Prevalence of osteoporotic fracture risk factors and antiosteoporotic treatments in the Valencia region, Spain. The baseline characteristics of the ESOSVAL cohort.

UNLABELLED: This study provides information on the prevalence of the most important risk factors for osteoporosis and osteoporotic fracture in a large sample of women and men from the Valencia region and also provides the FRAX 10-year major and hip fracture risks for this population, as well as data about the use of diagnostic tests and antiosteoporotic treatments. INTRODUCTION: The purpose of this study was to describe demographic characteristics, osteoporosis risk factors, the 10-year risk of osteoporotic fracture, and the use of densitometry and antiosteoporotic treatments in the Valencia region, Spain. METHODS: A cross-sectional study using the ESOSVAL cohort baseline data was conducted. We analyze the data from 5,310 women and 5,725 men aged 50 and over who attended to 272 collaborating primary care centers in 2009-2010. We collected the demographic, anthropometric, clinical, and pharmacy data from the electronic medical record. RESULTS: The mean age of participants was 64.3 years old for women and 65.6 years old for men. The most frequent fracture risk factors were sedentary life (22.2 %) and previous fracture (15.8 %) in women and low calcium intake (21.4 %) and current smoker (20.9 %) in men. According to FRAX(®), the 10-year risk of presenting a major fracture was 5.5 % for the women and 2.8 % for the men. The 10-year risk for hip fracture was 1.9 and 1.1 % for the women and the men, respectively; 23.8 % of the women and 5.2 % of the men had a densitometry test, 27.7 % of the women and 3.5 % of the men were taking calcium and/or vitamin D supplements, and 28.2 % of the women (22.0 % in the 50-64 age group) and 2.3 % of the men were taking antiosteoporotic drugs. CONCLUSIONS: The prevalence of certain fracture risk factors not included in the FRAX tool (sedentary life, falls, low calcium intake) is high. In young women, their low risks estimated by FRAX contrast with the high figures for densitometry testing and treatment.

Surrogate markers predicting overall survival for lung cancer: ELCWP recommendations.

The present systematic review was performed under the auspices of the European Lung Cancer Working Party (ELCWP) in order to determine the role of early intermediate criteria (surrogate markers), instead of survival, in determining treatment efficacy in patients with lung cancer. Initially, the level of evidence for the use of overall survival to evaluate treatment efficacy was reviewed. Nine questions were then formulated by the ELCWP. After reviewing the literature with experts on these questions, it can be concluded that overall survival is still the best criterion for predicting treatment efficacy in lung cancer. Some intermediate criteria can be early predictors, if not surrogates, for survival, despite limitations in their potential application: these include time to progression, progression-free survival, objective response, local control after radiotherapy, downstaging in locally advanced nonsmall cell lung cancer (NSCLC), complete resection and pathological TNM in resected NSCLC, and a few circulating markers. Other criteria assessed in these recommendations are not currently adequate surrogates of survival in lung cancer.

Predicting the duration of chemotherapy-induced neutropenia: new scores and validation.

BACKGROUND: the objective of this study was to develop predictive models to classify febrile neutropenic patients into two groups, according to a prediction of the duration of the chemotherapy-induced neutropenia episode. PATIENTS AND METHODS: for this retrospective analysis, 106 patients with solid tumours and an episode of febrile neutropenia (FN) were eligible. A score was attributed to each chemotherapy treatment drug according to its expected toxicity. Three new scores were proposed based only on this classification. Two of them are a combination of the individual drug scores and the third one was built using statistical techniques such as cluster analysis and classification trees. RESULTS: statistical techniques produced the best score, distinguishing two groups of patients with statistically different neutropenia durations, with median durations until haematological recovery of absolute neutrophil count 2 × 10(9)/l of 4 versus 2 days (P < 0.001). CONCLUSIONS: our methodological approach based on statistical techniques identifies the patients who will need the longest times to recover from FN. The input of this predictive system is only the aggressiveness of the cytotoxic agents in a chemotherapy regimen. Our proposal succeeded in distinguishing two groups of patients and the results show better performance than other scores in previous studies.

Validation and comparison of several published prognostic systems for patients with small cell lung cancer.

The aim of the present study was to validate and compare published prognostic classifications for predicting the survival of patients with small cell lung cancer. We pooled data from phase III randomised clinical trials, and used Cox models for validation purposes and concordance probability estimates for assessing predictive ability. We included 693 patients. All the classifications impacted significantly on survival, with hazard ratios (HRs) in the range 1.57-1.68 (all p<0.0001). Median survival times were 16-19 months for the best predicted groups, while they were 6-7 months for the most poorly predicted groups. Most of the paired comparisons were statistically significant. We obtained similar results when restricting the analysis to patients with extensive disease. Multivariate Cox models for fitting survival data were also performed. The HRs for a single covariate were 8.23 (95% CI 5.88-11.69), and 9.46 (6.67-13.50), and for extensive disease were 5.60 (3.13-9.93), 12.49 (5.57-28.01) and 8.83 (4.66-16.64). Concordance probability estimates ranged 0.55-0.65 (overlapping confidence intervals). Published classifications were validated and suitable for use at a population level. As expected, prediction at an individual level remains problematic. A specific model designed for extensive-disease patients did not appear to perform better.

[Temporal evolution of renal involvement in a necropsy study of HIV patients from the pre and HAART eras]. / Evolución temporal de la afectación renal en una serie necrópsica de pacientes VIH de las eras pre y TARGA.

BACKGROUND: The aim of the present study is to analyze the impact of high activity antiretroviral therapy (HAART) on renal lesions observed in autopsies of HIV patients. SUBJECTS AND METHODS: Clinical records and renal pathologic samples from 100 HIV patients, who had died between 1984 and 2006, were reviewed, 61 before 1997 (group I) and 39 after. 24 of them had not received HAART (group II) and 15 had (group III). Premortem clinical and analytical data were obtained. Renal samples were stained with hematoxilin-eosin, PAS, Masson trichrome and silver-methenamine. The final pathologic diagnosis was recorded along with the findings at glomerular, tubular and interstitial levels. HIVAN was defined as the presence of focal or segmental glomerulosclerosis with glomerular collapse and microcystic tubulo -interstitial lesions. RESULTS: The main causes of death were infections 68%, tumours 14%, and others 18%, especially liver diseases. Renal failure was present in 42% at the time of death. A predominance of tubular lesions exists in the three study groups, followed by interstitial lesions and glomerular lesions. The main diagnoses were acute tubular necrosis (ATN) and septic nephritis. Four cases of HIVAN were found. When the subjects who received HAART treatment were compared with those who did not, a significantly higher percentage of interstitial lesions in the group with HAART was observed. There were also more cases of acute tubular necrosis but these differences were not statistically significant. CONCLUSIONS: Renal lesions were frequent in HIV patients independent of the presence or absence of HAART.

Catastrophic antiphospholipid syndrome related to severe ovarian hyperstimulation.

Antiphospholipid syndrome (APS) is a cause of infertility and fetal loss. Ovarian stimulation can induce previously unknown APS. Ovarian hyperstimulation syndrome (OHS) is uncommon but potentially life-threatening, as well as catastrophic APS. A woman that simultaneously developed a severe OHS and a catastrophic APS is described in this paper. Both entities produced thrombotic cardiac and brain thrombosis. A peculiar mechanism of cardiac ischemia is also described. In spite of the life-threatening risk of this situation, the indication for preventive anti-aggregation and/or anticoagulation is not clear.

Phase II randomized trial comparing high-dose cisplatin with moderate-dose cisplatin and carboplatin in patients with advanced non-small-cell lung cancer. European Lung Cancer Working Party.

PURPOSE: A phase II randomized trial was conducted in patients with advanced non-small-cell lung cancer (NSCLC) to determine if the combination of moderate-dose cisplatin and carboplatin was active (primary end point) and could avoid the long-term limiting (renal, auditive, neurologic) toxicity of high-dose cisplatin, which prevents prolonged administration (secondary end point). PATIENTS AND METHODS: One hundred twenty-one patients, registered between April 1990 and September 1991, were randomized to receive high-dose cisplatin (120 mg/m2 intravenously [IV] on day 1) or a combination of moderate-dose carboplatin (200 mg/m2 IV on day 1 and moderate-dose cisplatin (30 mg/m2 IV on days 2 and 3). One hundred nine patients were eligible: 56 in the cisplatin arm and 53 in the combined arm; 52 and 47, respectively, were assessable for response. All had stage IV disease (or stage IIIB with pleural effusion) and none had received prior chemotherapy. RESULTS: There was a 23% objective response rate to cisplatin (23% of the eligible patients) and a 22% response rate to cisplatin plus carboplatin (21% of the eligible patients). The overall survival rate was not significantly different between the two study arms, but responders in the combined arm survived significantly longer than those in the high-dose cisplatin arm (respective median survival durations, 66 and 30 weeks). Although there was no difference between the arms for alopecia, emesis, and leukopenia, the combined arm was significantly associated with more thrombocytopenia (although rarely severe) and, more importantly, with less renal (19% v 36%), auditive (4% v 16%), and neurologic (0% v 16%) toxicity of any grade. CONCLUSION: The regimen combining moderate-dose cisplatin and carboplatin was active against advanced NSCLC and significantly less toxic than high-dose cisplatin.

Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party.

PURPOSE AND METHODS: The European Lung Cancer Working Party (ELCWP) performed a randomized trial with the primary end point to determine if maintenance chemotherapy with 12 courses of etoposide (120 mg/m2 on days 1 and 3) and vindesine (3 mg/m2 on day 3) could improve progression-free survival in small-cell lung cancer (SCLC) patients who responded to six courses of induction chemotherapy with ifosfamide, etoposide, and an anthracycline (doxorubicin or epirubicin). RESULTS: Among 235 eligible patients initially registered, 91 were randomized to receive maintenance therapy, including seven patients who were no longer responding. Among 84 randomized responders, progression-free survival was significantly improved (P = .003) by maintenance therapy, with median durations (maintenance v follow-up) of 25 versus 12 weeks after the second randomization, but survival was not significantly increased (P = .10), with median durations of 48 and 38 weeks. However, in a multi-variate analysis that took into account disease extent, maintenance therapy, Karnofsky performance status (PS), and absolute dose-intensity (ADI) of anthracycline given during induction, limited disease (LD) and maintenance were found to be independent positive predictors of survival. CONCLUSION: We conclude that maintenance chemotherapy in responding patients is beneficial in SCLC.

Phase III randomized trial comparing cisplatin and carboplatin with or without ifosfamide in patients with advanced non-small-cell lung cancer. European Lung Cancer Working Party.

PURPOSE: A phase III randomized trial in patients with advanced non-small-cell lung cancer (NSCLC) was performed to determine if the addition of ifosfamide to moderate-dose cisplatin and carboplatin improved response rate (primary end point) and survival. PATIENTS AND METHODS: A total of 529 patients were randomized to receive a combination of moderate-dose carboplatin (200 mg/m2 intravenously [i.v.] on day 1) and cisplatin (30 mg/m2 i.v. on days 2 and 3) with (CCI arm) or without (CC arm) ifosfamide (1.5 g/m2 i.v. on days 1 to 3). There were 248 eligible patients on the CC arm and 257 on the CCI arm, with 220 and 238 patients assessable for response, respectively. All but 23 had stage IV disease with pleural effusion. RESULTS: There was a 16% objective response (OR) rate to CC and a 31% OR rate to CCI. That observed difference was highly statistically significant (P < 0.001). Duration of response and survival were not statistically different between arms. The CCI regimen was associated with significantly more acute toxicities: emesis, alopecia, leukopenia, and thrombocytopenia. The frequency of chronic renal, auditive, and peripheral neurologic toxicity was low in both arms (4.6% and 6.6%, respectively, after six courses of chemotherapy). The relative dose-intensity (RDI) of the CCI arm was significantly lower than that of the CC arm. CONCLUSION: The addition of ifosfamide to moderate-dose cisplatin and carboplatin significantly improves the antitumoral response rate, but has no apparent effect an survival in advanced NSCLC.

Lymphoid tissue viral burden and duration of viral suppression in plasma.

OBJECTIVES: To assess virological response in lymphoid tissue and its impact on the durability of response in plasma in HIV-1-infected persons who achieved sustained suppression of plasma viraemia with different antiretroviral regimens. METHODS: Consecutive patients on first-line antiretroviral therapy were included if they had a plasma HIV-1 RNA viraemia < 20 copies/ml within the last 6 months and tonsillar tissue accessible for biopsy. First-line therapy contained two nucleoside analogues: alone (2NRTI group, n = 3); plus a HIV-1 protease inhibitor (PI group, n = 11) or plus nevirapine (NVP group; n = 16). Patients were followed until virus was detectable in plasma, they changed therapy or were lost to follow-up. RESULTS: Tonsillar HIV-1 RNA could be detected (> 100 copies/mg) in 10 patients: one in the PI group (9%), six (38%) in the NVP group and in all three patients in the 2NRTI group. Primary resistance mutations could be detected in only 2 of these 10 patients. After a median of 9 months after the biopsies, viral suppression in plasma had failed in 6 of these 10 patients whereas failure had only occurred in 1 out of 20 with initially undetectable viral load in lymphoid tissue (P = 0.01; log rank test). CONCLUSIONS: In patients with sustained viral suppression in plasma, triple therapy including a HIV-1 protease inhibitor was more potent than triple therapy containing nevirapine or dual therapy with nucleoside analogues to reduce viral burden in lymphoid tissue. A worse response in lymphoid tissue could not be explained by local selection of resistance and was associated with a less durable virological response in plasma.

Oral calcium supplementation reduces intraplatelet free calcium concentration and insulin resistance in essential hypertensive patients.

We evaluated the effect of oral calcium supplementation on blood pressure, calcium metabolism, and insulin resistance in essential hypertension. After receiving a standard diet with 500 mg of calcium per day during a 4-week period, 20 nondiabetic, essential hypertensive patients were randomized in a double-blind fashion to receive oral calcium supplementation (1500 mg of calcium per day) or placebo for 8 weeks. At the end of the 4-week period of low-calcium diet and after the 8-week period of intervention, we measured blood pressure (by both office and 24-hour ambulatory blood pressure monitoring), calcium-regulating hormones [urinary hydroxyproline and serum osteocalcin, parathormone, and 1,25(OH)2-vitamin D3], intraplatelet free calcium concentration, fasting plasma glucose and insulin levels, and the insulin-sensitivity index (euglycemic-hyperinsulinemic clamp). Compared with patients maintained at low calcium intake, essential hypertensive patients under oral calcium supplementation significantly reduced serum osteocalcin (from 22.2 +/- 1.9 to 17.9 +/- 2.0 micrograms/L; P = .0015), parathormone (from 4.20 +/- 0.38 to 3.30 +/- 0.36 pmol/L; P = .0003), and 1,25(OH)2-vitamin D3 (from 98.0 +/- 11.0 to 61.6 +/- 5.7 pmol/L; P = .0062). Likewise, we found a significant reduction in intraplatelet free calcium concentration (from 35.9 +/- 1.2 to 26.5 +/- 0.8 nmol/L; P = .0005) and fasting plasma insulin levels (from 71.8 +/- 5.9 to 64.6 +/- 6.2 pmol/L; P = .05) and a significant increase in the insulin-sensitivity index (from 2.89 +/- 0.77 to 4.00 +/- 0.95 mg.kg-1.min-1; P = .0007). None of these parameters were significantly modified in patients maintained at low calcium intake. Office and 24-hour mean values of systolic and diastolic blood pressure did not change after 8 weeks of oral calcium supplementation or placebo.

Renin-angiotensin system genetic polymorphisms and salt sensitivity in essential hypertension.

We evaluated the association between salt-sensitive hypertension and 3 different genetic polymorphisms of the renin-angiotensin system. Fifty patients with essential hypertension were classified as salt sensitive or salt resistant, depending on the presence or absence of a significant increase (P<0.05) in 24-hour ambulatory mean blood pressure (BP) after high salt intake. The insertion/deletion (I/D) angiotensin-converting enzyme (ACE) gene, the M235T angiotensinogen (AGT) gene, and the A1166C angiotensin II type 1 (AT1) receptor gene polymorphisms were determined with the use of standard polymerase chain reaction methods. Twenty-four (48%) patients with significantly increased (P<0.05) 24-hour mean BP with high salt intake (from 107.3+/-9.4 to 114.8+/-10.6 mm Hg) were classified as salt sensitive. In the remaining 26 patients (52%), high salt intake did not significantly modify 24-hour mean BP (from 107.6+/-10 to 107. 8+/-9 mm Hg), and they were classified as having salt-resistant hypertension. We did not find any significant association between either M235T AGT or A1166C AT1 receptor genotypes and the BP response to high salt intake. However, patients with essential hypertension homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake (9. 8+/-8.1 mm Hg for systolic BP and 5.2+/-4.2 mm Hg for diastolic BP) than that observed in patients homozygous for the deletion allele (DD) (1.2+/-5.9 mm Hg for systolic BP; P=0.0118 and -0.2+/-4.2 mm Hg for diastolic BP; P=0.0274). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension also was significantly higher (P=0.012) in II (67%) and DI patients (62%) compared with DD hypertensives (19%). We conclude that a significant association exists between the I/D polymorphism of the ACE gene and salt-sensitive hypertension. Patients with II and DI genotypes have significantly higher prevalence of salt sensitivity than DD hypertensives.

Long-term survival after chemotherapy containing platinum derivatives in patients with advanced unresectable non-small cell lung cancer. European Lung Cancer Working Party.

The study set out to determine the rate of long-term survivors (LTS) in patients treated with platinum-containing chemotherapy for advanced non-small cell lung cancer (NSCLC), to identify prognostic factors predicting long-term survival (> or = 2 years) and to report the LTS natural history. Eligible patients with advanced NSCLC treated by chemotherapy in one of seven trials conducted by the European Lung Cancer Working Party from December 1980 to August 1991 were included. All patients received cisplatin and/or carboplatin. Of these, 1052 patients were eligible and 24 variables were analysed as potential prognostic factors. Actuarial 2-year and 5-year survival rates were, respectively, 7.4 and 1.8%. All patients surviving for > or = 5 years had limited disease and were treated by complementary chest irradiation and/or surgery. Univariate prognostic factor analysis for LTS identified as significant no major weight loss, limited disease, no liver metastases, normal white blood cells and neutrophils and normal lactic dehydrogenase levels. By multivariate analysis, the only significant factor was limited disease. Objective response to chemotherapy was also found to be, as disease extent, a highly significant predictor for LTS. Thus, the two best prognostic factors for LTS were non-metastatic disease and response to chemotherapy.

A comparison of methods of calculation for estimating carboplatin AUC with a retrospective pharmacokinetic-pharmacodynamic analysis in patients with advanced non-small cell lung cancer. European Lung Cancer Working Party.

We retrospectively analysed the data obtained in a large randomised trial performed in 505 eligible patients with advanced non-small cell lung cancer. Its purpose had been to compare a combination of carboplatin (200 mg/m2) and cisplatin (60 mg/m2) with or without the addition of ifosfamide. The present retrospective analysis assessed two ways of dosing carboplatin: according to body surface area (mg/m2) or to the estimated targeted area under the concentration versus time curve (AUC). Two different methods were used in the latter calculation: the Calvert formula using the Cockroft approximation to evaluate the glomerular filtration rate and the Chatelut equation. There was an excellent linear correlation between them. With the Chatelut method, the calculated administered AUC were lower. Whichever method was used, carboplatin AUC was not significantly associated with antitumour response rate nor patient survival. A statistically significant increase in haematological toxicity, mainly thrombopenia, was observed with an increase in the AUC. This effect was observed whatever AUC variable was considered, i.e. total dosage at course one, total dosage during the first three chemotherapy courses or dose intensity during the first three courses. The effect remained highly significant after adjustment for treatment arm. We conclude that for a moderate carboplatin dose in non-small cell lung cancer, the therapeutic index could be improved if dosage is calculated according to the AUC.

Induction chemotherapy with ifosfamide, etoposide, and anthracycline for small cell lung cancer: experience of the European Lung Cancer Working Party.

Prospective trials comparing drug analogues in the treatment of small cell lung cancer are rare. The European Lung Cancer Working Party has conducted a randomized trial with a primary end point of determining the effect on survival of maintenance chemotherapy and a secondary end point of comparing doxorubicin (45 mg/m2) with a bioequivalent epirubicin dose (60 mg/m2) in one set of patients, and a standard with a high epirubicin dose (60 v 90 mg/m2) in a second set of patients. Anthracycline was given on day 1 of induction chemotherapy in combination with ifosfamide (1.5 g/m2 intravenously days 1 through 3) and etoposide (80 mg/m2 intravenously days 1 through 3). Six courses were given at 3-week intervals. In all, 235 eligible previously untreated patients with pathologically proven small cell lung cancer were randomized: 106 to the comparison of doxorubicin and epirubicin and 129 to the comparison of standard-dose versus high-dose epirubicin. There was no difference between the regimens in terms of objective response rate or survival, and the regimen containing the lower (60 mg/m2) epirubicin dose was better tolerated, with fewer toxic deaths and less need for dose and schedule adjustments.

Gemcitabine and low dose carboplatin in the treatment of elderly patients with advanced non-small cell lung cancer.

BACKGROUND: Fifty percent of lung cancers arise in patients over 65 years old and 30% in those over 70. The aim of this study was to evaluate response, survival and tolerability of the combination carboplatin-gemcitabine in elderly patients with advanced non-small cell lung cancer (NSCLC). METHODS: Between May 1998 and December 2000, 88 patients were included. Median age was 74 (range 65-83). Treatment consisted of gemcitabine 1250 mg/m(2) (1000 mg/m(2) in the first six patients) on days 1 and 8, and carboplatin AUC=4 on day 1, every 21 days. Prognostic factors for survival were analysed. Performance status (PS) and symptoms were evaluated before and after three and six courses. RESULTS: A total of 400 cycles were administered (median of four per patient). WHO grades 3-4 toxicities were: neutropenia in 13% of the cycles, thrombocytopenia and anaemia in 4.5 and 14.7% of patients in any cycle. There was one treatment-related death. According to the intent-to-treat analysis, 33 patients achieved objective response, 33 had stable disease, and 22 had treatment failure (progression in 18 patients). Median and 1 year survival were 9 months and 34%, respectively. Median time to progression was 8 months. Only disease stage and PS showed independent prognostic value. Comorbidity and PS displayed no close correlation. Symptom improvement was seen as follows: pain (61.7%), dyspnea (50%), haemoptysis (80%), anorexia (62.5%) and asthenia (61.5%). CONCLUSIONS: The combination carboplatin-gemcitabine at these doses is feasible in elderly patients with advanced non-small cell lung cancer. Tolerability and toxicity are acceptable. Response rate and survival stand in the range of the most active regimens. Comorbidity and PS showed prognostic independence.

Prognostic factors for response to chemotherapy containing platinum derivatives in patients with unresectable non-small cell lung cancer. (NSCLC).

PURPOSE: To identify pretreatment variables predicting response to platinum derivatives containing chemotherapy in patients with unresectable non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients included in one of the 7 consecutive clinical trials conducted by the European Lung Cancer Working Party between December 1980 and August 1991. All patients received a cisplatin or carboplatin containing chemotherapy. We analyzed 22 potential prognostic factors including sex, age, histology, performance status, weight loss, type of lesions, extent of disease, main metastatic sites and several biological parameters, namely white blood cell count (WBC), neutrophil count, platelet count, hemoglobinemia, creatininemia, serum alkaline phosphatases and LDH. RESULTS: On 1052 eligible patients. 107 were not assessable for response. The objective response rate was 26% (95% C.I.: 23, 29%). Univariate analysis identified as statistically significantly associated with a higher objective antitumoral response rate the following characteristics: a normal platelet count, the absence of skin metastasis, the absence of adrenal metastasis, a higher creatininemia, a normal hemoglobinemia, an older age and a normal WBC count. On a restricted set of variables including data from 777 patients, a multivariate logistic regression model disclosed age and platelet count as significantly and independently related to response rate. CONCLUSION: Clinical and demographic characteristics of patients with unresectable NSCLC, as well as routine laboratory parameters, could not accurately predict response to chemotherapy in a population of patients selected for a clinical trial. Future studies on this subject should include more sophisticated variables as new biomolecular makers.

Survival is better predicted with a new classification of stage III unresectable non-small cell lung carcinoma treated by chemotherapy and radiotherapy.

UNLABELLED: The 1997 International staging system (ISS) classification separated stage III non-small cell lung cancer (NSCLC) into stages IIIA and IIIB. In a previous study including unresectable NSCLC initially treated with chemotherapy, we analysed survival according to tumour (T) and node (N) stages and derived a classification into stages IIIbeta (T3-4N3) and IIIalpha (other TN stage III) that had a better discrimination on survival distribution. The aim of this study was to validate these results in a further set of patients. Patients with unresectable stage III NSCLC included in a phase III trial assessing the role of increased dose chemotherapy (SuperMIP: mitomycin 6 mg/m2, ifosfamide 4.5 g/m2, cisplatin 60 mg/m2, carboplatin 200 mg/m2) in comparison to standard chemotherapy MIP (mitomycin 6 mg/m2, ifosfamide 3 g/m2, cisplatin 50 mg/m2), before thoracic irradiation (60 Gy in 30 fractions over 6 weeks) were the subject of this study. Survival distributions were assessed by the method of Kaplan-Meier. Survival comparisons were made by the log-rank test. Multivariate analyses using Cox regression models, included all potential prognostic factors for survival with a P-value <0.2 in univariate analysis. According to the 1997 International staging system classification, 328 eligible patients were included in the study. There was no imbalance between the two arms. Five parameters were significantly associated (P < or = 0.05) with survival in univariate analysis: European lung cancer working party (ELCWP) staging (IIIalpha[n = 294 pts] versus IIIbeta [n = 46]), Karnofsky index, weight loss, platelet count and haemoglobin level. These variables as well as the 1997 ISS staging, white blood cell (WBC) count, LDH and sodium levels were included in a multivariate analysis. Two models were constructed, including either the ELCWP or the 1997 ISS. In model 1 (ISS included), Karnofsky index (HR 0.69; 95% confidence interval (CI) 0.47-1.00; P = 0.05) and haemoglobin (HR 1.49; 95% CI 1.11-1.99; P = 0.007) were found significant. In model 2, including ELCWP staging, two variables were associated with survival: ELCWP staging (HR 1.68; 95% CI 1.20-2.35; P = 0.002) and haemoglobin (HR 1.54; 95% CI 1.15-2.07; P = 0.01). CONCLUSION: In initially unresectable stage III NSCLC treated by chemotherapy and radiotherapy, we validated the results of our previous study. The classification into stages IIIbeta (T3-4N3M0) and IIIalpha (other TN stage III) better discriminates the patients in term of survival than the 1997 ISS classification.

Evaluation of the TN sub-staging in patients with initially unresectable stage III non-small cell lung cancer treated by induction chemotherapy. The European Lung Cancer Working Party.

PURPOSE: This study attempted to investigate, in a cohort of patients with clinical stage III initially unresectable non-small cell lung cancer (NSCLC) treated by the same induction chemotherapy regimen, the prognostic value of clinical T and N sub-groupings in order to validate the current International Staging System (ISS). PATIENTS AND METHODS: All the eligible patients with stage III NSCLC (428 patients) registered in a clinical trial were included in the study investigating, after three courses of induction chemotherapy, the role, in responders, of chest irradiation in comparison to further chemotherapy. The chemotherapy regimen consisted of mitomycin C, ifosfamide and cisplatin. RESULTS: Patients with ISS 1986 stage IIIA had a significantly better survival than those with stage IIIB (median survival 47 vs 36 weeks; P = 0.01). A RECPAM analysis showed that patients with T1-T2 N3 and T4 N0-1-2 stage had a more similar prognosis to those with stage IIIA. That result leads to define two new sub-groups: stage IIIlalpha (T3-T4 N0-N1; any T N2; T1-T2 N3) and IIIbeta (T3-T4 N3), with a highly significant difference in survival between them (median survival: 45 vs 29 weeks; P < 0.0001). The superiority of that new classification on the ISS documented in our series of stage III patients for discriminating survival and tumour response has to be confirmed on another series in a multivariate context. CONCLUSION: For unresectable NSCLC treated by induction chemotherapy, stage III sub-classification by moving T4 N0-1 and T1-2 N3 tumours from stage IIIB to stage IIIA appeared to better correlate with prognosis. The usefulness of this new sub-division has to be tested in validation studies.