Ronald Feld

Bloodstream infections in cancer patients with febrile neutropenia.

Bloodstream infections (bacteraemia) account for approximately 25-30% of febrile episodes in patients with febrile neutropenia (FN). In developed countries, Gram-positive pathogens predominate. Mortality is higher in Gram-negative bacteraemia. A recent study involving 2142 patients with FN was reviewed, including 168 patients with Gram-negative bacteraemia (mortality 18%), 283 patients with Gram-positive bacteraemia (mortality 5%) and 48 patients with polymicrobial bacteraemia (mortality 13%). Among patients who received prophylactic antibiotics, Gram-positive bacteraemia was far more common than Gram-negative bacteraemia (75% vs. 25%), compared with approximately 50% of each in patients without prophylactic antibiotics. Patients with a Multinational Association for Supportive Care in Cancer (MASCC) score <15 had a 36% mortality compared with 3% if the MASCC score was >21. The MASCC score may help risk stratification of patients with FN and bacteraemia, although these data require confirmation. In two series of patients from developing countries (Lebanon and Malaysia), Gram-negative bacteraemia was more common and mortality was higher. In developing countries, Gram-negative bacteraemia may be more frequent due to less use of prophylactic antibiotics and central lines. Laboratory markers may have predictive and prognostic value for bacteraemia in patients at the onset of FN, including mannose-binding lectin, interleukin (IL)-6, IL-8 and procalcitonin, but further studies are required before they can be recommended. New therapies are required to lower the mortality in patients with FN with a high risk for bacteraemia.

Referral Patterns for Adjuvant Chemotherapy in Patients with Completely Resected Non-small Cell Lung Cancer

Background: Lung cancer remains a leading cause of cancer-related mortality in North America. Despite potentially curative resection, non-small cell lung cancer (NSCLC) patients remain at high risk of relapse and death, with a 5-year survival rate of less than 67%. Several randomized trials now confirm a survival benefit with adjuvant platinum-based chemotherapy seen in the NSCLC Collaborative Group meta-analysis, including the International Adjuvant Lung Trial, National Cancer Institute of Canada BR.10, and Adjuvant Navelbine International Trialist Association (ANITA) trials, with absolute improvements in 4- and 5-year survival rates of 4% to 15%. This study examines whether referral patterns for adjuvant therapy in NSCLC have changed since the presentation of confirmatory trials. Methods: Retrospective chart review was undertaken at a major tertiary care center, identifying patients with completely resected stages I–IIIA NSCLC from May 2003 to May 2005. Results: A total of 204 patients were identified (59 IA, 77 IB, 8 IIA, 41 IIB, and 19 IIIA). Institutional policy before May of 2003 was not to administer adjuvant therapy outside a clinical trial. After presentation of the International Adjuvant Lung Trial in May 2003, 31% (36/115) of patients with completely resected NSCLC from May 2003 to May 2004 were referred for adjuvant chemotherapy. After presentation of the BR.10 and Cancer and Leukemia Group B 9633 results in June 2004, 63% (56/89) were referred between June 2004 and May 2005. Reasons for not referring to a medical oncologist included stage IA disease, surgeon thought adjuvant therapy inappropriate, patient declined, comorbidities, postoperative complications, and advanced age. Of 92 patients referred to medical oncology, 42 (46%) received adjuvant chemotherapy. Reasons for not prescribing adjuvant chemotherapy included patient refusal (50%), comorbidities (14%), stage IA (10%), and advanced age (4%). Vinorelbine/cisplatin was the regimen most commonly used (67%). Conclusions: The presentation of positive adjuvant therapy trials in NSCLC has changed clinical practice substantially, doubling the number of patients with completely resected NSCLC referred for adjuvant chemotherapy since May 2004 (31% versus 63%). Although new evidence to support adjuvant chemotherapy in lung cancer is being disseminated to and accepted by physicians, more patient education and decision support may be required to increase uptake of adjuvant therapy in the early stage NSCLC population.

Does intensive follow-up alter outcome in patients with advanced lung cancer?

Background: Despite aggressive multimodality treatment, 5-year survival of stage III non-small cell lung cancer (NSCLC) remains <30%. To detect relapse, progression, or development of a second primary cancer early, many clinicians perform follow-up scans. To assess the impact of routine scanning, we compared clinical trial patients who had study-mandated scans with those treated off-study who had less intensive radiologic follow-up. Methods: The hospital cancer registry and trials databases were searched for patients with locally advanced NSCLC who had undergone multimodality treatment with curative intent. Baseline demographics were collected as well as frequency and results of clinical and radiologic follow-up. Results: Forty trial patients and 35 nontrial control patients were identified. Trial patients underwent significantly more imaging, particularly in the first 2 years (2.9 versus 2.0 body scans per year, p = 0.0016; 1.1 versus 0.4 brain scans per year, p < 0.001) but did not have more frequent follow-up visits. Forty-five cancers were detected (41 relapses, four metachronous primary tumors) in 44 (59%) patients. Of these, 28 (64%) sought medical attention that led to detection before a scheduled appointment or procedure. There was no significant difference in time to relapse or second primary in trial and nontrial patients (p = 0.80). Twenty-three patients had localized relapse, but only 15 could be treated with curative intent. Despite the trial group demonstrating a higher number of asymptomatic cancers and being offered potentially curative therapy more frequently, there was no significant difference in survival between trial and nontrial patients. Conclusion: In patients with locally advanced NSCLC, frequent cross-sectional imaging does not alter survival after combined modality therapy.

An International, Multicenter, Randomized Phase III Study of First-Line Erlotinib Followed by Second-Line Cisplatin/Gemcitabine Versus First-Line Cisplatin/Gemcitabine Followed by Second-Line Erlotinib in Advanced Non–Small-Cell Lung Cancer: Treatment Rationale and Protocol Dynamics of the TORCH Trial

Herein, we present a randomized phase III Italian-Canadian trial named TORCH (Tarceva or Chemotherapy). In TORCH, we are investigating whether erlotinib as first-line therapy until progression followed by chemotherapy with cisplatin/gemcitabine will not be inferior in terms of survival to the standard arm, consisting of first-line cisplatin/gemcitabine for 6 cycles, followed at progression by erlotinib until second progression. The primary objective is overall survival, and an adjunctive primary endpoint is activity of first-line treatment with erlotinib in terms of progression-free rate after 9 weeks of treatment. Secondary objectives include response rate, progression-free survival, toxicity, quality of life, and exploratory evaluations of tumor tissue and blood samples for biologic or genomic determinants of outcome. The study design is based on a noninferiority survival comparison with about 900 patients expected to be recruited. An early analysis of activity will be performed in the experimental arm (first-line erlotinib followed by chemotherapy).

Gefitinib (IRESSA) with vinorelbine or vinorelbine/cisplatin for chemotherapy-naive non-small cell lung cancer patients.

This phase I study assessed the safety, pharmacokinetics, and efficacy of gefitinib (IRESSA) combined with vinorelbine or vinorelbine/cisplatin in chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC). Patients received gefitinib 250 mg/day and vinorelbine (group A; n = 6) or vinorelbine/cisplatin (group B; n = 8). An additional set of group B patients (n = 9) received gefitinib 500 mg/day with vinorelbine/cisplatin. Adverse events were consistent with individual treatments of gefitinib (mild reversible rash, diarrhea) and chemotherapy (asthenia, fever, nausea, vomiting, constipation), although there was a higher than expected incidence of Common Toxicity Criteria grade 3 or 4 hematologic adverse events, specifically febrile neutropenia and neutropenia. Pharmacokinetic data suggested that neither of the chemotherapy regimens affected steady-state exposure to gefitinib and also that steady-state gefitinib did not alter exposure to vinorelbine or cisplatin. Objective, durable antitumor activity was observed: five partial responses (one in group A; four in group B) and six patients with stable disease (all in group B). The safety data demonstrated that gefitinib with vinorelbine or vinorelbine/cisplatin resulted in severe myelosuppression leading to an unacceptable rate of febrile neutropenia. This study does not support the concurrent administration of gefitinib and vinorelbine, with or without cisplatin, as a valid treatment for advanced NSCLC.

Quality of Life Analysis of TORCH, a Randomized Trial Testing First-Line Erlotinib Followed by Second-Line Cisplatin/Gemcitabine Chemotherapy in Advanced Non–Small-Cell Lung Cancer

Introduction: The TORCH (Tarceva or Chemotherapy) trial randomized patients with advanced non–small-cell lung cancer to first-line erlotinib followed by second-line cisplatin/gemcitabine versus. standard inverse sequence. The trial, designed to test noninferiority in overall survival, was stopped at interim analysis because of inferior survival in the experimental arm. Quality of life (QoL), a secondary outcome, is reported here. Methods: QoL was assessed at baseline and every 3 weeks during first-line, using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 and QLQ–lung cancer specific module (LC13). Mean changes from baseline within arms were reported. QoL response and time-to-deterioration of QoL using a competing-risk approach were compared between treatment arms. Results: Six hundred and thirty patients (83%) completed baseline questionnaires. Compliance was affected by differential treatment efficacy, but was similar between arms for patients without progression or death. Significant differences in QoL responses were observed favoring chemotherapy for pain, sleeping, dyspnea, diarrhea, and favoring erlotinib for vomiting, constipation, sore mouth, and alopecia. In the small subset of patients with EGFR-mutated tumors, all selected items (global QoL, physical functioning, cough, dyspnea and pain) improved, whereas worsening or no change was observed in wild-type patients. Improvement was particularly evident in the first-line erlotinib arm as for global QoL and physical functioning. Conclusions: QoL was impacted by differential toxicity and efficacy between arms. Functional domains and global QoL did not differ, although some symptoms were better controlled with chemotherapy in unselected non–small-cell lung cancer patients.

Multinational cooperation in trials and guidelines dealing with febrile neutropenia.

Multinational cooperation has lead to many of the advances in the therapy of cancer patients with febrile neutropenia over the last two decades and will likely continue to do so. Some of the groups and societies that have contributed to this success include the European Organization for Research and Treatment of Cancer (EORTC) Antimicrobial Group, The Immunocompromised Host Society (ICHS), the Multinational Association for Supportive Care in Cancer (MASCC) infection subcommittee and the International Disease Society of America (IDSA). Some of these contributions are described in this manuscript. Without this approach the data from single institutions may not have been so well accepted in centers all over the world. Multinational cooperation in this field along with better antimicrobials have contributed significantly to the drop in mortality in high risk patients from >50% in the 1950s and 1960s to 5-10% noted in most recently published studies.

A clinical investigation of inhibitory effect of panobinostat on CYP2D6 substrate in patients with advanced cancer

PurposePanobinostat is a potent oral pan-deacetylase inhibitor with promising clinical activity in hematologic malignancies. Panobinostat was shown to inhibit CYP2D6 activity in vitro; thus understanding the magnitude of the potential clinical inhibition of panobinostat on co-medications that are CYP2D6 substrates becomes important.MethodsThis study evaluated the effects of co-administration of panobinostat with a sensitive CYP2D6 substrate, dextromethorphan (DM), in patients with advanced cancer who have functional CYP2D6 genes. Patients received 60xa0mg DM alone on day 1, panobinostat at 20xa0mg alone on days 3 and 5, and both agents on day 8. Plasma concentrations of DM and its metabolite dextrorphan (DX) were determined by liquid chromatography–tandem mass spectrometry following serial blood collections on day 1 (DM alone) and day 8 (in combination with panobinostat).ResultsPanobinostat increased DM exposure by 64xa0% [geometric mean ratio (GMR), 1.64 (90xa0% confidence interval (CI), 1.17–2.31)] and DX exposure by 29xa0% (GMR, 1.29 [90xa0% CI, 1.10–1.51]). These results indicated that panobinostat weakly inhibited a sensitive CYP2D6 substrate in cancer patients by increasing DM exposure by less than twofold.ConclusionSafety monitoring of sensitive CYP2D6 substrates with narrow therapeutic index is recommended when co-administering with panobinostat in future clinical practice.

A genetic sequence variant (GSV) at susceptibility loci of 5p15.33 (TERT-CLPTM1L) is associated with survival outcome in locally advanced and metastatic non-small-cell lung cancer (NSCLC)

INTRODUCTIONnLung cancer is a leading cause of cancer-related mortality in North America. In addition to tobacco smoking, inherited genetic factors can also influence the development of lung cancer. These genetic factors may lead to biologically distinct subsets of cancers that have different outcomes. We evaluated whether genetic sequence variants (GSVs) associated with lung cancer risk are associated with overall survival (OS) and progression-free survival (PFS) in stage-III-IV non-small-cell lung cancer (NSCLC) patients.nnnMETHODSnA total of 20 candidate GSVs in 12 genes previously reported to be associated with lung cancer risk were genotyped in 564 patients with stage-III or IV NSCLC. Multivariate Cox proportional hazard models adjusted for potential clinical prognostic factors were generated for OS and PFS.nnnRESULTSnAfter taking into account multiple comparisons, one GSV remained significant: rs4975616 on chromosome 5p15.33, located near the TERT-CLPTM1L gene. The adjusted hazard ratio (aHR) for OS was 0.75 (0.69-0.91), p = 0.002; for PFS aHR was 0.74 (0.62-0.89), p < 0.001 for each protective variant allele. Results were similar in both Stage III (OS: aHR = 0.70; PFS: aHR = 0.71) and Stage IV patients (OS: aHR = 0.81; PFS: aHR = 0.77).nnnCONCLUSIONnA GSV on 5p15.33 is not only a risk factor for lung cancer but may also be associated with survival in patients with late stage NSCLC. If validated, GSVs may define subsets of patients with different risk and prognosis of NSCLC.

A phase II study of capecitabine, irinotecan, and bevacizumab in patients with previously untreated metastatic colorectal cancer

BackgroundPrevious phase III studies raised concern about the safety of the combination of capecitabine and irinotecan in patients with metastatic colorectal cancer (mCRC). We conducted a single arm phase II study to evaluate the safety and efficacy of bevacizumab in combination with dose-reduced capecitabine and irinotecan in patients with previously untreated mCRC.Patients and methodsPatients with previously untreated mCRC were eligible. Capecitabine was given at 1,000xa0mg/m2 orally twice daily for 14xa0days and dose was reduced to 750xa0mg/m2 for patients over 65. Irinotecan was given at 200xa0mg/m2 and bevacizumab was given at 7.5xa0mg/kg intravenously on day 1. The treatment cycle was repeated every 21xa0days. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival, response rate, and toxicity.ResultsFifty patients were enrolled, the median age was 58, and 54% were ECOG 0. The most common grade 3/4 adverse events included hand-foot syndrome (14%), neutropenia (12%), and diarrhea (10%). Response rate was 51% and disease control rate (response and stable disease) was 98%. Median PFS was 11.5xa0months (95% CI: 9.2–13.7), and 6xa0month PFS was 90% (95% CI: 77–98%).ConclusionWith modest dose reductions, the combination of capecitabine, irinotecan, and bevacizumab was well tolerated and resulted in favorable outcomes for patients with previously untreated mCRC.