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Background: To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010., Objectives: To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival., Search Methods: We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations., Selection Criteria: We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment., Data Collection and Analysis: We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status., Main Results: We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low., Authors' Conclusions: Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.

Background: Randomized trials have demonstrated that adding a drug to a single-agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial., Objectives: To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC., Search Methods: There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and June 2006., Selection Criteria: Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC., Data Collection and Analysis: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (< 1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen)., Main Results: Sixty-five trials (13601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR 0.42, 95% confidence interval [CI] 0.37 to 0.47, P < 0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P < 0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P < 0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P < 0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97)., Authors' Conclusions: Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.

Background: Randomized trials have demonstrated that adding a drug to a single-agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial., Objectives: To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC., Search Strategy: There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and June 2006., Selection Criteria: Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC., Data Collection and Analysis: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (< 1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen)., Main Results: Sixty-five trials (13601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR 0.42, 95% confidence interval [CI] 0.37 to 0.47, P < 0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P < 0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P < 0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P < 0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97)., Authors' Conclusions: Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.

Background: Isolated lung metastases have been reported to occur in 10-20% of all women with breast carcinoma. The authors described a series of patients who underwent surgery for lung metastases from breast carcinoma., Methods: They reviewed the files of 125 consecutive patients who underwent surgery with a curative intent for lung metastases from breast carcinoma between 1972 an 1998 at a single institution. Survival curves were plotted by the Kaplan-Meier method. Prognostic factors were identified using the log-rank test and a Cox proportional hazards model for univariate and multivariate analyses, respectively., Results: The median age at surgery was 53 years. There was a median of 1 resected metastasis (range, 1-16 resected metastases). The median size of the largest metastasis was 19 mm (range, 5-70 mm). The median disease-free interval (DFI) was 3 years. The median follow-up time after surgery was 8.5 years (range, 25 days to 22 years). The 3-year, 5-year, and 10-year probabilities of survival were 58% (95% confidence interval [95% CI], 49-67%), 45% (95% CI, 36-55%), and 30% (95% CI, 21-41%), respectively. The median survival time after surgery was 4.2 years. Complete resection was achieved in 96 patients. The quality of the resection (complete vs. incomplete) was not a statistically significant prognostic factor by univariate analysis and there was no significant difference between these two groups in terms of adjuvant postoperative therapy. The characteristics of the primary tumor and the number of metastases (one vs. two or more) had no detectable influence on survival. The size of the largest metastasis (> 20 mm or < or = 20 mm) and the DFI (< or = 3 years vs. > 3 years) were highly significant prognostic factors (P = 0.006 and P = 0.003, respectively). This was confirmed by multivariate analysis. Patients with a DFI < or = 3 years and/or the largest metastasis > 20 mm reportedly had a poor outcome (median survival, 2.6 years vs. 8.5 years for patients with none of these poor prognostic factors)., Conclusions: Resection of lung metastases from breast carcinoma was associated with a significant 5-year survival rate of 45%. Whether these encouraging findings resulted from the surgical procedure itself or the preoperative selection of patients remained uncertain. When surgery is considered in this setting, the size of the largest metastasis and the DFI should be taken into account.

Background: Serum neuron specific enolase (NSE) is the most sensitive tumor marker of small cell lung carcinoma (SCLC) at diagnosis. Its prognostic value is still debated. Thus, the authors decided to assess the predictive value, in terms of complete response and survival, of serum NSE measured before and after one cycle of chemotherapy in patients with SCLC., Methods: Sera from 135 patients with histologically proven limited (n = 63) or metastatic (n = 72) SCLC were obtained. Clinical and biologic parameters with a known or suspected prognostic relevance were reviewed. Serum NSE was measured before chemotherapy (D1-NSE) and 28 days after its initiation (D28-NSE). The prognostic value of the parameters under study was evaluated in univariate and multivariate analyses using the Cox proportional hazards model and logistic regression analysis., Results: The level of serum NSE was raised in 120 patients (88%) prior to therapy. The probability of a normal D28-NSE value was not affected by the baseline D1-NSE value. Disease extension (P = 0.0005), performance status (P = 0.0001), D28-NSE (P = 0.003), and carcinoembryonic antigen (CEA) levels (P = 0.008) were found to be predictive for survival, whereas age, gender, plasma sodium, serum protides, and D1-NSE were not. Median survival and 2-year overall survival were 15.3 months and 21% (95% confidence interval [CI], 13-31%) when D28-NSE was normal and 8.1 months and 15% (95% CI, 8-27%) when it was not (P < 0.03). Only performance status (P = 0.001), disease extension (P = 0.002), and D28-NSE (P = 0.02) were found to be independent prognostic parameters for survival in the multivariate analysis. A simple prognostic index was developed using these 3 variables. Limited disease, a normal D28-NSE value, and a normal CEA value prior to therapy were the only parameters predictive for complete response in the univariate analysis, and D28-NSE (P = 0.01) and disease extension (P = 0.0001) were found to be independent variables in multivariate analysis. A complete response to therapy occurred in 62% with a normal D28-NSE value and in only 34% in the opposite case., Conclusions: Normal serum D28-NSE is a strong, independent early predictor of both complete response to therapy and survival. This simple tool may be proposed for use in the clinic and in research, in association with an assessment of disease extension and performance status, to predict the outcome of patients with SCLC.

Background: Patients with inflammatory breast cancer have a high risk of developing a local recurrence and/or distant metastases. Treatment with combined chemotherapy and locoregional radiotherapy contributes to a decrease in both risks. This study presents treatment results and evaluates the pattern of failure when an alternating chemoradiotherapy schedule is used., Methods: One hundred twenty-five patients with nonmetastatic inflammatory breast cancer were treated with an alternating schedule of radiotherapy and chemotherapy. All women recruited were younger than 70 years of age and had a T4d, histologically proven infiltrating carcinoma with N0 to N2 axillary disease. The protocol consisted of three cycles of induction chemotherapy with doxorubicin, vincristine, cyclophosphamide, methotrexate, and 5-fluorouracil followed by three series of locoregional radiotherapy, delivering a total dose of 65-75 Gy to the breast tumor. Five additional cycles of chemotherapy with 5-fluorouracil/doxorubicin/cyclophosphamide were to be administered in between the first two and after the third radiotherapy course. A 1-week gap was respected between each course of chemotherapy and each series of radiotherapy., Results: Toxicity was moderate and this strategy proved feasible although most of the patients only received six instead of the eight planned cycles of chemotherapy. Eighty-two percent of the patients achieved a complete response at the end of the treatment. The cumulative 5-year local failure and distant metastasis rates were 27% and 53%, respectively. Assuming competing events, local failures, contralateral recurrences, and distant metastases were the first site of failure in 18%, 5%, and 38% of patients, respectively. The 5-year overall and disease free survival rates were 50% and 38%, respectively. The main prognostic factor was tumor size., Conclusions: Alternating high doses of radiotherapy and chemotherapy is a feasible treatment schedule and permits breast conservation. Disease free survival is comparable to that of recently published series. As the main causes of failure are distant metastases, higher dose chemotherapy should be evaluated, in an attempt to further improve overall survival.

Background: The effect of adjuvant chemotherapy after resection of nonsmall cell lung cancer (NSCLC) remains an unresolved question., Methods: From October, 1982, to November, 1986, 267 patients with resected NSCLC were included in a randomized trial. The adjuvant allocated treatments were either postoperative radiotherapy, 60 Gy in 6 weeks (radiotherapy group = 129 patients), or three courses of postoperative COPAC (cyclophosphamide, doxorubicin, cisplatin, vincristine, lomustine) chemotherapy followed by a similar radiotherapy schedule (chemotherapy/radiotherapy group = 138 patients)., Results: The sex ratio (M:F) was 19/1; mean age was 57 +/- 9 years. According to postoperative staging, 8 patients were Stage I, 70 were Stage II, and 189 were Stage III. The histologic type was squamous cell carcinoma in 175 patients, adenocarcinoma in 57, and large cell carcinoma in 35. The minimum follow-up was 6 years. Four patients were lost to follow-up. Death was recorded in 233 patients. No significant difference was observed in terms of disease free interval (P = 0.47, log-rank test), or overall survival (P = 0.68, log-rank test). With respect to the first site of relapse, distant metastasis occurred more frequently in the radiotherapy group (P = 0.09, log-rank test) whereas local relapse occurred similarly in both groups (P = 0.27). An interaction was observed between lymph node involvement and treatment in terms of overall survival., Conclusions: The COPAC chemotherapy as postoperative treatment failed to improve overall survival in patients with resected NSCLC receiving postoperative radiotherapy but decreased the pattern of metastatic progression, mainly in the N2 patients.

Background: Surgical resection of pulmonary metastases (PMs) has been shown to produce approximately a 35% 5-year survival rate, but specific data about late survival are not available in the literature., Methods: A retrospective review and survival analysis of 186 adult patients who underwent surgery for PMs at a single center before June 1984 is presented., Results: Of the 186 patients who had surgery, of whom 34 (18%) had an incomplete resection, the 10-year survival rate (Kaplan-Meier) was 23% (95% CI, 16-30%), and 36 patients, with PMs from nine different primary sites, were still at risk at 10 years. Two patients died of their primary disease more than 10 years after the first thoracotomy, and two are alive with uncontrolled disease. Thirty-one patients are currently alive and disease free. Comparison between the 36 10-year survivors and the 150 nonsurvivors revealed that only the percentage of incomplete resections and the mean number of resections per patient were significantly different between the two groups (P < 0.001); the histologic type of the primary tumor, the disease-free interval, and the number of resected PMs at the first thoracotomy were not found to be statistically significant prognostic factors., Conclusions: The 23% 10-year survival and the high rate of disease free 10-year survivors in this study constitute support for complete resection as an efficient therapeutic approach in patients with isolated PMs. Relevant criteria to select more precisely those patients who will benefit from resection remain to be developed.

The triangular test has been used to monitor survival data from a randomized trial in patients with small cell lung cancer. The results of consecutive interim analyses and the problems met by the data monitoring committee and the co-ordinators are described. The methods as well as the consequences of the early stopping on the analysis and the results of this trial are discussed. From this experience, we believe that statistical stopping rules--only one of the factors to be taken into account when deciding to stop a trial--should be used with caution. Independent data monitoring committees may be useful in helping to review the ongoing results and advise the participants in the trial.

This report describes an isolated case of cardiac metastasis of a myxoid liposarcoma that was successfully resected by surgery after clinical and ultrasound diagnosis. Although cardiac metastases are rarely diagnosed during patients' lifetimes, a search should be made for such lesions whenever cardiac disorders appear suddenly in cancer patients. Echocardiography appears to be one of the best investigative techniques for such purposes. Despite generally poor therapeutic results, surgical resection occasionally permits long periods of survival.

Evidence that supports the use of systemic, presurgical induction chemotherapy to render soft tissue sarcomas resectable or to minimize the extent of surgical excision is presented. Induction chemotherapy was administered in 34 cases of nonmetastatic soft tissue sarcomas. All patients had large tumors for which only mutilating surgery, if any, was possible. In 21 patients, a combination of Adriamycin (doxorubicin), cyclophosphamide, cisplatin, vindesine, and DTIC (DCPAV) produced two complete remissions (CR) and 6 partial remissions (PR). A combination of cyclophosphamide, vincristine, Adriamycin, and DTIC (CYVADIC) produced three PR in eight patients, and a combination of Adriamycin and ifosfamide (AI) produced two PR in five patients. After two to seven cycles of chemotherapy, 24 patients underwent surgery. In 19, gross tumor excision was performed; 12 proved to be microscopically fully resected. Disease in two patients entered CR with chemotherapy alone, but surgery was performed in both patients as well. Irradiation was administered in ten patients to produce or insure CR (eight cases of residual disease postoperatively), and in two patients with unresectable disease. Four patients with disease in CR after surgery also received radiation due to the initial massive tumor size. The Kaplan-Meier survival curves at 2 years showed 18% total survival in the patients in whom CR of disease was not achieved, and 80% survival in patients with disease in CR. Of the 22 patients with disease in CR (by all means), disease-free survival was 1 to 44 months (mean, 13.7). Disease currently remains in CR in ten patients with a mean follow-up of 13.6 months (3 to 34 months from end of therapy). Ten patients had a local recurrence following a CR after 3 to 44 months (mean, 15.3 months).

A retrospective study is reported of 120 consecutive cases of patients presenting with brain metastases as the primary sign of their malignancy. Primary site was found in 62 patients (53 while alive and 9 at postmortem examination) and remained unknown in 58. Lung was the most frequent primary site (45% of known sites), and digestive malignancies were surprisingly the second most frequent primary site (19% of known sites), whereas breast was found in less than 5%. When primary site was disclosed, in 85% it was after history, clinical exam, chest x-ray, and pathologic findings. Survival was almost identical in both known and unknown primary sites: 54% versus 44% at 6 months, 20% versus 16% at 1 year, and 6% versus 5% at 2 years. It was concluded that extensive evaluations to identify primary sites do not appear to be rational in patients presenting with brain metastases.