Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer.

BACKGROUND: Previous findings showed that cediranib-olaparib increased PFS in women with recurrent platinum-sensitive ovarian cancer compared to olaparib alone. METHODS: BAROCCO trial randomized 123 patients: 80mg/m2 paclitaxel weekly up to 24 weeks (control), olaparib 300mg tablets twice daily together with 20mg cediranib daily (continuous schedule) or with 20mg cediranib 5 days/week (intermittent schedule) until progression. The primary objective was the PFS comparison between each experimental arm and the control (alpha one-sided 5%; power 80%; HR 0.5). RESULTS: The median platinum-free interval was 1.9 months, 60% of patients had been pretreated with 3 or more chemotherapy lines. Median PFS for paclitaxel, the continuous, and the intermittent schedules were 3.1, 5.6, and 3.8 months. The HR for PFS in the continuous arm vs control was 0.76 (90% CI: 0.50-1.14, p = 0.265). The HR for PFS in the intermittent arm vs control was 1.03 (90% CI: 0.68-1.55, p = 0.904). Treatment was discontinued due to adverse events in 15%, 20%, and 5% of patients in the control, continuous and intermittent arms. Grade ≥ 3 anemia and diarrhea and hypertension of any grade occurred only in the experimental arms, and peripheral neuropathies and alopecia only in the control arm. Five serious adverse drug reactions occurred and two were fatal: one in the control and one in the continuous arm. CONCLUSIONS: The combination of cediranib-olaparib was not superior to chemotherapy in terms of PFS in heavily pretreated platinum-resistant ovarian cancer patients. However, this oral doublet, is active and may offer a non-chemotherapy option in this difficult to treat population. CLINICAL TRIAL IDENTIFICATION: IRFMN-OVA-7289, EudraCT: 2016-003964-38, NCT03314740.

Incorporating patient centered benefits as endpoints in randomized trials of maintenance therapies in advanced ovarian cancer: A position paper from the GCIG symptom benefit committee.

BACKGROUND: Quality of life and patient reported outcome measures (PROMs) are important secondary endpoints and incorporated in most contemporary clinical trials. There have been deficiencies in their assessment and reporting in ovarian cancer clinical trials, particularly in trials of maintenance treatment where they are of particular importance. The Gynecologic Cancer InterGroup (GCIG) symptom benefit committee (SBC) recently convened a brainstorming meeting with representation from all collaborative groups to address questions of how to best incorporate PROMs into trials of maintenance therapies to support the primary endpoint which is usually progression free survival (PFS). These recommendations should harmonize the collection, analysis and reporting of PROM's across future GCIG trials. METHODS: Through literature review, trials analysis and input from international experts, the SBC identified four relevant topics to address with respect to promoting the role of PROMs to support the PFS endpoint in clinical trials of maintenance treatment for OC. RESULTS: The GCIG SBC unanimously accepted the importance of integrating PROM's in future maintenance trials and developed four guiding principles to be considered early in trial design. These include 1) adherence to SPIRIT-PRO guidelines, 2) harmonization of selection, collection and reporting of PROM's; 3) combining Health Related Quality of Life (HRQL) measures with clinical endpoints and 4) common approaches to dealing with incomplete HRQL data. CONCLUSIONS: Close attention to incorporating HRQL and PROM's is critical to interpret the results of ovarian cancer clinical trials of maintenance therapies. There should be a consistent approach to assessing and reporting patient centered benefits across all GCIG trials to enable cross trial comparisons which can be used to inform practice.

Bevacizumab, carboplatin, and paclitaxel in the first line treatment of advanced ovarian cancer patients: the phase IV MITO-16A/MaNGO-OV2A study.

OBJECTIVE: To explore the clinical and biological prognostic factors for advanced ovarian cancer patients receiving first-line treatment with carboplatin, paclitaxel, and bevacizumab. METHODS: A multicenter, phase IV, single arm trial was performed. Patients with advanced (FIGO (International Federation of Gynecology and Obstetrics) stage IIIB-IV) or recurrent, previously untreated, ovarian cancer received carboplatin (AUC (area under the curve) 5), paclitaxel (175 mg/m2) plus bevacizumab (15 mg/kg) on day 1 for six 3-weekly cycles followed by bevacizumab single agent (15 mg/kg) until progression or unacceptable toxicity up to a maximum of 22 total cycles. Here we report the final analysis on the role of clinical prognostic factors. The study had 80% power with a two-tailed 0.01 α error to detect a 0.60 hazard ratio with a factor expressed in at least 20% of the population. Both progression-free and overall survival were used as endpoints. RESULTS: From October 2012 to November 2014, 398 eligible patients were treated. After a median follow-up of 32.3 months (IQR 24.1-40.4), median progression-free survival was 20.8 months (95% CI 19.1 to 22.0) and median overall survival was 41.1 months (95% CI 39.1 to 43.5). Clinical factors significantly predicting progression-free and overall survival were performance status, stage, and residual disease after primary surgery. Neither baseline blood pressure/antihypertensive treatment nor the development of hypertension during bevacizumab were prognostic. There were two deaths possibly related to treatment, but no unexpected safety signal was reported. CONCLUSIONS: Efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel and as maintenance were comparable to previous data. Hypertension, either at baseline or developed during treatment, was not prognostic. Performance status, stage, and residual disease after primary surgery remain the most important clinical prognostic factors. TRIAL REGISTRATION NUMBER: EudraCT 2012-003043-29; NCT01706120.

Multicenter, randomised, open-label, non-comparative phase 2 trial on the efficacy and safety of the combination of bevacizumab and trabectedin with or without carboplatin in women with partially platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Trabectedin, in addition to its antiproliferative effect, can modify the tumour microenvironment and this could be synergistic with bevacizumab. The efficacy and safety of trabectedin and bevacizumab ± carboplatin have never been investigated. METHODS: In this phase 2 study, women progressing between 6 and 12 months since their last platinum-based therapy were randomised to Arm BT: bevacizumab, trabectedin every 21 days, or Arm BT+C: bevacizumab, trabectedin and carboplatin every 28 days, from cycles 1 to 6, then trabectedin and bevacizumab as in Arm BT. Primary endpoints were progression-free survival rate (PFS-6) and severe toxicity rate (ST-6) at 6 months, assuming a PFS-6 ≤35% for BT and ≤40% for BT+C as not of therapeutic interest and, for both arms, a ST-6 ≥ 30% as unacceptable. RESULTS: BT+C (21 patients) did not meet the safety criteria for the second stage (ST-6 45%; 95%CI: 23%-69%) but PFS-6 was 85% (95%CI: 62%-97%). BT (50 patients) had 75% PFS-6 (95%CI: 60%-87%) and 16% ST-6 (95%CI 7%-30%). CONCLUSIONS: BT compared favourably with other platinum- and non-platinum-based regimens. The combination with carboplatin needs to be assessed further in a re-modulated safer schedule to confirm its apparent strong activity. CLINICAL TRIAL REGISTRATION: NCT01735071 (Clinicaltrials.gov).

A phase II randomised (calibrated design) study on the activity of the single-agent trabectedin in metastatic or locally relapsed uterine leiomyosarcoma.

BACKGROUND: Patients with recurrent/metastatic uterine leiomyosarcoma (U-LMS) have a dismal prognosis. This phase II study aims to evaluate trabectedin efficacy and safety in advanced U-LMS. METHODS: Eligible patients had received ≥ one line of chemotherapy. Gemcitabine ± docetaxel naive patients were randomised to Arm A: trabectedin 1.3 mg/m2 or calibration Arm B: gemcitabine 900 mg/m2 and docetaxel 75 mg/m2. Patients who had already received gemcitabine ± docetaxel directly entered Arm A. Primary end-point: 6-month progression-free rate (PFS-6). The null hypothesis that the true PFS-6 = 14% was tested against a one-sided alternative. This design yielded a 5% type I error rate and 90% power when the true PFS-6 is 25%. RESULTS: Overall, 126 patients entered Arm A (45 from randomisation and 81 directly) and 42 Arm B. Arm A patients characteristics: median age = 57; ≥2 previous chemotherapy lines = 37.4%; metastatic disease = 93%. The study met the condition for trabectedin activity: PFS-6 = 35.2% (95% CI: 26.2-45). No difference in PFS by the number of previous chemotherapy lines emerged. Median OS = 20.6 months (IQR: 8-36.4). In Arm B, the PFS-6 = 51.5% (95% CI: 33.5-69.2). No toxic deaths occurred. In Arm A, only 4 patients interrupted treatment for toxicity. CONCLUSIONS: Trabectedin is active and well tolerated, retaining similar efficacy across one to three previous lines of chemotherapy.

Secondary analyses from a randomized clinical trial: age as the key prognostic factor in endometrial carcinoma.

OBJECTIVE: The purpose of this study was to explore in greater depth the outcomes of the Italian randomized trial investigating the role of pelvic lymphadenectomy in clinical early stage endometrial cancer. In the attempt to identify the patients with poorer prognosis, the impact of age and body mass index were also thoroughly investigated by cancer-specific survival (CSS) analyses. STUDY DESIGN: Survival outcomes of trial patients were analyzed in relation to age (≤65 years and >65 years) in the 2 arms (lymphadenectomy and no lymphadenectomy) and in the whole population of the trial. RESULTS: Univariate and multivariable analyses of CSS and overall survival (OS) of patients showed that age >65 years is a strong independent poor prognostic factor (5-y OS 92.1% and 78.4% in ≤65 years and >65 years patients, respectively, P < .0001; 5-y CSS 93.8% and 83.5% in ≤65 years and >65 years patients, respectively, P = .003). Among women ≤65 years, node negative patients had 94.4% 5-y OS and 96.3% 5-y CSS vs 74.3% 5-y OS and 74.3% 5-y CSS for node positive patients (P = .009 and P = .002, respectively), while among women >65 y, node negative patients had 75.7% 5-y OS and 83.6% 5-y CSS vs 74.1% 5-y OS and 83.3% 5-y CSS for node positive patients (P = .55 and P = .58, respectively). Univariate and multivariable survival analyses in the whole trial population showed that older age, and higher tumor grade and stage were significantly associated to a worse prognosis. CONCLUSION: Older women faced an intrinsic poorer survival whether or not they underwent lymphadenectomy, and, unexpectedly, irrespective of the presence of nodal metastasis. Only in older patients was obesity (body mass index >30) significantly associated with scarce prognosis.

Long-Term Toxicity and Health-Related Quality of Life After Adjuvant Chemoradiation Therapy or Radiation Therapy Alone for High-Risk Endometrial Cancer in the Randomized PORTEC-3 Trial.

PURPOSE: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL). METHODS AND MATERIALS: In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed. RESULTS: Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population. CONCLUSIONS: This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer.

Modified radical hysterectomy versus extrafascial hysterectomy in the treatment of stage I endometrial cancer: results from the ILIADE randomized study.

BACKGROUND: Five percent to 20% of stage I endometrial cancer patients undergoing total abdominal hysterectomy and bilateral salpingo-oophorectomy develop vaginal and pelvic recurrences. Adjuvant radiotherapy can improve locoregional control but not survival. This randomized trial aimed to determine whether a modified radical (Piver-Rutledge class II) hysterectomy can improve survival and locoregional control compared to the standard extrafascial (Piver-Rutledge class I) hysterectomy. METHODS: Eligible patients (n = 520) with stage I endometrial cancer were randomized to class I or class II hysterectomy. Primary endpoint was overall survival. RESULTS: The median length of parametria and vagina removed were 15 and 5 vs. 20 mm and 15 mm for class I and class II hysterectomy, respectively (P > 0.001). Operating time and blood loss were statistically significantly higher for class II hysterectomy. At a median follow-up of 70 months, 51 patients had died. Five-year disease-free and overall survival were similar between arms (87.7 and 88.9% in the class I arm and 89.7 and 92.2% in the class II arm, respectively). The unadjusted hazard ratios for recurrence was 0.91 (95% confidence interval, 0.55-1.51, P = 0.72), and the hazard ratio for death was 0.77 (95% confidence interval, 0.44-1.33, P = 0.35). CONCLUSIONS: Class II hysterectomy did not improve locoregional control and survival compared to class I hysterectomy, but when an adequate vaginal cuff transection is not feasible with class I hysterectomy, a modified radical hysterectomy allows to obtain an optimal vaginal and pelvic control of disease with a minimal increase in surgical morbidity.

Expression levels of p53 and p73 isoforms in stage I and stage III ovarian cancer.

The p53 gene has been investigated for its role in epithelial ovarian cancer but data collected until now are contradictory. The evidence that p53 belongs with p63 and p73 to a family of transcription factors re-opened interest in this gene family. Here, we used quantitative real time RT-PCR to determine expression levels of TAp53, TAp73 and their N-terminal splice variants in a cohort of 169 ovarian cancer patients with stage I and stage III disease. The TAp73 levels in stage III biopsies differed by 100-fold depending on the p53 status and overall survival appears to be significantly related to DeltaNp73 expression. Kaplan-Meyer analyses did not suggest a correlation between overall survival and levels of TAp73, DeltaNp73 or the DeltaNp73/TAp73 ratio. In conclusion, these data suggest that at least in our patient cohort p53 and p73 expression levels are not correlated to malignant progression of ovarian cancer. They might, however, play a role in tumour initiation.

Physician-delivered advice to quit smoking among Italian smokers.

OBJECTIVE: A clinical practice guideline for smoking cessation was released in Italy in 2002, but to date little is known about the implementation of these recommendations among primary care physicians. The objectives of this study were to estimate the prevalence of receiving physician-delivered advice to quit smoking and to determine what factors were related to the receipt of advice among adult Italian smokers. METHODS: The data were collected as part of the Italian 2004-2006 adult tobacco surveys (analyzed in 2007), conducted by DOXA, the Italian branch of the Gallup International Association, and representative of the population aged>or=18 years. Each year smokers were asked whether they had received advice to quit smoking from their family physician during the previous year. Demographic, socioeconomic, tobacco-related, and physician-related variables were examined for their association with the receipt of advice. A logistic regression model was then fit to the data to determine which variables were related to receiving advice to quit smoking. RESULTS: Overall, 22% of smokers reported receiving advice to quit smoking from their physician in the previous year. Less likely to receive advice to quit were smokers who: were single (compared to divorced, widowed, or separated); lived in the South; had a higher level of education; were lighter smokers; had no previous quit attempts; and had physicians who likely smoked. CONCLUSIONS: The data suggest that Italian physicians are not advising smokers to quit at a high rate. Future research should focus on methods that encourage physicians to counsel smokers to quit during a patient-provider encounter.

A double-blind, placebo-controlled, randomized trial of bupropion for smoking cessation in primary care.

BACKGROUND: Studies undertaken in academic settings have shown that bupropion hydrochloride can double the odds of smoking cessation compared with placebo. To assess whether these results are applicable in primary care, we launched a double-blind, placebo-controlled, randomized trial to be conducted by general practitioners. METHODS: We assigned 593 healthy smokers to receive bupropion hydrochloride, 150 mg twice a day, or placebo daily for 7 weeks (hereinafter, bupropion group [n = 400] and placebo group [n = 193], respectively). After the baseline visit, 4 clinical visits and 3 telephone calls were scheduled over the 1-year period. The primary end points were biochemically confirmed continuous abstinence at week 7 and at week 52. RESULTS: Seventy-one Italian general practitioners enrolled participants from April 2004 to May 2005. Of the bupropion group, 41.0% were continuously abstinent from week 4 to week 7 compared with 22.3% of the placebo group (multivariate odds ratio, 2.37; 95% confidence interval, 1.60-3.53). The continuous abstinence rates from week 4 to week 52 were 25% in the bupropion group and 14% in the placebo group (odds ratio, 2.11; 95% confidence interval, 1.32-3.39). The mean weight gain was similar in both groups and among long-term abstainers was 3 kg in women and 4 kg in men. More participants in the bupropion group experienced an adverse event than those in the placebo group, but the percentage who discontinued use of the study medication was similar. CONCLUSIONS: Bupropion more than doubled the odds of continuous abstinence from smoking. The adherence of general practitioners and participants to the protocol was excellent, making our findings robust and easy to generalize to the context of primary care.

An evaluation of the Italian version of the Fagerström Test for Nicotine Dependence.

This study examined the psychometric properties of an Italian version of the Fagerström Test for Nicotine Dependence in a sample of 593 smokers who were enrolled in a randomized Phase IV clinical trial to compare bupropion to placebo. This version was administered at baseline, and from each participant an expired air carbon monoxide (CO) measure was taken. Spearman correlations between the Total score and CO concentration were .27 in the combined sample and .27 and .25 among men and women. With respect to the internal consistency reliability, the coefficient alpha was low (alpha= .55) in the combined sample and among men (.59) and women (.50). While the Total score predicted abstinence at 7 wk., it was not significantly related to continuous abstinence at 12 mo. postrandomization. The properties of the Italian version of the Fagerström Test for Nicotine Dependence appear to be consistent with other versions described in the literature.

Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study.

PURPOSE: Neoadjuvant chemotherapy may represent an alternative to irradiation in locally advanced squamous cell cervical cancer. Aims of this study were to compare a three-drug (paclitaxel, ifosfamide, and cisplatin [TIP]) with a two-drug (ifosfamide and cisplatin [IP]) regimen and to assess the prognostic value of pathologic response on survival. PATIENTS AND METHODS: Patients (n = 219) were randomly assigned to ifosfamide 5 g/m(2) during 24 hours plus cisplatin 75 mg/m(2), or paclitaxel 175 mg/m(2) plus ifosfamide 5 g/m(2) during 24 hours and cisplatin 75 mg/m(2) every 3 weeks for three courses. RESULTS: Grades 3 to 4 neutropenia, anemia, and thrombocytopenia were more frequent with TIP. We recorded four deaths related to toxicity. The optimal pathologic response (OPT) rate (residual disease < 3 mm stromal invasion) was higher with TIP than with IP (48% v 23%; odds ratio, 3.22; 95% CI, 1.69 to 5.88; P = .0003). At a median follow-up of 43.4 months, 79 women experienced disease progression or died (46 in the IP arm, 33 in the TIP arm). Patients receiving TIP experienced a treatment failure rate 25% less than those receiving IP, but this difference was not statistically significant (hazard ratio [HR], 0.75; 95% CI, 0.48 to 1.17; P = .20). Sixty-one patients died (37 in the IP arm, 24 in the TIP arm), and the HR of death was in favor of TIP, although not significantly (HR, 0.66; 95% CI, 0.39 to 1.10; P = .11). In patients assessable for response (n = 189), the average death rates were higher in the group that did not achieve OPT (HR, 5.88; 95% CI, 2.50 to 13.84; P < .0001). CONCLUSION: The TIP regimen is associated with a higher response rate than the IP regimen, without a statistically significant effect on overall survival. OPT was a prognostic factor for survival.

Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies.

INTRODUCTION: Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled. METHODS: Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy. RESULTS: In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01). CONCLUSION: Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.

Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group.

PURPOSE: Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non-small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy. PATIENTS AND METHODS: Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial. RESULTS: With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin. CONCLUSION: Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.

Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial.

BACKGROUND: Pelvic lymph nodes are the most common site of extrauterine tumor spread in early-stage endometrial cancer, but the clinical impact of lymphadenectomy has not been addressed in randomized studies. We conducted a randomized clinical trial to determine whether the addition of pelvic systematic lymphadenectomy to standard hysterectomy with bilateral salpingo-oophorectomy improves overall and disease-free survival. METHODS: From October 1, 1996, through March 31, 2006, 514 eligible patients with preoperative International Federation of Gynecology and Obstetrics stage I endometrial carcinoma were randomly assigned to undergo pelvic systematic lymphadenectomy (n = 264) or no lymphadenectomy (n = 250). Patients' clinical data, pathological tumor characteristics, and operative and early postoperative data were recorded at discharge from hospital. Late postoperative complications, adjuvant therapy, and follow-up data were collected 6 months after surgery. Survival was analyzed by use of the log-rank test and a Cox multivariable regression analysis. All statistical tests were two-sided. RESULTS: The median number of lymph nodes removed was 30 (interquartile range = 22-42) in the pelvic systematic lymphadenectomy arm and 0 (interquartile range = 0-0) in the no-lymphadenectomy arm (P < .001). Both early and late postoperative complications occurred statistically significantly more frequently in patients who had received pelvic systematic lymphadenectomy (81 patients in the lymphadenectomy arm and 34 patients in the no-lymphadenectomy arm, P = .001). Pelvic systematic lymphadenectomy improved surgical staging as statistically significantly more patients with lymph node metastases were found in the lymphadenectomy arm than in the no-lymphadenectomy arm (13.3% vs 3.2%, difference = 10.1%, 95% confidence interval [CI] = 5.3% to 14.9%, P < .001). At a median follow-up of 49 months, 78 events (ie, recurrence or death) had been observed and 53 patients had died. The unadjusted risks for first event and death were similar between the two arms (hazard ratio [HR] for first event = 1.10, 95% CI = 0.70 to 1.71, P = .68, and HR for death = 1.20, 95% CI = 0.70 to 2.07, P = .50). The 5-year disease-free and overall survival rates in an intention-to-treat analysis were similar between arms (81.0% and 85.9% in the lymphadenectomy arm and 81.7% and 90.0% in the no-lymphadenectomy arm, respectively). CONCLUSION: Although systematic pelvic lymphadenectomy statistically significantly improved surgical staging, it did not improve disease-free or overall survival.

Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial.

BACKGROUND: The role of systematic aortic and pelvic lymphadenectomy in patients with optimally debulked advanced ovarian cancer is unclear and has not been addressed by randomized studies. We conducted a randomized clinical trial to determine whether systematic aortic and pelvic lymphadenectomy improves progression-free and overall survival compared with resection of bulky nodes only. METHODS: From January 1991 through May 2003, 427 eligible patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIB-C and IV epithelial ovarian carcinoma were randomly assigned to undergo systematic pelvic and para-aortic lymphadenectomy (n = 216) or resection of bulky nodes only (n = 211). Progression-free survival and overall survival were analyzed using a log-rank statistic and a Cox multivariable regression analysis. All statistical tests were two-sided. RESULTS: After a median follow-up of 68.4 months, 292 events (i.e., recurrences or deaths) were observed, and 202 patients had died. Sites of first recurrences were similar in both arms. The adjusted risk for first event was statistically significantly lower in the systematic lymphadenectomy arm (hazard ratio [HR] = .75, 95% confidence interval [CI] = 0.59 to 0.94; P = .01) than in the no-lymphadenectomy arm, corresponding to 5-year progression-free survival rates of 31.2 and 21.6% in the systematic lymphadenectomy and control arms, respectively (difference = 9.6%, 95% CI = 1.5% to 21.6%), and to median progression-free survival of 29.4 and 22.4 months, respectively (difference = 7 months, 95% CI = 1.0 to 14.4 months). The risk of death was similar in both arms (HR = 0.97, 95% CI = 0.74 to 1.29; P = .85), corresponding to 5-year overall survival rates of 48.5 and 47%, respectively (difference = 1.5%, 95% CI = -8.4% to 10.6%), and to median overall survival of 58.7 and 56.3 months, respectively (difference = 2.4 months, 95% CI = -11.8 to 21.0 months). Median operating time was longer, and the percentage of patients requiring blood transfusions was higher in the systematic lymphadenectomy arm than in the no-lymphadenectomy arm (300 versus 210 minutes, P<.001, and 72% versus 59%; P = .006, respectively). CONCLUSION: Systematic lymphadenectomy improves progression-free but not overall survival in women with optimally debulked advanced ovarian carcinoma.