Influence of chemotherapeutic drug-related gene polymorphisms on toxicity and survival of early breast cancer patients receiving adjuvant chemotherapy.

BACKGROUND: We investigated whether GSTT1 ("null" allele), GSTM1 ("null"allele), GSTP1 (A313G), RFC1 (G80A), MTHFR (C677T), TS (2R/3R) polymorphisms were associated with toxicity and survival in patients with early breast cancer (EBC) treated with adjuvant chemotherapy (CT). METHODS: This prospective trial included patients with stage I-III BC subjected to CT with CMF or FEC regimens. PCR-RFLP was performed for MTHFR, RFC1 and GSTP1, while PCR for TS, GSTT1 and GSTM1 genes. RESULTS: Among the 244 patients consecutively enrolled, 48.7% were treated with FEC and 51.3% with CMF. Patients with TS2R/3R genotype showed less frequently severe neutropenia (G3/G4) than those with TS2R/2R and 3R/3R genotype (p = 0.038). Patients with MTHFRCT genotype had a higher probability of developing severe neutropenia than those with MTHFR CC genotype (p = 0.043). Patients with RFC1GG or GSTT1-null genotype or their combination (GSTT1-null/RFC1GG) were significantly associated with a shorter disease free survival (DFS) (p = 0.009, p = 0.053, p = 0.003, respectively) and overall survival (OS) (p = 0.036, p = 0.015, p = 0.005, respectively). Multivariate analysis confirmed the association of RFC1GG genotype with a shorter DFS (p = 0.018) and of GSTT1-null genotype of a worse OS (p = 0.003), as well as for the combined genotypes GSTT1-null/RFC1GG, (DFS: p = 0.004 and OS: p = 0.003). CONCLUSIONS: Our data suggest that TS2R/2R and 3R/3R or MTHFR CT genotypes have a potential role in identifying patients with greater risk of toxicity to CMF/FEC and that RFC1 GG and GSTT1-null genotypes alone or in combination could be important markers in predicting clinical outcome in EBC patients.

Delayed emesis: moderately emetogenic chemotherapy (single-day chemotherapy regimens only).

PURPOSE: An update of the recommendations for the prophylaxis of delayed emesis induced by moderately emetogenic chemotherapy discussed during the third Perugia Consensus Conference (June 2009) sponsored by MASCC-ESMO was presented. The review considered new studies published since the second consensus conference (April 2004). METHODS: An online search was used conducting PubMed and the search terms moderately, chemotherapy, and emesis with a restriction to papers in English. RESULTS: Overall, nine randomized controlled studies were included: four evaluating NK1 receptor antagonists, one palonosetron, and four dopamine receptor antagonists. CONCLUSIONS: In patients receiving a combination of anthracycline plus cyclophosphamide treated with a combination of aprepitant, a 5-HT(3) receptor antagonist and dexamethasone to prevent acute nausea and vomiting, aprepitant is suggested to prevent delayed emesis. In patients who do not receive aprepitant for the prophylaxis for acute emesis and in which palonosetron is recommended, a multiday oral dexamethasone is the preferred treatment for the prevention of delayed emesis. Levels of evidence and of consensus for both recommendations are moderate.

Consensus recommendations for the prevention of vomiting and nausea following high-emetic-risk chemotherapy.

In this update of our 2005 document, we used an evidence-based approach whenever possible to formulate recommendations, emphasizing the results of controlled trials concerning the best use of antiemetic agents for the prevention of emesis and nausea following anticancer chemotherapies of high emetic risk. A three-drug combination of a 5-hydroxytryptamine type 3 receptor (5-HT(3)) receptor antagonist, dexamethasone, and aprepitant beginning before chemotherapy and continuing for up to 4 days remains the standard of care. We address issues of dose, schedule, and route of administration of five selective 5-HT(3) receptor antagonists. We conclude that, for each of these five drugs, there is a plateau in therapeutic efficacy above which further dose escalation does not improve outcome. In trials designed to prove the equivalence of palonosetron to ondansetron and granisetron, palonosetron proved superior in emesis prevention, while adverse effects were comparable. Furthermore, for all classes of antiemetic agents, a single dose is as effective as multiple doses or a continuous infusion. The oral route is as efficacious as the intravenous route of administration.

Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study.

BACKGROUND: Clinical trials are needed to assess the clinical benefit of antithrombotic prophylaxis in patients with cancer who are receiving chemotherapy, since these patients are at an increased risk of developing a thromboembolism. We did a trial to assess the clinical benefit of the low-molecular-weight heparin nadroparin for the prophylaxis of thromboembolic events in ambulatory patients receiving chemotherapy for metastatic or locally advanced solid cancer. METHODS: Between October, 2003, and May, 2007, ambulatory patients with lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer were randomly assigned in a double-blind manner to receive subcutaneous injections of nadroparin (3800 IU anti-Xa once a day, n=779) or placebo (n=387), in a 2:1 ratio. Study treatment was given for the duration of chemotherapy up to a maximum of 4 months. The primary study outcome was the composite of symptomatic venous or arterial thromboembolic events, as assessed by an independent adjudication committee. All randomised patients who received at least one dose of study treatment were included in the efficacy and safety analyses (modified intention-to-treat population). The study is registered with ClinicalTrials.gov, NCT 00951574. FINDINGS: 1150 patients were included in the primary efficacy and safety analyses: 769 patients in the nadroparin group and 381 patients in the placebo group. 15 (2.0%) of 769 patients treated with nadroparin and 15 (3.9%) of 381 patients treated with placebo had a thromboembolic event (single-sided p=0.02). Five (0.7%) of 769 patients in the nadroparin group and no patients in the placebo group had a major bleeding event (two-sided p=0.18). The incidences of minor bleeding were 7.4% (57 of 769) with nadroparin and 7.9% (30 of 381) with placebo. There were 121 (15.7%) serious adverse events in the nadroparin goup and 67 (17.6%) serious adverse events in the placebo group. INTERPRETATION: Nadroparin reduces the incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced cancer who are receiving chemotherapy. Future studies should focus on patients who are at a high risk for thromboembolic events. FUNDING: Italfarmaco SpA, Milan, Italy.

Biological markers and DNA flow cytometric analysis in radically resected patients with non-small cell lung cancer. A study of the Perugia Multidisciplinary Team for Thoracic Tumors.

AIMS AND BACKGROUND: The aim of this study was to evaluate the relationship between a panel of biological markers (p53, Bcl-2, HER-2, Ki67, DNA ploidy and S-phase fraction) and clinical-pathological parameters and its impact on outcome in non-small cell lung cancer (NSCLC). METHODS AND STUDY DESIGN: Tumor tissue specimens obtained after surgical resection were collected from consecutive patients with NSCLC. We used an immunocytochemical technique for p53, Bcl-2, HER-2 and Ki67 analysis in fine-needle aspirates obtained from surgical samples that were also evaluated by flow cytometric DNA analysis using a FACScan flow cytometer. RESULTS: From April 2000 to December 2005, 136 patients with radically resected NSCLC were recruited. Median age was 66 years (range, 31-84 years), male/female ratio 117/19, ECOG performance status 0/1 127/4, stage I/II/III 76/25/35, squamous/adenocarcinoma/large-cell/mixed histology 62/49/17/8, smokers yes/no 121/11. Positivity of p53, Bcl-2, HER-2 and Ki67 was detected in 51.4%, 27.9%, 25.0% and 55.8% of the samples, respectively; 82.9% of the cases revealed aneuploid DNA histograms and 56.7% presented an S-phase fraction of more than 12%. Statistically significant associations between high Ki67 and poorly differentiated tumors (P = 0.016) and a smoking history (P = 0.053); p53 positivity and high Ki67 (P = 0.002); HER-2 positivity and adenocarcinoma subtype (P = 0.015) and presence of lymph node involvement (P = 0.006); and Bcl-2 positivity and squamous cell carcinoma subtype (P = 0.058) were observed. At univariate analysis, high Ki67 proved to be the only marker associated with disease-free survival (P = 0.047). After adjusting for stage, none of the examined immunocytochemical markers emerged as an independent factor for disease-free and overall survival; only pathological stage was identified as an independent prognostic factor for disease-free survival (P = 0.0001) and overall survival (P = 0.0001). In the group of 76 patients classified as TNM stage I, high Ki67 was the only marker associated with recurrence of disease (P = 0.05). CONCLUSIONS: Our data do not support a relevant prognostic role of immunocytochemical markers in NSCLC, even if the Ki67 index might have particular relevance to identify patients with more aggressive tumors who are at high risk for disease relapse.

Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer.

Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. The identification and implementation of predictive genetic markers of response-specific cytotoxic drugs is a priority of current research and future trials. In this study, we have used quantitative PCR to analyse expression of beta-tubulin III, stathmin, RRM1, COX-2 and GSTP1 in mRNA isolated from paraffin-embedded tumor biopsies of 75 nonsmall-cell lung cancer patients treated as part of a large randomized trial. In total, 22 patients were treated with gemcitabine/cisplatin, 25 with vinorelbine/cisplatin and 28 with paclitaxel/carboplatin. There were no differences in clinical characteristics and transcript levels in the pretreatment biopsies according to treatment arm. Patients with low beta-tubulin III levels had better response in the paclitaxel/carboplatin arm (P=0.05), and those with low RRM1 levels showed a tendency to better response in the gemcitabine/cisplatin arm. Time to progression was influenced by beta-tubulin III (P=0.03) and stathmin (P=0.05) levels in the vinorelbine/cisplatin arm, and there was a tendency toward correlation between beta-tubulin III levels and time to progression in the paclitaxel/carboplatin arm. RRM1 levels influenced time to progression (P=0.05) and even more so, survival (P=0.0028) in the gemcitabine/cisplatin arm. The predictive value of beta-tubulin III, stathmin and RRM1 should be tested in prospective customized chemotherapy trials, the results of which will help tailor chemotherapy to improve patient survival.

The multidisciplinary rectal cancer treatment: main convergences, controversial aspects and investigational areas which support the need for an European Consensus.

BACKGROUND AND PURPOSE: During the past decades staging and treatment of rectal cancer are used different in Europe and in North America. To promote a process to integrate the daily practice with the best evidence of the literature an International Conference was organized in Italy. Agreement between Experts, Centres, and specialists who participated in the Conference are reported. METHODS: Five aspects were analyzed and a questionnaire was tailored for this purpose. The questionnaire had 159 questions. During the Conference, at the beginning of each Session, the moderators showed the answers from the Experts and the Centres, and, at the end of the session, the audience voted in all controversial issues. Agreements were scored at three levels: minimum, if it was between 51 and 74% of votes for each group; moderate, between 75 and 94%; large, more than 94%. RESULTS: The main results are: staging: endoanal ultrasound was considered as mandatory in T staging, in the evaluation of sphincter infiltration, and in the restaging of T after chemoradiotherapy (chRT). Magnetic Resonance Imaging is mandatory in the evaluation of mesorectal fascia infiltration. Endoscopy had a moderate agreement for the definition of tumour location, and the barium enema as optional. Digital rectal examination is complementary for staging and PET-CT investigational for T, N and yT staging. Preoperative radiotherapy: for T4 stage chRT was always the preferred treatment, often with moderate agreement, for any tumour location and N status. For T3, chRT received the same agreement except for high location and N0-N1. For T2 stage, N2 and positive nodes outside the mesorectum, chRT received minimum agreement for low and middle tumours; for high tumours only positive nodes outside the mesorectum was agreed upon. Preoperative radiotherapy, negative specimen and sphincter preservation: chRT was agreed by many for all T stages and N presentations of lower third tumours, except for T1-2 N0-N1. Postoperative treatments: the selection for these treatments often received moderate agreement according to the infiltration of surrounding organs, positive nodal status and circumferential radial margins. Therapy of metastatic disease: an agreement was found for FOLFOX as first-line therapy and for FOLFIRI as second-line, although comparative studies show similar activity of FOLFOX and FOLFIRI regimens. CONCLUSIONS: This process represents an expertise opinion process that may contribute to increased scientific debate and to promote the development of 'guidelines', 'clinical recommendations' and ultimately a Consensus on the evolving approach to rectal cancer treatment.

HER2 overexpression as a predictive marker in a randomized trial comparing adjuvant cyclophosphamide/methotrexate/5-fluorouracil with epirubicin in patients with stage I/II breast cancer: long-term results.

BACKGROUND: HER2 overexpression/amplification has been reported to be a predictor of prognosis in breast cancer and a potential marker for selecting the optimal adjuvant chemotherapy. PATIENTS AND METHODS: HER2 expression and its interaction with treatment were retrospectively evaluated in 266 of 348 patients in a trial comparing adjuvant CMF (cyclophosphamide/methotrexate/5-fluorouracil) with weekly epirubicin in stage I/II breast cancer. HER2 expression was determined by immunohistochemistry (IHC) using the monoclonal antibody CB11. Initially, any cell showing definite membrane staining was counted, and HER2 overexpression was analyzed as a continuous variable and as a dichotomous variable, with a cutoff of > 50% of positively stained cells. Subsequently, the same slides were reanalyzed with the HercepTest. RESULTS: Of the 266 tumors immunostained for HER2, 34% exhibited nearly homogeneous staining with > 50% positive cells. When the HercepTest was applied, 8% of tumors were IHC 3+ and 8% were IHC 2+. At 8 years, no statistically significant difference in relapse-free survival (RFS) and overall survival (OS) was observed between the treatment arms in patients with low versus high HER2 overexpression, although the number of events is low. The OS was statistically shorter in patients with high HER2 overexpression in the CMF arm, whereas no difference was observed in the epirubicin arm, suggesting that patients whose cancer overexpresses HER2 could benefit more from anthracycline-based therapy. CONCLUSION: HER2 overexpression was associated with a poorer OS but not a poorer RFS. However, a Cox regression model did not confirm the prognostic role of HER2 for OS.

Effects of gefitinib on serum epidermal growth factor receptor and HER2 in patients with advanced non-small cell lung cancer.

PURPOSE: The aim of this study was to assess serum extracellular binding domains of epidermal growth factor receptor (EGFR) and HER2 as surrogate markers of Gefitinib (Iressa, ZD1839, AstraZeneca, London, United Kingdom) activity in patients with non-small cell lung cancer. EXPERIMENTAL DESIGN: Serum EGFR and HER2 levels were monitored in blood samples taken within 1 week of starting Gefitinib at day 28 and at every computed tomography scan evaluation. EGFR and HER-2 were assayed in duplicate using commercial sandwich enzyme-linked immunosorbent assay kits (Oncogene Science Bayer Corporation, Cambridge, UK). A logistic regression analysis was performed to evaluate: (1) the relationship between best overall tumor response and basal EGFR and HER2 levels, and (2) the association between best overall tumor response and the differences of EGFR and HER2 levels obtained at the best overall tumor response and at baseline. RESULTS: Forty-six pretreated patients were evaluated, including F/M:11/35, Eastern Cooperative Oncology Group performance status 0-1/2:39/7, IIIB/IV:11/35, and adenocarcinoma/nonadenocarcinoma 29/17. Five partial responses (11%) and 14 stable disease responses (30%) were observed. Median pretreatment EGFR and HER2 were 83.3 ng/ml and 13.7 ng/ml. For baseline EGFR and HER2, the odds ratio of progression was 0.95 [95% confidence interval (CI), 0.91-0.98; P=0.01] and 0.87 (95% CI, 0.74-1.03; P=0.11), respectively. The difference between the best overall tumor response and basal EGFR value was predictive for response with a 6% increase in the odds of progression for an increase of 1 ng/ml (odds ratio, 1.06; 95% CI, 1.01-1.11; P=0.009) and for progression-free survival with a hazard ratio of 1.03 (95% CI, 1.01-1.04; P=0.003). CONCLUSION: Modifications of EGFR serum values during treatment seem to reflect Gefitinib activity.

Double-blind evaluation of analgesic efficacy of orally administered diclofenac, nefopam, and acetylsalicylic acid (ASA) plus codeine in chronic cancer pain.

The analgesic efficacy and toxicity of oral diclofenac sodium 50 mg (q.i.d.) vs. nefopam 60 mg (q.i.d.) and a combination of 640 mg ASA and 40 mg codeine (q.i.d.) in cancer patients with moderate to severe chronic pain has been evaluated in a randomized double-blind study. Planned duration of treatment was 10 days. Pain intensity was evaluated by a visual analog scale. The length of patient participation in the trial, the patient's final global evaluation and the incidence of side effects were also evaluated. Ninety-nine patients were enrolled in the study. All treatments produced a statistically significant pain relief (P less than 0.01) without differences among groups but only 26 of 99 patients (26.3%) completed the planned treatment period. Mean time in the study was 4.65 days. Inefficacy and side effects were the main reasons for premature treatment interruption. Patients treated with nefopam had a significantly shorter period in the study than patients treated with the other 2 treatments. Adverse effects were slightly more frequent with the nefopam and ASA + codeine regimens. The 3 therapeutic regimens appear to be similar as to analgesic efficacy, but diclofenac presents the advantage of a slightly better safety profile than nefopam and the ASA + codeine combination.

Consensus conference on medical treatment of non-small cell lung cancer: adjuvant treatment.

The 5-year survival rate for patients with non-small cell lung cancer (NSCLC) who undergo complete surgical resection is only 40-69%, depending on the stage. It is well known that distant metastatic disease is the dominant site of recurrence in such patients and this observation served as the basis for trials of postoperative systemic therapy. The earliest trials of adjuvant chemotherapy, which consisted of single alkylating agents, did not achieve this goal or, even worse, showed a detrimental effect on survival. The introduction of more active drugs, such as cisplatin and vinca alkaloids, made it possible to obtain more promising results in terms of delayed recurrence of the disease. A recent meta-analysis of all randomized trials with accrual from January 1965 to December 1991 showed that the absolute risk of death was reduced by 3% at 2 years and by 5% at 5 years for patients who were treated with postoperative cisplatin-containing regimens compared with patients who were treated with surgery alone. Although the results of this meta-analysis suggest that postoperative cisplatin chemotherapy regimens may result in a slight survival improvement, adjuvant chemotherapy in NSCLC cannot be considered a standard therapy, and it is important that large, carefully conducted, randomized trials are performed in this group of patients. Four such randomized trials are being conducted in Europe. One of them, the ALPI trial, recently completed its accrual with 1200 patients. The IALT, ANITA, and MRC trials are still ongoing. The results of such trials are eagerly awaited and it is hoped that, once the value of postoperative chemotherapy is well ascertained, future developments can further improve results of combined treatment. In such direction, the recently reported results of PORT meta-analysis evaluating the role of radiation therapy are of great contribution in selecting a suitable population for future studies. In fact, only patients with pN2 disease seem to have a beneficial effect in terms of survival, especially if they have a good performance status, while radiotherapy is not justified in N0-1 patients. The optimal integration of chemotherapy and radiation therapy when both therapies are indicated represents another goal for future research.

The clinical relevance of Bcl-2, Rb and p53 expression in advanced non-small cell lung cancer.

PURPOSE: The aim of this study was to evaluate the impact of Bcl-2, retinoblastoma (Rb) and p53 proteins on overall survival of 102 patients with locally advanced and metastatic NSCLC who underwent cisplatin-based chemotherapy. MATERIALS AND METHODS: Paraffin-embedded bronchial biopsy and fine-needle biopsy specimens were evaluated by an immunostaining method. RESULTS: Median age of analyzed patients was 61 years. Male/female ratio was 88/14. There were 10 (10%) patients with stage IIIA, 37 (36%) with stage IIIB and 55 (54%) with stage IV NSCLC. Only 15 (15%) tumor specimens had no detectable alterations for analyzed factors. Forty-six samples (45%) had positive immunostaining for p53, 61 (60%) had negative immunostaining for Rb and 8 (8%) had positive immunostaining for Bcl-2. Median and 5-year survival of analyzed population was 12 months and 6%, respectively. In univariate analysis Bcl-2 overexpression, stage (III versus IV) and normal lactate dehydrogenase (LDH) serum levels were associated with better overall survival (P<0.02, 0.001 and 0.03). In multivariate analysis, only stage was identified as an independent predictive factor. CONCLUSION: High frequency of Rb and Bcl-2 loss was detected in patients with advanced NSCLC. P53, Rb and Bcl-2 have not been shown to be independent predictors of survival even if Bcl-2 might have a particular relevance in patients with advanced NSCLC and should be better explored in this setting.

Relevance of p53, bcl-2 and Rb expression on resistance to cisplatin-based chemotherapy in advanced non-small cell lung cancer.

PURPOSE: Tumors with p53 overexpression have been associated with enhanced resistance to cisplatin-based chemotherapy in a few and small studies involving non-small cell lung cancer. The relationships and interactions between p53, Rb and bcl-2 immunostaining, clinical parameters and response to cisplatin-based chemotherapy were evaluated in the present study. EXPERIMENTAL DESIGN: Histological specimens obtained by bronchial or fine-needle biopsy from patients who underwent cisplatin-based chemotherapy between 1992 and 1999 were evaluated by immunostaining. RESULTS: There were 102 patients, 88 men. Median age was 63 years; 47 had stage III and 55 stage IV disease. Forty-six tumor samples (45%) had positive immunostaining for p53, 61 (59%) had negative immunostaining for Rb and 8 (8%) had positive immunostaining for bcl-2. The response rate of the group with p53 positive immunostaining was 26% versus 57% of the p53 negative group (P=0.004). In multivariate analyses p53 positive immunostaining was identified as an independent predictive factor for resistance to cisplatin-based chemotherapy (P=0.006). CONCLUSIONS: Our study confirmed an association of p53 immunostaining and response rate of patients treated with cisplatin-based chemotherapy.

Vascular endothelial growth factor, p53, Rb, Bcl-2 expression and response to chemotherapy in advanced non-small cell lung cancer.

Vascular endothelial growth factor (VEGF) increases microvascular permeability and stimulates endothelial cell growth. p53 Overexpression has been associated with resistance to cisplatin-based chemotherapy in patients (pts) with NSCLC. The aim of this study was to evaluate the predictive role of VEGF for chemotherapy response, its relationship with p53, Rb, Bcl-2 and hemoglobin levels and its impact on overall survival in pts with advanced NSCLC. Bronchial or fine-needle biopsy specimens from 85 pts with NSCLC obtained before chemotherapy were analyzed using an immunohistochemical method for VEGF, p53, Rb and Bcl-2. There were 73 males and 12 females with a median age of 62.6 years. The majority of pts (48%) had squamous cell histology. Ten pts had stage IIIA, 25 stage IIIB and 50 stage IV. Thirty six (43%) pts had positive immunostaining for VEGF, 37 (44%) had positive p53, 53 (62%) had negative Rb and 4 (5%) had positive Bcl-2. VEGF was negatively correlated with Rb (r(s) = 0.26; P = 0.015), positively with Bcl-2 (r(s) = 0.22; P = 0.42), whereas no statistically significant correlation with p53, age, stage and histological type was found. In a logistic regression model, adjusting for treatment, VEGF expression was not associated with chemotherapy response (odds ratio (OR) = 1.01; P = 0.085 ), unlike p53 positivity and Rb negativity ( OR = 4.0, P = 0.005; OR = 2.6, P = 0.016, respectively). A statistically significant higher VEGF expression was detected in the subgroups defined, using as cut-off value Hb median level (13.3g/dl) (chi-square = 5.00; ; one d.f.; P = 0.025). At a median follow-up time of 8.4 years, 2-year survival was 21%. After adjustment for stage and chemotherapy treatment, VEGF expression was not associated with a better overall survival (OR = 1.06; P = 0.80), unlike Bcl-2 positivity showed a statistically significant effect (OR = 0.28; p = 0.02). Our results suggest that VEGF is weakly correlated with regulators of apoptosis and has not been shown to be an independent predictive factor for resistance to cisplatin-based chemotherapy and prognostic for survival.

Long-term results of induction chemotherapy followed by concurrent chemotherapy and thoracic irradiation in limited small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a chemoresponsive tumor but overall survival remains poor even in limited disease (LD). With the aim of eradicating chemoresistant tumor cells and reducing toxicity, we investigated in this phase II trial the feasibility and outcome of a sequential approach of induction chemotherapy (CT) followed, in responding patients with LD-SCLC, by intensified platinum-based CT and concurrent thoracic irradiation (TI). MATERIALS AND METHODS: We treated 55 consecutive LD-SCLC patients with three 21-day cycles of cyclophosphamide, epiadriamycin and vincristine (CEV) as induction CT. In 44 (80%) patients there was an objective response and they received treatment intensification consisting of TI and concomitant CT with carboplatin and etoposide plus recombinant granulocite colony stimulating factor. Twenty-five (57%) patients were submitted to twice-daily thoracic irradiation (TDTI; 1.5 Gy per fraction, to a total dose of 45 Gy) and 19 (43%) to once-daily thoracic irradiation (ODTI; 2 Gy per fraction, to a total dose of 50 Gy). RESULTS: Median follow up was 75 months (range, 42-102). Of 44 patients submitted to intensification with TI plus CT, 32 (73%) had a complete and 12 (27%) a partial response. Median overall survival of all 55 patients was 17 months with actuarial survival probabilities of 2 and 5 years, 32 and 25%, respectively. Analysis of patient sub-groups showed a 5-month median survival in non-responders, 19 in TDTI and 17 in ODTI patients, respectively. Two and 5 year survival probabilities were 0% in non-responders, 40 and 35% in TDTI and 39 and 21% in ODTI patients, respectively. At present, 13 of 44 responders are still alive, of which nine (20%) have been progression-free from 45 to 93 months (median 60). Treatment failure was registered in 31 (70%) of 44 patients who received both induction and intensification treatment. One-half of patients had intrathoracic recurrence, eight of which only local and the remaining seven local and distant. Fourteen (32%) patients had brain metastases. Grade 3-4 neutropenia occurred in 24 (55%) patients with no differences between treatment groups. Grade 3 esophagitis was registered in four (9%) patients: in 3/25 (12%) and 1/19 (5%) of those who received TDTI and ODTI, respectively (P=not significant). Acute radiation pneumonitis occurred in three (12%) patients submitted to TDTI. No clinically debilitating pulmonary fibrosis, permanent esophageal stricture or toxic death was observed. CONCLUSIONS: In LD-SCLC patients late concurrent CT plus TI is feasible and effective. Our long-term results are similar to the best reported in the literature. Despite the high incidence of complete response obtained, however, one-half of the patients had intrathoracic relapse and one-third brain metastases.

Randomized phase II feasibility study of combining the matrix metalloproteinase inhibitor BMS-275291 with paclitaxel plus carboplatin in advanced non-small cell lung cancer.

BACKGROUND: This randomized, double-blind, placebo-controlled study was designed to assess whether the addition of the matrix metalloproteinase (MMP) inhibitor BMS-275291 to combined paclitaxel and carboplatin chemotherapy had an adverse impact on expected tumor response or had significant toxicity, especially arthrotoxicity, in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Seventy-five chemotherapy-naive patients with stage IIIB-IV NSCLC were randomly assigned to BMS-275291 or placebo. All patients received paclitaxel 200mg/m(2) as a continuous 3-hour infusion followed by carboplatin calculated using the Calvert formula for a target AUC of 6 mg / (ml min), every 21 days for a maximum of eight cycles. BMS-275291 or placebo was administered on an outpatient basis at a daily oral dosage of 1200 mg. RESULTS: All 75 patients were evaluable for toxicity and 65 (86.7%) for response. Drug-related arthrotoxicity > or =grade 2 occurred in 12 patients (31.6%) in the BMS-275291 group (lower limit of one-sided 95% CI: 19.3) and in 11 patients (29.7%) in the placebo treatment arm. The incidence of rash was higher in patients receiving BMS-275291 (28.9% versus 18.9%). An objective response rate of 21.9% was observed in the BMS-275291 treatment arm and 36.4% in the placebo arm. CONCLUSION: BMS-275291 plus paclitaxel/carboplatin was well tolerated and active in advanced non-small cell lung cancer. Treatment with BMS-275291 was not limited by drug-related arthrotoxicity and tumor response was as expected. As planned, patient accrual continued to further investigate the effect of BMS-275291 on overall and progression-free survival in a phase III setting.

Weekly paclitaxel in metastatic breast cancer patients: a phase II study.

UNLABELLED: AIMS ANID BACKGROUND: Paclitaxel, a microtubule inhibitor, is one of the most active drugs in metastatic breast cancer. A weekly schedule, at a median dose-intensity of 91 mg/m2, is effective and has less side effects than a 3-week schedule. In this phase II study, we evaluated the toxicity and the activity of weekly 1 hr paclitaxel infusions in metastatic breast cancer patients. STUDY DESIGN: Between February 1999 and February 2001, 26 patients with metastatic breast cancer were treated with weekly paclitaxel (60-90 mg/m2/1 hour iv infusion/weekly). The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, paclitaxel was stopped after 6 months of therapy. RESULTS: At a median follow-up of 18.7 months (range, 6.8-30.8), all patients are assessable for response and toxicity. We obtained 8 partial responses (30.8%), 8 stable disease (30.8%) and 10 disease progression (38.4.%). The overall response was 30.8% (95% CI, 13.1-48.5). The median duration of response was 7.6 months (range, 1.8-12.4); median time to progression was 4.86 months (range, 1.4-12.4); median overall survival was 9.9 months (range, 1.7-29.2+). Treatment was well tolerated. Hematological toxicity was mild and only one patient developed grade 3 anemia. Two patients experienced grade 3 cardiovascular toxicity; both had received anthracycline-based regimens. CONCLUSIONS: In our experience, weekly administration of paclitaxel shows a substantial degree of activity even in pretreated metastatic breast cancer patients. The toxicity profile is favorable.

Outbreak of infusion-related septicemia by Ralstonia pickettii in the Oncology Department.

Hospital acquired blood stream infection by Ralstonia pickettii in 9 cancer patients related to the heparin solution contamination used to flush the central venous catheter.

Aprepitant versus dexamethasone for preventing chemotherapy-induced delayed emesis in patients with breast cancer: a randomized double-blind study.

PURPOSE: A combination of aprepitant, a 5-HT3 receptor antagonist, and dexamethasone is recommended for the prophylaxis of acute or delayed emesis induced by chemotherapy containing anthracyclines plus cyclophosphamide in patients with breast cancer. The aim of this study was to verify whether dexamethasone is superior to aprepitant in preventing delayed emesis in patients receiving the same prophylaxis for acute emesis. PATIENTS AND METHODS: A randomized double-blind study comparing aprepitant versus dexamethasone was completed in chemotherapy-naive patients with breast cancer treated with anthracyclines plus cyclophosphamide. Before chemotherapy, all patients were treated with intravenous palonosetron 0.25 mg, dexamethasone 8 mg, and oral aprepitant 125 mg. On days 2 and 3, patients randomly received oral dexamethasone 4 mg twice per day or aprepitant 80 mg once per day. Primary end point was rate of complete response (ie, no vomiting or rescue treatment) from days 2 to 5 after chemotherapy. RESULTS: Of 580 enrolled patients, 551 were evaluable: 273 received dexamethasone, and 278 received aprepitant. Day 1 complete response rates were similar: 87.6% for dexamethasone and 84.9% for aprepitant (P < .39). From days 2 to 5, complete response rates were the same with both antiemetic prophylaxes (79.5%; P < 1.00), as were results of secondary end points (ie, complete protection, total control, no vomiting, no nausea, score of Functional Living Index-Emesis; P < .24). Incidences of insomnia (2.9% v 0.4%; P < .02) and heartburn (8.1% v 3.6%; P < .03) were significantly greater with dexamethasone on days 2 to 5. CONCLUSION: In patients with breast cancer treated with anthracycline plus cyclophosphamide chemotherapy and receiving the same antiemetic prophylaxis for acute emesis, dexamethasone was not superior to aprepitant but instead had similar efficacy and toxicity in preventing delayed emesis.