatigue, nausea, diarrhea, and electrolyte abnormalities were common, but &lt;2 cases each of G3-G4 toxicity occurred. 1 case of G5 non-neutropenic sepsis occurred. 29 pts received &gt;2 cycles of chemotherapy (mean 4.6). 12 pts had PR (41.4%), 9 had SD (31.0%), and 8 had no response (27.6%) by PSA. No objective responses were seen by CT imaging among 10 pts with measurable disease. 3 pts remain on trial. For evaluable pts, overall median TTP was 6.4 months (95% CL: 4.8, 8.4 months) compared with TTP of 5 months seen in previous trials. 23 (79%) pts had PSA progression, 3 pts died before progression, and 3 pts remain on trial. For all evaluable pts who had PR or SD by PSA (N = 21), median TTP was 7.1 months (95% CL: 5.5, 9.1 months). Median OS was 23.1 months (95% CL: 11.61 months, NR), compared with 18.9 months for GC Conclusions: Docetaxel on day 1 plus imatinib 10 days of each 21-day cycle resulted in meaningful improvement in TTP in the subset of pts who showed a response. Toxicity precludes its use in the general population, although its role in select pts with good performance status needs to be explored. [Table: see text]

Cetuximab (C225) plus irinotecan/cisplatin (CPT/Cis) for CPT/Cis-refractory esophageal cancer

15580 Background: In esophageal cancer, weekly CPT/Cis is an active regimen, with a response rate (RR) of 57% and time-to- progression (TTP) of 4.2 months (JCO 17:3270;1999). Epidermal growth factor receptor (EGFR) is overexpressed in 30–90% of esophageal tumors and is associated with advanced stage, chemotherapy resistance and poor prognosis. In colon cancer (CA), adding C225, an anti-EGFR monoclonal antibody, to CPT for CPT-refractory patients (Pts) increases RR and TTP (NEJM 351: 337;2004). Methods: Pts with metastatic esophageal/gastroesophageal junction CA who progressed by RECIST criteria on prior CPT/Cis within 3 months of enrollment were eligible. Up to a total of 2 prior regimens were allowed, including interim therapy between progression on prior CPT/Cis and enrollment. CPT/Cis was continued at the prior dose to a maximum of CPT 65 mg/m2/Cis 30 mg/m2 weekly 2 of 3 weeks. C225 was added at 400 mg/m2 week 1, then 250 mg/m2 weekly. Tumor tissue was tested for EGFR overexpression by immunohistochemistry (IHC). Results: 8 Pts were enrolled. 6 male (75%), 2 (25%) female, median age 53, median Karnofsky performance status 80%, 7 adenocarcinoma (adenoCA), 1 squamous cell (SCC). 6 of 8 Pts were EGFR positive (2 1+/ 2 2+/2 3+ by IHC). Median TTP on prior CPT/Cis was 4.4 months (range, 1.8 to 14.4 months). 1 confirmed partial response (PR) was seen in a Pt with adenoCA (EGFR 3+). 2 Pts had stable disease (SD) and 5 had progressive disease (PD). 1 Pt with SD for 2.9 months had SCC (EGFR 2+) while the other with SD for 3.7 months had adenoCA (EGFR negative). Significant grade 3/4 toxicities included lymphopenia (4 Pts, all grade 3), neutropenia (1 Pt, grade 4), hypomagnesemia (1 Pt, grade 3). Rash was manageable, with 4 Pts with grade 1 and 3 Pts with grade 2 skin toxicity. 1 Pt died of non-neutropenic sepsis from PD after 3 weeks of therapy (this Pt was off treatment for 3–4 weeks prior to death). Conclusions: Adding C225 to CPT/Cis for CPT/Cis-refractory esophageal cancer is well-tolerated; 1 PR has been observed to date. Accrual is ongoing to 25 Pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, Genentech, Pfizer, sanofi-aventis

Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy

BackgroundLenalidomide is active and well tolerated in relapsed and refractory multiple myeloma. We conducted a phase I/II trial of the combination of lenalidomide and chemotherapy to evaluate the safety and efficacy of the combination. MethodsThe 62 patients enrolled received liposomal doxorubicin 40 mg/m2 i.v. and vincristine 2 mg i.v. on day 1, dexamethasone 40 mg p.o. on days 1–4 (DVd), and lenalidomide on days 1–21 in 28-day cycles. Primary end points were maximum tolerated dose (MTD) of lenalidomide with DVd chemotherapy and overall response rate (ORR) by Southwest Oncology Group criteria of the combination. FindingsThe median age was 62 years, 70% of patients were males and 65% had refractory multiple myeloma. The MTD of lenalidomide with DVd chemotherapy was 10 mg and the dose-limiting toxicity was non-neutropenic sepsis. After 7.5 months of median follow-up, the ORR of the combination was 75%, with 29% of patients achieving a complete or near complete remission. The median progression-free survival was 12 months, while the median overall survival has not yet been reached. InterpretationThe combination of lenalidomide and DVd chemotherapy was well tolerated and resulted in high response rates in this mostly refractory patient population. Evaluation of this combination in newly diagnosed patients is warranted.

Phase II trial of trastuzumab and paclitaxel or docetaxel administered every 3 weeks to patients receiving a first treatment for HER2+ metastatic breast cancer

806 Background: Trastuzumab (Herceptin, H) is a humanized monoclonal antibody which showed a significant survival benefit in a randomized trial comparing chemotherapy + H vs. chemotherapy alone in first-line therapy of HER2+ MBC. This phase II multicenter trial assesses safety with particular attention to cardiac toxicity and efficacy in women receiving q3 week H with q3 week taxane as first-line treatment of HER2+ MBC. Methods: Patients had not previously received cytotoxic or H therapy for HER2+ MBC (IHC 3+ or FISH+), had normal left ventricular ejection fraction (LVEF), and had measurable disease. All patients received H (8 mg/kg load -> 6 mg/kg q3 weeks) with either paclitaxel or docetaxel at standard q 3 week doses (choice of taxane per treating physician). H/taxane was to be given for a minimum of 6 cycles followed by H alone until disease progression or limiting toxicity. LVEF was monitored by serial echocardiograms. Results: 36 patients have been enrolled: median age 55yr, ER+/PR+ (31%), ER+/PR- (19%), ER+/PR unknown (3%), ER-/PR+ (8%), ER-/PR- (39%). The objective response rates (ORR = CR + PR) and clinical benefit rates (CBR = CR + PR + SD >6 months) for 32 evaluable patients are shown below. Both H/taxane combinations were well tolerated. Grade 4 toxicities: neutropenic fever (1), resolved. Grade 3 toxicities: hypertension (3), thrombosis (3), nausea/vomiting (2), leukopenia (2), infection (2), non-neutropenic sepsis (1). There were no cases of clinical CHF. The median LVEF was 62% at baseline, 60% at week 9 and 60% at week 18. Conclusions: The combination of H plus a taxane given on a q3 week schedule for HER2+ MBC is well-tolerated and active for both ER+ and ER- patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Aventis; Genentech Genentech Genentech Genentech

Phase II trial of trastuzumab and paclitaxel or docetaxel administered every 3 weeks to patients receiving a first treatment for HER2+ metastatic breast cancer

806 Background: Trastuzumab (Herceptin, H) is a humanized monoclonal antibody which showed a significant survival benefit in a randomized trial comparing chemotherapy + H vs. chemotherapy alone in first-line therapy of HER2+ MBC. This phase II multicenter trial assesses safety with particular attention to cardiac toxicity and efficacy in women receiving q3 week H with q3 week taxane as first-line treatment of HER2+ MBC. Methods: Patients had not previously received cytotoxic or H therapy for HER2+ MBC (IHC 3+ or FISH+), had normal left ventricular ejection fraction (LVEF), and had measurable disease. All patients received H (8 mg/kg load -> 6 mg/kg q3 weeks) with either paclitaxel or docetaxel at standard q 3 week doses (choice of taxane per treating physician). H/taxane was to be given for a minimum of 6 cycles followed by H alone until disease progression or limiting toxicity. LVEF was monitored by serial echocardiograms. Results: 36 patients have been enrolled: median age 55yr, ER+/PR+ (31%), ER+/PR- (19%), ER+/PR unknown (3%), ER-/PR+ (8%), ER-/PR- (39%). The objective response rates (ORR = CR + PR) and clinical benefit rates (CBR = CR + PR + SD >6 months) for 32 evaluable patients are shown below. Both H/taxane combinations were well tolerated. Grade 4 toxicities: neutropenic fever (1), resolved. Grade 3 toxicities: hypertension (3), thrombosis (3), nausea/vomiting (2), leukopenia (2), infection (2), non-neutropenic sepsis (1). There were no cases of clinical CHF. The median LVEF was 62% at baseline, 60% at week 9 and 60% at week 18. Conclusions: The combination of H plus a taxane given on a q3 week schedule for HER2+ MBC is well-tolerated and active for both ER+ and ER- patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Aventis; Genentech Genentech Genentech Genentech

Plasma concentrations of defensins and lactoferrin in children with severe sepsis.

We hypothesized that systemic release of endogenous leukocyte-derived polypeptide antimicrobial defensins (polymorphonuclear leukocyte-specific) and lactoferrin (polymorphonuclear leukocyte and epithelial cell derived) occurs in nonneutropenic children with severe sepsis. We performed a prospective cross-sectional and longitudinal study in a university children's hospital pediatric intensive care unit. Ninety-two consecutive children meeting criteria for sepsis and 14 critically ill children without sepsis (controls) were enrolled, and plasma defensins and lactoferrin concentrations were measured on Days 1 and 3 of sepsis. Nonneutropenic sepsis patients (n = 71) had increased defensins and lactoferrin plasma concentrations compared with critically ill control patients [defensins, 450 ng/ml vs. 150 ng/ml; lactoferrin, 332 ng/ml vs. 176 ng/ml (median values); P < 0.05] and neutropenic sepsis patients [n = 21; defensins, 450 ng/ml vs. 50 ng/ml; lactoferrin, 332 ng/ml vs. 20 ng/ml (median values); P < 0.05]. Neutropenic sepsis patients had similar plasma defensin concentrations and a decrease in plasma lactoferrin concentrations compared with control patients (P < 0.05). Defensins and lactoferrin plasma concentrations correlated to total white blood cell and absolute neutrophil count (P < 0.05). There was no association between plasma defensin concentration and organ failure or outcome; however, increased plasma lactoferrin concentrations were observed with the development of organ failure (P < 0.05). These data suggest that increased circulating defensins and lactoferrin release are dependent in part on neutrophil count and might play a role in host defense in children with severe sepsis.

A phase II study of continuous-infusion 5-fluorouracil with cisplatin and epirubicin in inoperable pancreatic cancer

Carcinomas of the exocrine pancreas respond poorly to most chemotherapy regimens. Recently continuous infusional 5-fluorouracil (200 mg m-(2)day-1) with 3 weekly cisplatin (60 mg m-2) and epirubicin (50 mg m-2) (the ECF regimen) has proven to be an active regimen in gastric and breast cancer and consequently worthy of further study in pancreatic cancer. Thirty-five patients were treated with the ECF regimen as above, of whom 29 were evaluable for response and 32 were evaluable for toxicity. The mean age was 59 years (range 37-75). Sixteen patients had locally advanced disease at presentation and 19 had metastases. Objective tumour responses were documented in five (17.3%) patients who achieved a partial response; in 18 (62%) patients there were no change and six (20.7%) patients progressed on therapy. Patients with either stable disease or partial response had a significantly improved overall survival (median = 253 days) compared with patients who progressed (median = 170 days; P = 0.01). Grade 3/4 (WHO) toxicity (all cycles) included alopecia in 18 (56%) patients, nausea/vomiting in eight (25%) stomatitis in three (9%) and diarrhoea in seven (22%) patients, with rhinorrhoea and excessive lacrimation in one patient each. Neutropenic sepsis occurred in 13 cycles in ten patients, and there was one toxic death due to sepsis. There were eight other episodes of non-neutropenic sepsis requiring hospital admission. Fourteen patients (40%) experienced complications with their Hickman lines, including thrombotic episodes (six patients) or their line falling out (five patients). ECF can prolong survival in patients with locally advanced or metastatic pancreatic cancer who demonstrate a response or stabilisation of their disease. However, this is associated with considerable toxicity.