Predicting Functional Recovery and Quality of Life in Older Patients Undergoing Colorectal Cancer Surgery: Real-World Data From the International GOSAFE Study.

PURPOSE: The GOSAFE study evaluates risk factors for failing to achieve good quality of life (QoL) and functional recovery (FR) in older patients undergoing surgery for colon and rectal cancer. METHODS: Patients age 70 years and older undergoing major elective colorectal surgery were prospectively enrolled. Frailty assessment was performed and outcomes, including QoL (EQ-5D-3L) recorded (3/6 months postoperatively). Postoperative FR was defined as a combination of Activity of Daily Living ≥5 + Timed Up & Go test <20 seconds + MiniCog >2. RESULTS: Prospective complete data were available for 625/646 consecutive patients (96.9%; 435 colon and 190 rectal cancer), 52.6% men, and median age was 79.0 years (IQR, 74.6-82.9 years). Surgery was minimally invasive in 73% of patients (321/435 colon; 135/190 rectum). At 3-6 months, 68.9%-70.3% patients experienced equal/better QoL (72.8%-72.9% colon, 60.1%-63.9% rectal cancer). At logistic regression analysis, preoperative Flemish Triage Risk Screening Tool ≥2 (3-month odds ratio [OR], 1.68; 95% CI, 1.04 to 2.73; P = .034, 6-month OR, 1.71; 95% CI, 1.06 to 2.75; P = .027) and postoperative complications (3-month OR, 2.03; 95% CI, 1.20 to 3.42; P = .008, 6-month OR, 2.56; 95% CI, 1.15 to 5.68; P = .02) are associated with decreased QoL after colectomy. Eastern Collaborative Oncology Group performance status (ECOG PS) ≥2 is a strong predictor of postoperative QoL decline in the rectal cancer subgroup (OR, 3.81; 95% CI, 1.45 to 9.92; P = .006). FR was reported by 254/323 (78.6%) patients with colon and 94/133 (70.6%) with rectal cancer. Charlson Age Comorbidity Index ≥7 (OR, 2.59; 95% CI, 1.26 to 5.32; P = .009), ECOG ≥2 (OR, 3.12; 95% CI, 1.36 to 7.20; P = .007 colon; OR, 4.61; 95% CI, 1.45 to 14.63; P = .009 rectal surgery), severe complications (OR, 17.33; 95% CI, 7.30 to 40.8; P < .001), fTRST ≥2 (OR, 2.71; 95% CI, 1.40 to 5.25; P = .003), and palliative surgery (OR, 4.11; 95% CI, 1.29 to 13.07; P = .017) are risk factors for not achieving FR. CONCLUSION: The majority of older patients experience good QoL and stay independent after colorectal cancer surgery. Predictors for failing to achieve these essential outcomes are now defined to guide patients' and families' preoperative counseling.

Quality of Life in Older Adults After Major Cancer Surgery: The GOSAFE International Study.

BACKGROUND: Accurate quality of life (QoL) data and functional results after cancer surgery are lacking for older patients. The international, multicenter Geriatric Oncology Surgical Assessment and Functional rEcovery after Surgery (GOSAFE) Study compares QoL before and after surgery and identifies predictors of decline in QoL. METHODS: GOSAFE prospectively collected data before and after major elective cancer surgery on older adults (≥70 years). Frailty assessment was performed and postoperative outcomes recorded (30, 90, and 180 days postoperatively) together with QoL data by means of the three-level version of the EuroQol five-dimensional questionnaire (EQ-5D-3L), including 2 components: an index (range = 0-1) generated by 5 domains (mobility, self-care, ability to perform the usual activities, pain or discomfort, anxiety or depression) and a visual analog scale. RESULTS: Data from 26 centers were collected (February 2017-March 2019). Complete data were available for 942/1005 consecutive patients (94.0%): 492 male (52.2%), median age 78 years (range = 70-95 years), and primary tumor was colorectal in 67.8%. A total 61.2% of all surgeries were via a minimally invasive approach. The 30-, 90-, and 180-day mortality was 3.7%, 6.3%, and 9%, respectively. At 30 and 180 days, postoperative morbidity was 39.2% and 52.4%, respectively, and Clavien-Dindo III-IV complications were 13.5% and 18.7%, respectively. The mean EQ-5D-3L index was similar before vs 3 months but improved at 6 months (0.79 vs 0.82; P < .001). Domains showing improvement were pain and anxiety or depression. A Flemish Triage Risk Screening Tool score greater than or equal to 2 (odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.13 to 2.21, P = .007), palliative surgery (OR = 2.14, 95% CI = 1.01 to 4.52, P = .046), postoperative complications (OR = 1.95, 95% CI = 1.19 to 3.18, P = .007) correlated with worsening QoL. CONCLUSIONS: GOSAFE shows that older adults' preoperative QoL is preserved 3 months after cancer surgery, independent of their age. Frailty screening tools, patient-reported outcomes, and goals-of-care discussions can guide decisions to pursue surgery and direct patients' expectations.

Clinical research activities during COVID-19: the point of view of a promoter of academic clinical trials.

BACKGROUND: During the COVID-19 emergency, IRST IRCCS, an Italian cancer research institute and promoter of no profit clinical studies, adapted its activities and procedures as per European and national guidelines to maintain a high standard of clinical trials, uphold participant safety and guarantee the robustness and reliability of the data collected. This study presents the measures adopted by our institute with the aim of providing information that could be useful to other academic centers promoting clinical trials during the pandemic. MAIN TEXT: After an in-depth analysis of European and Italian guidelines and consultation and analysis of publications regarding the actions implemented by international no profit clinical trial promoters during the emergency, we monitored the way in which the institute managed clinical trials, verifying compliance with regulatory guidelines and clinical procedures, and evaluating screening and recruitment trends in studies. During the pandemic, our center activated a new clinical trial for the treatment of patients with COVID-19. A number of procedural changes in clinical trials were also authorized through notified amendments, in accordance with Italian Medicines Agency (AIFA) guidelines. Patient screening and enrolment was not interrupted in any site participating in multicenter interventional clinical trials on drugs. The institute provided clear indications about essential procedures to be followed, identifying those that could be postponed or carried out by telephone/teleconference. All external sites were monitored remotely, avoiding on-site visits. Although home-working was encouraged, the presence of staff in the central office was also guaranteed to ensure the continuity of promoter activities. CONCLUSIONS: Some measures adopted by IRST could also be effective outside of the COVID-19 period, e.g. numerous activities relating to clinical trial management could be performed on a home-working basis, using suitable digital technologies. In the future, electronic medical records and shared guidelines will be essential for the correct identification and management of trial risks, including the protection of the rights and privacy of subjects taking part. Promoter supervision could be increased by implementing centralized monitoring tools to guarantee data quality. Closer collaboration between promoters and local study staff is needed to optimize trial management.

Is it possible to conduct clinical trials during a pandemic? The example of a trial of hydroxychloroquine.

OBJECTIVES: to examine the factors that, in the context of the current pandemic, have influenced the conduct of a randomized clinical trial on hydroxychloroquine in Italy. DESIGN: the trend of enrolment in the PROTECT study, "A randomized study with Hydroxychloroquine versus observational support for prevention or early phase treatment of Coronavirus disease (COVID-19)" (Eudract number: 2020-001501-24, NCT04363827), conducted in the period from May to September 2020, was analysed to evaluate the possible association of the enrolment rate with the amount of information published in the national and local press on hydroxychloroquine. SETTING AND PARTICIPANTS: the PROTECT clinical study is an Italian interventional superiority study, open label, with cluster randomization, aimed at evaluating whether treatment with hydroxychloroquine can reduce the percentage of symptomatic subjects compared to observation only in a population of subjects exposed to SARS-CoV-2 virus consisting of cohabitants/contacts of COVID-19 patients and asymptomatic or paucisymptomatic subjects diagnosed with COVID-19. MAIN OUTCOME MEASURES: the number of asymptomatic or paucisymptomatic COVID-19 patients and the number of contacts/cohabitants of COVID-19 patients enrolled in the Protect study from May to September 2020. RESULTS: from May to September 2020, the number of patients diagnosed with COVID-19 enrolled in the PROTECT clinical trial showed a decrease consistent with the number of news on hydroxychloroquine appearing in the national and local press, starting from the time when the first criticisms of the efficacy of hydroxychloroquine were made known; the number of contacts/cohabitants of COVID-19 patients showed a more marked and more timely decrease. CONCLUSIONS: in the context determined by the current COVID-19 pandemic, conducting a controlled clinical trial is strongly influenced by public opinion on scientific issues. Adherence to a clinical study can become highly problematic and invalidate the possibility of answering a scientific question and the validity of a project. In the current pandemic situation, randomized controlled trials may not always be the optimal tool to reach the expected scientific evidence, due to a number of problems. It is preferable to use a sequential or adaptive design. Furthermore, study protocols should implement innovative approaches that also include the involvement of participants in the decision-making process. In any case, the influence of public information on scientific issues is an extremely important factor to consider in the design of clinical trials in exceptional situations such as a pandemic.

How Many Cancer Clinical Trials Can a Clinical Research Coordinator Manage? The Clinical Research Coordinator Workload Assessment Tool.

PURPOSE: Cancer clinical trials (CTs) are now more complex than ever before and require dedicated personnel (clinical research coordinators [CRCs]) to perform regulatory and administrative activities and protocol- and patient-related procedures. We developed a simple tool to measure the workload (WL) of CRCs involved in cancer research and to estimate personnel requirements within a Clinical Trial Center. METHODS: A literature review and 2-month period in which CRCs recorded their activities in a diary provided valuable information that led to the Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Workload Assessment Tool (IWAT) being divided into three sections: Protocol, On-Treatment Patients, and Follow-Up Patients. Twelve full-time senior CRCs from three sites of the Network measured their monthly WL for 30 months to evaluate IWAT reproducibility and accuracy. RESULTS: The IWAT proved to be a user-friendly tool (3-6 minutes required for each CT), with high reproducibility (interobserver reproducibility ranged from 82% to 100% for each IWAT item). In December 2017, the Network had 185 ongoing CTs, with a median of 2.5 active centers for each CT. On the basis of 448 total IWAT measures by CRCs, the majority of trials were academic (57%) or dealt with advanced disease (77%). The median IWAT WL score for each study was 20.98 ± 22.90 (range, 2-188) and 475 ± 229 (range, 150 [junior staff] - 930 [extreme heavy WL]) for each CRC. On the basis of our experience, a monthly WL score of 500-600 was considered an appropriate value for a full-time CRC. CONCLUSION: The IWAT could prove useful in evaluating CT complexity, estimating appropriate CRC WLs, and defining personnel requirements. Independent validation by other CRCs working in different organizational contexts and in different countries is needed.

Hydroxychloroquine as Prophylaxis for COVID-19: A Review.

The impact of the COVID-19 pandemic worldwide has led to a desperate search for effective drugs and vaccines. There are still no approved agents for disease prophylaxis. We thus decided to use a drug repositioning strategy to perform a state-of-the-art review of a promising but controversial drug, hydroxychloroquine (HCQ), in an effort to provide an objective, scientific and methodologically correct overview of its potential prophylactic role. The advantage of using known drugs is that their toxicity profile is well known and there are fewer commercial interests (e.g., expired patents), thus allowing the scientific community to be freer of constraints. The main disadvantage is that the economic resources are almost always insufficient to promote large multinational clinical trials. In the present study, we reviewed the literature and available data on the prophylactic use of HCQ. We also took an in-depth look at all the published clinical data on the drug and examined ongoing clinical trials (CTs) from the most important CT repositories to identify a supporting rationale for HCQ prophylactic use. Our search revealed a substantial amount of preclinical data but a lack of clinical data, highlighting the need to further assess the translational impact of in vitro data in a clinical setting. We identified 77 CTs using a multiplicity of HCQ schedules, which clearly indicates that we are still far from reaching a standard of care. The majority of the CTs (92%) are randomized and 53% are being conducted in a phase 3 or 2/3 setting. The comparator is placebo or control in 55 (77%) of the randomized studies. Forty-eight (62%) CTs expect to enroll up to 1,000 subjects and 50 (71%) plan to recruit healthcare workers (HCW). With regard to drug schedules, 45 (58.5%) CTs have planned a loading dose, while 18 (23.4%) have not; the loading dose is 800 mg in 19 trials (42.2%), 400 mg in 19 (42.2%), 600 mg in 4 (8.9%) and 1,200 mg in 1 (2.2%). Forty trials include at least one daily schedule, while 19 have at least one weekly schedule. Forty-one (53.2%) will have a treatment duration of more than 30 days. Awaiting further developments that can only derive from the results of these prospective randomized CTs, the take-home message of our review is that a correct methodological approach is the key to understanding whether prophylactic HCQ can really represent an effective strategy in preventing COVID-19.

Prognostic role of a new index (multi inflammatory index) in patients with metastatic colorectal cancer: results from the randomized ITACa trial.

AIMS: We created a new index (Multi Inflammatory Index, MII) composed of an inflammatory index [neutrophil-to lymphocyte-ratio (NLR): MII-1; platelet-to-lymphocyte ratio (PLR): MII-2; or systemic immune-inflammation index (SII): MII-3] and C-reactive protein (CRP). Our aim was to evaluate the prognostic and/or predictive capacity of the MII in the randomized ITACa (Italian Trial in Advanced Colorectal Cancer) study on patients with metastatic colorectal cancer undergoing first-line chemotherapy. METHODS: Between November 2007 and March 2012, baseline NLR, PLR; SII and CRP were available for 131 patients, 66 receiving chemotherapy plus bevacizumab and 65 receiving chemotherapy alone. RESULTS: Patients with low (<25) MII-1 levels had a better outcome than those with high (⩾25) levels: median progression-free survival (PFS) was 12.4 versus 8.9 months [hazard ratio (HR) = 1.74, 95% confidence interval (CI) 1.21-2.51, p = 0.003] and median overall survival (OS) was 30.9 months versus 15.0 months (HR = 2.05, 95% CI 1.40-3.02, p = 0.0002), respectively. Similar results were obtained for patients with low (<1424) MII-2 levels compared with those with high (⩾1424) levels: median PFS was 12.6 versus 8.9 months (HR = 1.95, 95% CI 1.35-2.82, p = 0.0004) and median OS was 32.4 versus 14.6 months, respectively (HR = 2.42, 95% CI 1.64-3.57, p < 0.0001). Patients with low (<6068) MII-3 levels had a longer median PFS and OS than those with high (⩾6068) levels: 12.6 versus 8.9 months (HR = 1.91, 95% CI 1.33-2.76, p = 0.005) and 30.9 versus15.0 months (HR = 2.10, 95% CI 1.43-3.09, p = 0.0002), respectively. Following adjustment for clinical covariates, multivariate analysis confirmed all MII indexes as independent prognostic factors for predicting PFS and OS. CONCLUSION: All MII indexes appear to be useful as prognostic markers. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01878422 (registration date: 07/06/2013) https://clinicaltrials.gov/ct2/show/NCT01878422.

PROTECT Trial: A cluster-randomized study with hydroxychloroquine versus observational support for prevention or early-phase treatment of Coronavirus disease (COVID-19): A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: Hydroxychloroquine has shown to have antiviral activity in vitro against coronaviruses, specifically SARS-CoV-2. It is believed to block virus infection by increasing endosomal pH required for virus cell fusion and glycosylation of viral surface proteins. In addition to its antiviral activity, hydroxychloroquine has an immune-modulating activity that may synergistically enhance its antiviral effect in vivo, making it a potentially promising drug for the prevention and the cure of SARS-CoV-19. However, randomized controlled trials are needed to assess whether it can be used safely to treat COVID-19 patients or to prevent infection. The main objective of the present study is to evaluate the efficacy of hydroxychloroquine for (I) the prevention of COVID-19 or related symptoms in SARS-CoV-2-exposed subjects, such as as household members/contacts of COVID-19 patients and (II) the treatment of early-phase asymptomatic or paucisymptomatic COVID-19 patients. TRIAL DESIGN: This is a controlled, open label, cluster-randomized, superiority trial with parallel group design. Subjects will be randomized either to receive hydroxychloroquine or to observation (2:1). PARTICIPANTS: SARS-CoV-2-exposed subjects, including household members and/or contacts of COVID-19 patients and healthcare professionals (Group 1) or patients with COVID-19 (positive PCR test on a rhinopharyngeal or oropharyngeal swab for SARS-CoV-2), asymptomatic or paucisymptomatic in home situations who are not undergoing treatment with any anti COVID-19 medication (Group 2), will be enrolled. Paucisymptomatic patients are defined as patients with a low number of mild symptoms. All subjects must be aged ≥18 years, male or female, must be willing and able to give informed consent and must not have any contraindications to take hydroxychloroquine (intolerance or previous toxicity for hydroxychloroquine/chloroquine, bradycardia or reduction in heart rhythm with arrhythmia, ischemic heart disease, retinopathy, congestive heart failure with use of diuretics, favism or glucose-6-phosphate dehydrogenase (G6PD) deficiency, diabetes type 1, major comorbidities such as advanced chronic kidney disease or dialysis therapy, known history of ventricular arrhythmia, any oncologic/hematologic malignancy, severe neurological and mental illness, current use of medications with known significant drug-drug interactions, and known prolonged QT syndrome or current use of drugs with known QT prolongation). The study is monocentric and will be conducted at Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS. Subjects will be enrolled from a large epidemic region (North-Central Italy). The Public Health Departments of several Italian regions will collaborate by identifying potentially eligible subjects. INTERVENTION AND COMPARATOR: The participants will be randomized (2:1 randomization) to receive either hydroxychloroquine (Arm A) or to Observation (Arm B). Hydroxychloroquine will be administered with the following schedule: Group1: A loading dose hydroxychloroquine 400 mg twice daily on day 1, followed by a weekly dose of hydroxychloroquine 200 mg twice daily on days 8, 15 and 22, for a total of one month of treatment. Group 2: A loading dose hydroxychloroquine 400 mg twice daily on day 1 followed by 200 mg twice daily for a total of 5-7 days. The comparator in this trial is observation given that currently neither treatment is administered to asymptomatic or paucisymptomatic subjects, nor prophylaxis is available for contacts. Hydroxychloroquine will be shipped to subjects within 24 hours of randomization. Given the extraordinary nature of the COVID-19 pandemic, only telephonic interviews will be carried out and electronic Patient Reported Outcomes (ePRO) completed. During treatment, each subject will be contacted every other day for the first week and weekly thereafter (Group 2) or weekly (Group 1) by a study physician to assess early onset of any COVID-19 symptom or any adverse reaction to hydroxychloroquine and to check subject compliance. Furthermore, all subjects will receive periodic ePROs which may be completed through smartphone or tablets to record drug self-administration and onset of any symptom or adverse event. All subjects will be followed up for a total of 6 months by periodic telephonic interviews and ePROs. MAIN OUTCOMES: The primary endpoint/outcome measure for this trial is: for Group 1, the proportion of subjects who become symptomatic and/or swab-positive in each arm within one month of randomization; for Group 2, the proportion of subjects who become swab-negative in each arm within 14 days of randomization. RANDOMIZATION: All household members and/or contacts of each COVID-19 index case, and the COVID-19 patient himself/herself, fulfilling all inclusion criteria will be grouped into a single cluster and this cluster will be randomized (2:1) to either arm A or arm B. Information on each subject will be recorded in specific data records. Randomization lists will be stratified according to the following factors regarding COVID-19 index cases: 1. COVID-19 risk level on the basis of province of residence (high vs. low/intermediate); 2. Index case is a healthcare professional (yes vs.no) 3. Index case with COVID-19 treatment (yes vs. no) An independent statistician not otherwise involved in the trial will generate the allocation sequence, and COVID-19 response teams will be unaware of the allocation of clusters. Randomization will be performed through an interactive web-based electronic data-capturing database. An Independent Data Monitoring Committee has been established. BLINDING (MASKING): This study is open label. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): For Group 1, a sample size of about 2000 SARS-CoV-2-exposed subjects such as household members and/or contacts of COVID-19 patients will take part in the study. Assuming around 1.5-2.0 asymptomatic household members and/or contacts for each COVID-19 patient, we expect to identify approximately 1000-1300 COVID-19 index cases to be randomized. An interim analysis on efficacy is planned using standard alpha-spending function. For Group 2, sufficient power for primary objective (negative swab within 14 days of randomization) will be reached given a sample size of 300 asymptomatic or paucisymptomatic COVID-19 subjects in home situations not treated for COVID-19 (25%-30% of about 1000-1300 expected index cases). Since up to date reduced evidence about COVID-19 infection epidemiology, the continuous update of diagnostic and therapeutic approaches, the sample size estimation could be updated after a one third of population will be recruited and eventually modified according to a substantial protocol amendment. An interim analysis at 100 enrolled COVID-19 patients is planned. We have planned a Generalized Estimating Equation analysis, which is more efficient than a cluster level analysis, to take advantage of subject-specific covariates. The above reported sample size analysis is therefore to be considered conservative. TRIAL STATUS: The current version of the PROTECT trial protocol is 'Final version, 15 April 2020'. The study started on 9th May 2020. The first patient was enrolled on 14th May 2020. Recruitment is expected to last through September 2020. TRIAL REGISTRATION: The PROTECT trial is registered in the EudraCT database (no. 2020-001501-24) and in ClinicalTrials.gov ( NCT04363827 ), date of registration 24 April 2020. FULL PROTOCOL: The full PROTECT protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interests of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol (Protocol final version, 15th April 2020). The study protocol has been reported in accordance with Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

A Phase II Study of Everolimus Plus Oral Prednisone in Patients with Metastatic Renal Cell Cancer.

LESSONS LEARNED: The combination of everolimus and low-dose prednisone administered daily was hypothesized to prevent noninfectious pneumonitis (NIP) and mucositis, two common adverse events related to everolimus. Although mucositis was detected in only one case, all-grade NIP occurred in four of eight cases (50%), and this was considered enough to stop accrual of the study.These data suggest the need for careful monitoring of patients receiving everolimus who are treated with corticosteroids. BACKGROUND: Everolimus is standard of care in the treatment of patients affected by metastatic renal cell carcinoma (mRCC) that has progressed after at least one previous line of treatment. Stomatitis and noninfectious pneumonitis (NIP) are common adverse events (AEs) in patients treated with everolimus. Prednisone could reduce the incidence of stomatitis, and it is commonly used to treat NIP. We hypothesized that low doses of prednisone could reduce the incidence and/or the severity of everolimus-induced NIP and stomatitis. METHODS: We have conducted an open-label, single-arm, phase II trial of prednisone 5 mg b.i.d. added to everolimus 10 mg/day in patients with mRCC. We planned to evaluate the safety, tolerability, and activity of this combination in mRCC patients. We aimed to reduce incidence of drug discontinuations due to stomatitis or NIP from 25% to 10%. RESULTS: Three (38%) of the first eight patients enrolled experienced grade ≥2 pneumonitis and stopped treatment. Grade 1 stomatitis occurred in only one patient (13%). Five of eight patients experienced disease progression at the 2-month evaluation. Two patients (25%) were reported free of disease progression at 1 year of treatment. CONCLUSION: The incidence of NIP in these patients was considered too high for completing accrual of this study. These results may be of interest for investigating the pathogenesis of NIP and suggest that patients should be carefully followed if treated with chronic corticosteroids while receiving everolimus.

eNOS polymorphisms as predictors of efficacy of bevacizumab-based chemotherapy in metastatic colorectal cancer: data from a randomized clinical trial.

BACKGROUND: Bevacizumab plus chemotherapy is a widely used therapeutic option for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of bevacizumab efficacy have not yet been identified. We analyzed vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) polymorphisms in relation to response to bevacizumab. METHODS: Two hundred and thirty-seven patients with mCRC enrolled onto the phase III prospective multicentre randomized "Italian Trial in Advanced Colorectal Cancer (ITACa)" trial were evaluated. One hundred fourteen patients received chemotherapy plus bevacizumab (CT + B) and 123 received chemotherapy (CT) alone. Five single nucleotide polymorphisms (SNPs) (-2578, -1498, -1154, -634 and +936) for VEGF and 2 SNPs (-786, +894) and one variable number tandem repeat in intron 4 for eNOS were analyzed for each patient. The polymorphisms were assessed in relation to progression-free survival (PFS), objective response rate (ORR) and overall survival (OS). RESULTS: VEGF 936C/T, eNOS +894 G/T and VNTR were significantly correlated with outcome in CT + B patients, but not in CT-only patients. In particular, patients with a specific haplotype combination of the 2 eNOS polymorphisms (defined eNOS Haplo1/Haplo1 and eNOS Haplo 2/Haplo2) showed significantly longer PFS (15.0 vs 9.1 months, P = 0.001) and OS (34.5 vs 20.5 months P = 0.002), and a higher ORR (71 vs 45.9%, P = 0.013) than those with the other genotypes, respectively. CONCLUSIONS: Specific eNOS polymorphisms may be capable of identifying a subset of mCRC patients who are more responsive to bevacizumab-based chemotherapy. If confirmed, these results would permit individually tailored treatment with bevacizumab.

Gemcitabine and paclitaxel combination as second-line chemotherapy in patients with small-cell lung cancer: a phase II study.

BACKGROUND: Although small-cell lung cancer is a chemosensitive malignancy, most patients rapidly relapse. Results of second-line treatment are generally poor. We conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy. PATIENTS AND METHODS: Eligible patients were refractory or relapsed small-cell lung cancer, with an Eastern Cooperative Oncology Group performance status of 0-2 and measurable disease. Paclitaxel was administered at 135 mg/m(2) days 1 and 8 immediately followed by gemcitabine at 1000 mg/m(2) every 3 weeks up to 6 courses. Restaging of disease was scheduled every 3 courses. RESULTS: Forty-one patients were enrolled. The median age was 65 years. Nineteen patients were considered refractory (progressive disease during or within 90 days from completion of first-line treatment), whereas 22 patients were chemotherapy sensitive. A total of 135 courses was administered (range, 1-6; median, 3). Nine patients achieved a partial remission (partial response, 22%), and 10 patients had stable disease (24%), with a disease control rate (partial response + stable disease) of 46%: in 12 (55%) of 22 patients who were sensitive and in 7 (37%) of 19 patients with refractory disease, respectively. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months. The most-frequent severe toxicities were neutropenia grade 3-4 and neurologic grade 3 in 24% and 7% of delivered courses, respectively. CONCLUSIONS: The combination of gemcitabine and paclitaxel investigated in our study achieved a high disease control rate, but the schedule we adopted appeared to be quite toxic.