A phase II study of dose-dense and dose-intense ABVD (ABVDDD-DI ) without consolidation radiotherapy in patients with advanced Hodgkin lymphoma.

We explored activity and safety of a dose-dense/dose-intense adriamycin, bleomycin, vinblastine and dacarbazine regimen (ABVDDD-DI ) in 82 patients with advanced Hodgkin Lymphoma. Patients entered a two-stage Bryant-Day Phase II study to receive six cycles of ABVDDD-DI without consolidation radiotherapy. Cycles were supported with granulocyte colony-stimulating factor and delivered every 21 d; drugs were administered on days 1 and 11 at the same doses of standard ABVD except for doxorubicin (35 mg/m2; first four cycles only). Co-primary endpoints were complete response (CR) rate and severe acute cardiopulmonary toxicity; secondary endpoints were event-free (EFS) and disease-free survival (DFS). All patients received the four doxorubicin-intensified courses and 96% concluded all six cycles (82.3% within the intended 18 weeks). This translated into a 66.9% increase of received dose-intensity for doxorubicin and 31.8% for the other agents over standard ABVD. The CR rate was 95.1% (78/82) and 87.8% (72/82) achieved a metabolic CR after two cycles. Cardiopulmonary toxicity never exceeded grade 2 and affected 14.6% of patients. Most frequent toxicities were grade 4 neutropenia (10%) and anaemia (9%), grade 3 infection (17%) and grade 2 mucocutaneous changes (30%). Five-year EFS and DFS was 88.3% and 93.7%, respectively. ABVDDD-DI regimen was well-tolerated and ensured substantial CR and EFS rates without radiotherapy.

The impact of decreasing cutoff values for maximal oxygen consumption (VO(2)max) in the decision-making process for candidates to lung cancer surgery.

BACKGROUND: Maximal oxygen consumption (VO(2)max) is considered a decisive test for risk prediction in patients with borderline cardiopulmonary reserve. Guidelines have adopted decreasing VO(2)max cut-off values to define operability within acceptable mortality and morbidity limits. We wanted to investigate how the adoption of decreasing VO(2)max cut-off-values assessment contributed to better select lung surgery candidates. METHODS: One hundred and nineteen consecutive surgical candidates have been prospectively analyzed as a sample population. Preoperative work-up included spirometry and transfer factor (DLco); irrespective of the spirometric values, these patients were subjected to VO(2)max assessment. Surgical eligibility was decided by the same surgeon throughout the series. In the postoperative period, overall mortality and the occurrence of any, major or minor complications was recorded and graded according to the Common Terminology Criteria for Adverse Events v.4.3. RESULTS: Three arbitrary cut-offs were introduced at 15, 14 and 12 mL(.)kg(-1) (.)min(-1). Notably, 15 and 12 mL(.)kg(-1) (.)min(-1) correlated with percentage VO(2)max values of 50% and 35% of predicted (P<0.0001 and 0.0079), respectively. Accordingly, the patients were subdivided into groups in which the prevalence of postoperative morbidity was recorded. The groups were homogeneous as to age, BMI, preoperative absolute and percentage FEV1 and DLco. In the Cox proportionate-hazards multivariate analysis, VO(2)max less than 35% (P=0.0017) and CTCAE >2 (P=0.0457) emerged as significant predictors of survival after surgery. Conversely on logistic regression analysis, age over 70 years (P=0.03) and pneumonectomy (P=0.001), but not VO(2)max cut-off values, were significant predictors of major (CTCAE >2) morbidity. CONCLUSIONS: Since VO(2)max is increasingly used to contribute to risk prediction for the individual patient, surgeons need to be advised that the concept of a definitive, generalized cut-off value for VO(2)max is probably a contradiction in terms. Patient-specific VO(2)max values are more likely to contribute to risk assessment since they may reflect the primarily affected component among the determinants of maximal oxygen consumption. Whether patient-specific VO(2)max should be routinely used by surgeons to define operability for borderline patients needs further evaluation.

Management of localized pneumothoraces after pulmonary resection with intrapulmonary percussive ventilation.

BACKGROUND: Intrapulmonary percussive ventilation (IPV) aims at clearing retained secretions through oscillary vibrations generated by high frequency bursts of gas delivered into the airways at rates between 200 and 300 breaths per minute and at a delivery pressure of 10 to 20 cm water. In addition, IPV can improve recruitment of alveolar units and deliver aerosolized medications. The use of IPV to resolve challenging postlobectomy localized pneumothoraces is hereafter described. METHODS: Between January 2005 and March 2009, four patients with long-term complicated postresectional residual air spaces persisting 6 months (mean, 187 days) after primary surgery were treated by IPV. The type of operation was upper lobectomy and lower lobectomy-wedge resection in 1 and 3 patients, respectively. Mean preoperative and immediate postsurgical forced expiratory volume in the first second of expiration were 2.31 L and 1.49 L, respectively. Mean preoperative and immediate postsurgical forced vital capacity were 3.13 L and 2.1 L, respectively. Patients were subjected to 12-minute-long IPV sessions up to a total of 8 to 12 sessions administered every other day in an outpatient setting. RESULTS: Complete resolution of the spaces within a mean of 22 days of beginning of treatment was noted. The post-IPV forced expiratory volume in the first second of expiration and forced vital capacity were 1.72 and 2.4 liters, respectively. No treatment-related morbidity was observed. CONCLUSIONS: Intrapulmonary percussive ventilation can be expected to decisively contribute to resolving long-term localized pneumothoraces after subtotal pulmonary resections in an outpatient setting.

A model to predict the immediate postoperative FEV1 following major lung resections.

OBJECTIVE: FEV1 measured on the first postoperative day has shown to be a better predictor of complications than traditional ppoFEV1. Therefore, its estimation before operation may enhance risk stratification. The objective of this study was to develop and validate a model to predict FEV1 on the first postoperative day after major lung resection. METHODS: FEV1 was prospectively measured on the first postoperative day in 272 patients submitted for lobectomy or pneumonectomy at two centers. A random sample of 136 patients was used to develop a model estimating the first day FEV1 by using multiple regression analysis including several preoperative and operative factors. The model was then validated by bootstrap analysis and tested on the other sample of 136 patients. RESULTS: Factors reliably associated with postoperative first day FEV1 were age (p=0.002), preoperative FEV1 (p<0.0001), the presence of epidural analgesia (p<0.0001), and the percentage of non-obstructed segments removed during operation (p=0.001). The following model estimating the first day postoperative FEV1 was derived: -2.648+0.295 x age+0.371 x FEV1+8.216 x epidural analgesia - 0.338 x percentage of non-obstructed segments removed during operation. In the validation set, the mean predicted first day postoperative FEV1 value did not differ from the observed one (42.6 vs 42.0, respectively; p=0.3) and the plot of the observed versus the predicted first day FEV1 showed a satisfactory calibration. CONCLUSIONS: We developed a model predicting the first day postoperative FEV1. If future analyses will prove its role in stratifying the early postoperative risk, it may be integrated in preoperative evaluation algorithms to refine risk stratification.

Evidence of lower alteration of expiratory volume in patients with airflow limitation in the immediate period after lobectomy.

BACKGROUND: Recently published papers have shown that lobectomy improves lung function in selected patients with chronic obstructive pulmonary disease (COPD) months after surgery, but little information can be found discussing the effect of lobectomy on pulmonary function in the immediate period after surgery in these cases. The aim of this multicenter prospective study is to evaluate whether preoperative COPD influences the decrease of forced expiratory volume in 1 second the day after surgery. METHODS: One hundred eighty-five patients undergoing nonextensive lobectomy were included. Selection criteria and perioperative management were homogeneous; all procedures were performed by muscle-sparing or video-assisted thoracoscopic surgical approach. Multivariate regression analysis was performed to identify whether COPD index (calculated by adding the percent preoperative forced expiratory volume in 1 second to the preoperative ratio of forced expiratory volume in 1 second to forced vital capacity, both values taken in decimal form) had an independent and reliable association with the decrease in forced expiratory volume in 1 second observed on the first postoperative day corrected for the effect of other preoperative and operative factors. The regression analysis was then validated by bootstrap analysis. RESULTS: Thirty-day mortality of the series was 1.1% (2 patients) and cardio-respiratory morbidity 20% (37 patients). Patients with lower preoperative pulmonary volumes had lower postoperative decrease of the pulmonary function (Pearson correlation coefficient, 0.28; p < 0.001). At linear regression, COPD index (p = 0.008), modality of analgesia (p < 0.0001), pain score (p = 0.01), the percentage of functioning parenchyma removed during operation (p = 0.006), and the presence of coronary artery disease (p = 0.03) had independent and reliable influence on the dependent variable (p < 0.001 and 0.003, respectively). CONCLUSIONS: Preoperative COPD degree (measured as COPD index) has a direct independent correlation with the decrease in postoperative forced expiratory volume in 1 second the day after surgery.

Measured FEV1 in the first postoperative day, and not ppoFEV1, is the best predictor of cardio-respiratory morbidity after lung resection.

INTRODUCTION AND OBJECTIVE: There is a low correlation between predicted postoperative FEV1 (ppoFEV1) and FEV1 measured the days after pulmonary resection, when most complications are developed. The hypothesis of this investigation is that ppoFEV1 does not predict postoperative morbidity in patients undergoing lung resection when immediate postoperative FEV1 is considered in the predictive model. METHODS: One hundred ninety-eight consecutive patients undergoing lobectomy or pneumonectomy were included in a prospective, multiinstitutional study. INDEPENDENT VARIABLES: age, body mass index, ppoFEV1, surgical approach (VATS or muscle-sparing thoracotomy), type of analgesia (epidural or intraveous), postoperative visual analogue pain score and FEV1 measured the day after the operation. Target variable: occurrence of postoperative cardio-respiratory complications. Method of analysis: classification tree (CART) dividing the population at random in two subsets and developing a bootstrap set of 100 trees resampling training data. The relative importance of each variable and the accuracy of both initial and committee trees to predict the outcome were presented. RESULTS: One hundred seventy-seven lobectomies and 21 pneumonectomies were included. Overall cardio-respiratory morbidity was 22%. According to CART results, first day FEV1 was the most important variable to classify cases as primary splitter and as a surrogate of each primary splitter (100% importance). Patient age followed (51%) and ppoFEV1 was third (43%) with a score similar to postoperative pain score (42%) and type of analgesia (36%). Sensitivity and specificity of the initial tree were, respectively, 0.5 and 0.7; values for committee tree were 0.5 sensitivity and 0.7 specificity. CONCLUSION: Postoperative cardio-respiratory complications are more related to FEV1 measured in the first postoperative day than to ppoFEV1 value.

Predicted versus observed FEV1 in the immediate postoperative period after pulmonary lobectomy.

OBJECTIVE: Scanty information can be found regarding ppoFEV1% correlation with true FEV1% in the immediate days after surgery, when most cardio-respiratory complications are developed. This prospective multicentric investigation aims to describe the evolution of FEV1 in a series of uneventful lobectomy cases before hospital discharge, and to identify factors associated with the variation of postoperative residual FEV1, with the ratio between the actual and the predicted postoperative FEV1 measured during the first 6 postoperative days. METHODS: One hundred and sixty-one patients submitted to lobectomy were prospectively enrolled in the study. Patients with chest wall resections and postoperative complications were excluded. Data from a total of 125 patients were thus used for the analysis. The following clinical variables were recorded: age, preoperative FEV1, ppoFEV1, presence of chronic obstructive pulmonary disease (COPD), surgical approach (VATS or muscle-sparing thoracotomy), side (right or left) and site (upper or lower) of resection, type of analgesia (epidural or intravenous), and daily visual analogue pain score (VAS). FEV1 was measured in every patient at hospital admission and daily until discharge or up to postoperative day 6. Random effects time-series cross-sectional regression analyses were performed to identify factors associated with variation of postoperative residual function (100-(preoperative FEV1-postoperative FEV1/preoperative FEV1 x 100)), and of FEV1 ratio ((actual postoperative FEV1 x 100)/ppoFEV1). For these analyses, the dependent variables (postoperative residual function and FEV1 ratio) and the pain score were analysed as panel longitudinal data. The regression analyses were subsequently validated by bootstrap procedure. RESULTS: FEV1% was lower at first postoperative day and increased gradually up to day 6 but mean values never reached ppoFEV1%. Pain scores decreased from day 1 to day 6. Preoperative FEV1 (p<0.0001) and postoperative pain score (p<0.0001) resulted independently and reliably inversely associated with postoperative residual FEV1 (model R2, 0.16). Preoperative FEV1 (p=0.001), postoperative pain score (p<0.0001), and epidural analgesia (p=0.04) resulted independently and reliably associated with postoperative FEV1 ratio (model R2, 0.13). CONCLUSION: Current methods of prediction of postoperative FEV1 greatly underestimated the real functional loss in the immediate postoperative period. Therefore, for the purpose of a more accurate risk stratification we need to correct the traditional prediction of postoperative FEV1.

Has lung cancer in the elderly different characteristics at presentation?

Lung cancer is the first cause of cancer death for males aged > or =35 years, and the second for females aged between 35 and 70 years. Elderly patients seem to have the worst performance status (PS) and earlier stage of disease at diagnosis. We analyzed data concerning 1,035 patients with lung cancer referred to the National Cancer Institute of Naples. The variables considered in the analysis were: gender; type of cancer [small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)]; ECOG (Eastern Cooperative Oncology Group) PS, the stage of disease at diagnosis, the histological type, age at diagnosis. In order to better assess the relevance of age at diagnosis in lung cancer patients we categorized the age into two groups (young < or =70; old >70 years). The statistical analyses were performed using chi2 trend test with corresponding p-value and odds ratios (OR) for the examined variables, with a corresponding 95% confidence interval. These were derived using multiple logistic regression, fitted by the maximum likelihood method. For all the 1035 patients the risk between the age at diagnosis and the performance status was not statistically significant (OR=1.1, 95%CI 0.8-1.5). We repeated the same risk distinguishing the histological type and we analyzed the performance status for the SCLC (OR=1.0, 95%CI 0.4-2.5) and the stage at diagnosis (OR=1.0, 95%CI 0.4-3.0), without any significant difference. Our study showed that elderly patients with lung cancer do not seem to have different characteristics at presentation, particularly related to stage of disease, PS and histology, as compared to their younger counterpart. Other characteristics such as type and number of co-morbidities and organ function differ in the two groups of populations.