[A randomized clinical trial of preoperative neoadjuvant chemotherapy followed by surgery in the treatment of stage III non-small cell lung cancer]. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. Neoadjuvant chemotherapy in locally advanced non-small cell lung cancer. [The study of peri-operative chemotherapy in stage I-IIIa NSCLC]. Neoadjuvant chemotherapy for non-small cell lung cancer. Failure of the perioperative PCV neoadjuvant polychemotherapy in resectable bronchogenic non‐small cell carcinoma results from a randomized phase II trial A randomized trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage IIIA N2 non-small cell lung cancer (JCOG 9209). A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial. Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer.
BACKGROUND To explore the feasibility and toxicity of preoperative neoadjuvant chemotherapy followed by surgery in the treatment of stage III NSCLC and to evaluate its effects on tumor response , resection rate , tumor downstaging , and survival rate . METHODS From Jan. 1990 to Jan. 2001 , 624 patients were r and omly devided into group A ( preoperative neoadjuvant chemotherapy group ) and group B ( control group , without neoadjuvant chemotherapy ) . Group A had 314 patients and group B had 310 cases . The patients in group A were give 2 cycles of neoadjuvant chemotherapy , and operations were performed in 4 weeks after finishing the last chemotherapy . Twenty-one patients were given bronchial artery intervensional chemotherapy . The other 293 cases were given intravenous chemotherapy . The regimens included MVP in 68 cases , CAP in 36 cases , EP in 67 cases , VIP in 20 cases , Gem+ DDP in 30 cases , NVB+ DDP in 32 cases , Taxol+ NVB in 30 cases , and Taxol+ DDP in 10 cases . The patients in group B were firstly operated . Thoracic radiation therapy of 50 - 55 Gy was g iven in the patients with N1 and N2 disease both in group A and group B. RESULTS The tumor response to induction chemotherapy was 73 . 57 % ( 231/ 314 ) in group A. The tumor downstaging was 43 . 63 % ( 137/ 314 ) . The histological complete response was 15 . 92 % ( 50/ 314 ) . The resection rate was 97 . 69 % in group A , and 91 . 94 % in group B. No significant differences of blood loss , operative complications and mortality were observed between the group A and group B. The 1- , 3- , 5- and 10-year survival rates were 89 . 35 % , 67 . 46 % , 34 . 39 % and 29 . 34 % in group A , and 87 . 53 % , 51 . 54 % , 24 . 19 % and 21 . 64 % in group B respectively . The long-term survival rate in group A was remarkably higher than that in group B ( P < 0 . 01 ) . CONCLUSIONS The results demonstrate that the preoperative neoadjuvant chemotherapy is safe and effective . It is helpful to decrease the tumor staging , to increase the resection rate of the tumor , and to improve the long-term survival rate and life qualities of patients with stage III NSCLC Our previously reported r and omized study of patients with untreated , potentially resectable clinical stage IIIA non-small-cell lung cancer found that patients treated with perioperative chemotherapy and surgery had a significant increase in median survival compared to patients treated with surgery alone . We have now re-analyzed the results of the study with a median time from r and om allocation to analysis for all patients of 82 months . The increase in survival conferred by perioperative chemotherapy was maintained during the period of extended observation OBJECTIVE The objective of this study was to evaluate the role of neoadjuvant chemotherapy in the treatment of locally advanced non small cell lung cancer ( NSCLC ) followed by radiotherapy versus radiotherapy alone . MATERIAL AND METHODS Sixty nine patients were r and omized to chemotherapy ( group A ) or radiotherapy alone ( group B ) . The induction chemotherapy consists of cisplatin ( 80 mg/m2 ) day 1 and Gemcitabine ( 1250 mg/m2 ) , infusion day 1 and 8 . Cycles were repeated every 3 weeks . Radiotherapy was given 4 - 6 weeks after chemotherapy to a dose of 60 Gy/30 fractions/6 weeks . RESULTS A total of 66 patients were evaluable for response ; 34 in group A and 32 in group B. The overall response rate was 41.2 % for group A and 21.8 % for group B ( P < 0.5 ) but with no complete response observed in either group . At a median follow up of 15 months , the overall survival was 65 % and median survival was 12 months for group A. However in group B the overall survival at 15 months was 30 % and the median survival was 9 nt ( P < 0.001 ) . Treatment toxicity in group A was mainly haemotological in 79 % of patients none of them was grade II or IV . Grade Nausea and vomiting was reported in 73.5 % of patients , grade I esophagitis in 5.8 % of patients , grade I , radiation pneumonitis in 26.4 % of patients . Alopecia was observed in 29.4 % of patients , nephrotoxicity in 17.4 % . Treatment toxicity in group B were generally less than in group A but not statistically significant except fr grade III vomiting ( 15.6 % ) and alopecia ( 0 % ) . CONCLUSION Combination chemotherapy of cisplatin and gemcitabine is a tolerable and active induction chemotherapy regimen for patients with locally advanced NSCLC . Sequential radiotherapy given after induction chemotherapy is tolerable and offers a hope of improved locoregional control and survival compared with radiotherapy alone OBJECTIVE A number of studies had evaluated the benefit of neoadjuvant chemotherapy combined surgery on stage IIIa-IIIb NSCLC , survival benefit was found in several papers . We attempt to evaluate the survival and prognosis of cisplatinum-based schedule as peri-operative CT for resectable stage I-IIIa NSCLC . METHODS A prospect i ve , r and omized , multicenter study was conducted by Shanghai Lung Cancer Team ( supported by Shanghai Branch of Discipline Foundation ) since 1995 - 1997 for 211 cases of stage I-IIIa NSCLC with curative resection ( 99 stage I , 47 stage II , 65 stage III ) , age of < or= 75 , KPS > or= 80 , staged by 1997 AJC TNM Criteria . They were r and omized to be 103 cases with 1 - 2 cycles of pre-operative CT and 108 cases with no pre-operative CT , 2 - 4 cycles of post-operative CT  were used for stage II and stage IIIa NSCLC , it was totally 4 cycles of MVP or MOP CT schedule each case . Follow-up team had been trained , the follow-up rate should be > or= 95 % , last follow-up date was March of 2002 . Lobectomy was performed for most patients . Accumulated survival , log rank , MST , Cox uni-variance and multi-variance analyses were used as statistics for evaluation . RESULTS The two arms were well balanced for baseline demographic and clinical characteristics ( P > 0.05 for all ) . Stage I NSCLC had the best year-survival in whole patients . No statistical survival difference was found between the group with pre-op CT and with no pre-op CT , P = 0.074 , 0.087 and 0.097 , respectively , 5-year survival rates were of 31.98%:36.68 % . In various stage , a statistical survival difference was only shown in stage IINSCLC , P = 0.042 , 5-year survival rates and MST were worse in the group with pre-operation CT , 20%:65.2 % and 24 months:48 months , respectively , but no difference was seen in stage I and stage IIIa NSCLC . Stage and post-operation CT were the only two meaningful parameters with statistical survival difference calculated by multi-variance analyses , P = 0.000 all , but no difference was found in others 4 parameters ( age , sex , type and pre-operation CT ) . The response rate of pre-operation CT was of 50 % . Though there was no statistical difference , the responders were with slightly better year-survival rates than MR + NR patients , 38.9 % and 33.3 % , respectively . In the cases with pathological " T " down stage and " T " unchanged after pre-operation CT had a better yr-survival rates than " T " up-stage , P = 0.03 , 5-year survival rates were of 41.67 % , 40.51 % and 11.76 % , respectively , thus , effective chemotherapy might be beneficial to survival . Besides , in the cases with > or= 3 cycles of post-operation CT have better survival rates than less cycles . CONCLUSION A prospect i ve , r and omized , multicenter peri-operation CT study for stage I-IIIa NSCLC conducted in Shanghai , China . , it showed there had no benefit in survival between with pre-operation CT arm and with no pre-operation CT arm . In stage II NSCLC , pre-operation CT cases had a worse year-survival than with no pre-operation CT , P = 0.042 , but no difference was seen in stage I and stage IIIa NSCLC . The responder of CT and " T " down stage , " T " unchanged had better survival rates than those of not response and " T " up-stage . From multivariate analyses , stage and post-operation CT were the two meaningful parameters to year-survival , > or= 3 - 4 cycles of post-operation CT had a better statistical higher year-survival than less cycles . Nutrition , supportive treatment , immunity status and prevention of toxicity might be the next study worthy to conduct , for CT combined with OP Even with aggressive surgical treatment , relapse rates remain high for patients with resectable non-small cell lung cancer ( NSCLC ) . In an effort to improve survival in these patients , numerous clinical trials have evaluated neoadjuvant and adjuvant chemotherapy . Three large , r and omized clinical trials and two meta-analyses have demonstrated a survival benefit for adjuvant cisplatin-based chemotherapy compared to surgery alone . Adjuvant chemotherapy has become the st and ard of care for patients with resected NSCLC . A neoadjuvant approach offers several potential advantages over adjuvant therapy , including earlier treatment of micrometastatic disease , improved compliance and pathologic confirmation of efficacy . R and omized trials have shown neoadjuvant therapy to be feasible and safe and some studies have yielded promising efficacy . The applicability of these results has been limited due to patient heterogeneity , imprecise staging and lack of st and ardization with respect to inclusion of radiation therapy . With novel agents , improved staging , better supportive care and relevant molecular markers , a neoadjuvant strategy is promising for future clinical trials in NSCLC In 1985 , the authors began a phase II study to assess the PCV perioperative polychemotherapy ( cisplatin 100 mg/m2 , cyclophosphamide 600 mg/m2 , vindesine 3 mg/m2 ) in patients with resectable bronchogenic non‐small cell carcinoma . Patients were r and omized to receive either two preoperative courses of PCV chemotherapy , surgery , and two postoperative courses of PCV chemotherapy ( PCV group ) or immediate surgery ( surgery group ) . A staging procedure using the CT scan was performed before r and omization and , additionally , before surgery in the PCV group . There were 26 r and omized patients , 13 in each group . In the PCV group , 11 patients agreed to receive the two preoperative courses of chemotherapy .  A response was observed in five patients ( 45 % ) , and a progression was observed in four patients ( 36 % ) leading to a cancellation of surgery in two of them . Postoperative care was the same for each group . Although no death could be related to chemotherapy , it was decided to stop entering new patients into this trial because of the rate of preoperative progression in the PCV group OBJECTIVE We performed a prospect i ve r and omized trial in patients with potentially resectable stage IIIA N2 non-small cell lung cancer to confirm the efficacy of induction chemotherapy before surgical resection . METHODS Patients with stage IIIA N2 non-small cell lung cancer , all with histologically or cytologically confirmed metastases to the ipsilateral mediastinal lymph nodes , were r and omly assigned to receive either three cycles of induction chemotherapy ( cisplatin at 80 mg/m(2 ) on 1 day and vindesine at 3 mg/m(2 ) on 2 days ) followed by surgery or surgery alone . RESULTS This trial was prematurely terminated because the accrual rate was too slow , which lowered the study 's statistical power considerably . From June 1993 through April 1998 , a total of 62 patients were enrolled , and 31 patients were assigned to each treatment group . The objective clinical response rate of induction chemotherapy was 28 % . Complete resection was achieved in 20 patients in the induction chemotherapy group ( 65 % ) and 24 in the surgery alone group ( 77 % ) . Median follow-up was 6.2 years . Median overall survivals were 17 months for the induction group and 16 months for the surgery alone group . The estimated 1- , 3- , and 5-year survivals , respectively , were 68 % ( 95 % confidence interval 51%-85 % ) , 23 % ( 95 % confidence interval 8%-38 % ) , and 10 % ( 95 % confidence interval 0%-20 % ) for the induction chemotherapy group and 65 % ( 95 % confidence interval 48%-82 % ) , 26 % ( 95 % confidence interval 11%-41 % ) , and 22 % ( 95 % confidence interval 7%-37 % ) for the surgery alone group . There was no statistically significant difference in survival between the groups ( P = .5274 ) . Treatment-related death was not observed in either group . CONCLUSION This r and omized trial to compare induction chemotherapy ( cisplatin and vindesine ) followed by surgery with surgery alone for patients with stage IIIA N2 non-small cell lung cancer did not demonstrate a survival difference between the groups , although this may have been because the statistical power was limited BACKGROUND The efficacy of surgery for patients with non-small-cell lung cancer is limited , although recent studies suggest that preoperative chemotherapy may improve survival . We conducted a r and omized trial to examine the possible benefit of preoperative chemotherapy and surgery for the treatment of patients with non-small-cell lung cancer . METHODS We studied 60 patients ( 59 men and 1 woman ) with stage IIIA non-small-cell lung cancer . The patients were r and omly assigned to receive either surgery alone or three courses of chemotherapy ( 6 mg of mitomycin per square meter of body-surface area , 3 g of ifosfamide per square meter , and 50 mg of cisplatin per square meter ) given intravenously at three-week intervals and followed by surgery . All patients received mediastinal radiation after surgery . The resected tumors were evaluated by means of K-ras oncogene analysis and flow cytometry . RESULTS The median period of survival was 26 months in the patients treated with chemotherapy plus surgery , as compared with 8 months in the patients treated with surgery alone ( P < 0.001 ) ; the median period of disease-free survival was 20 months in the former group , as compared with 5 months in the latter ( P < 0.001 ) . The rate of recurrence was 56 percent in the group treated with chemotherapy plus surgery and 74 percent in the group treated with surgery alone . The prevalence of mutated K-ras oncogenes was 15 percent among the patients receiving preoperative chemotherapy and 42 percent among those treated with surgery alone ( P = 0.05 ) . Most of the patients treated with chemotherapy plus surgery had tumors that consisted of diploid cells , whereas the patients treated with surgery alone had tumors with aneuploid cells . CONCLUSIONS Preoperative chemotherapy increases the median survival in patients with non-small-cell lung cancer PURPOSE The treatment of patients with advanced non-small-cell lung cancer ( NSCLC ) is based on clinical trials experience . Molecular characteristics that impact metabolism and efficacy of chemotherapeutic agents are not used for decision making . Ribonucleotide reductase subunit 1 ( RRM1 ) is crucial for nucleotide metabolism , and it is the dominant molecular determinant of gemcitabine efficacy . Excision repair cross-complementing group 1 gene ( ERCC1 ) , a component of the nucleotide excision repair complex , is important for platinum-induced DNA adduct repair . We hypothesized that selection of double-agent chemotherapy based on tumoral RRM1 and ERCC1 expression would be feasible and beneficial for patients with advanced NSCLC . PATIENTS AND METHODS We conducted a prospect i ve phase II clinical trial in patients with advanced NSCLC . Patients were required to have a dedicated tumor biopsy for determination of RRM1 and ERCC1 gene expression by real-time quantitative reverse transcriptase polymerase chain reaction . Double-agent chemotherapy consisting of carboplatin , gemcitabine , docetaxel , and vinorelbine was selected based on gene expression . Disease response and patient survival were monitored . RESULTS Eighty-five patients were registered , 75 had the required biopsy without significant complications , 60 fulfilled all eligibility criteria , and gene expression analysis was not feasible in five patients .  RRM1 expression ranged from 0 to 1,637 , ERCC1 expression ranged from 1 to 8,103 , and their expression was correlated ( Spearman 's rho = 0.46 ; P < .01 ) . Disease response was 44 % . Overall survival was 59 % and progression-free survival was 14 % at 12 months , with a median of 13.3 and 6.6 months , respectively . CONCLUSION Therapeutic decision making based on RRM1 and ERCC1 gene expression for patients with advanced NSCLC is feasible and promising for improvement in patient THE R AND OMIZED controlled trial ( RCT ) , more than any other methodology , can have a powerful and immediate impact on patient care . Ideally , the report of such an evaluation needs to convey to the reader relevant information concerning the design , conduct , analysis , and generalizability of the trial . This information should provide the reader with the ability to make informed judgments regarding the internal and external validity of the trial . Accurate and complete reporting also benefits editors and review ers in their deliberations regarding su bmi tted manuscripts . For RCTs to ultimately benefit patients , the published report should be of the highest possible st and ard PURPOSE To evaluate whether preoperative chemotherapy ( PCT ) could improve survival in resectable stage I ( except T1N0 ) , II , and IIIA non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS A r and omized trial compared PCT to primary surgery ( PRS ) . PCT consisted of two cycles of mitomycin ( 6 mg/m(2 ) , day 1 ) , ifosfamide ( 1.5 g/m(2 ) , days 1 to 3 ) and cisplatin ( 30 mg/m(2 ) , days 1 to 3 ) , and two additional postoperative cycles for responding patients . In both arms , patients with pT3 or pN2 disease received thoracic radiotherapy . RESULTS Three hundred fifty-five eligible patients were r and omized . Overall response to PCT was 64 % . There were two preoperative toxic deaths . Postoperative mortality was 6.7 % in the PCT arm and 4.5 % in the PRS arm ( P = .38 ) . Median survival was 37 months ( 95 % confidence interval [ CI ] , 26.7 to 48.3 ) for PCT and 26.0 months ( 95 % CI , 19.8 to 33.6 ) for PRS ( P = .15 ) . Survival differences between both arms increased from 3.8 % ( 95 % CI , 1.3 % to 25.1 % ) at 1 year to 8.6 % ( 95 % CI , 2.64 % to 24.4 % ) at 4 years . A quantitative interaction between N status and treatment was observed , with benefit confined to N0 to N1 disease ( relative risk [ RR ] , 0.68 ; 95 % CI , 0.49 to 0.96 ; P = .027 ) . After a nonsignificant excess of deaths during treatment , the effect of PCT was significantly favorable on survival ( RR , 0.74 ; 95 % CI , 0.56 to 0.99 ; P = .044 ) . Disease-free survival time was significantly longer in the PCT arm ( P = .033 ) . CONCLUSION Although impressive differences in median , 3-year , and 4-year survival were observed , they were not statistically significant , except for stage I and II disease In 1989 , we began a multicenter study to evaluate the potential benefit of preoperative chemotherapy with cisplatin , ifosfamide and mitomycin over surgery alone in CT-visible N2 non-small-cell lung cancer . We present here a 7-year assessment of this r and omized trial . Sixty patients were r and omized to receive either surgery alone or three cycles of mitomycin 6 mg/m2 , ifosfamide 3 g/m2 and cisplatin 50 mg/m2 , given intravenously on day 1 of each cycle at 3-week intervals and followed by surgery . All patients received thoracic irradiation after surgery . The resected tumors were evaluated for the presence of K-ras gene point mutations . Treatment arms were well-balanced in characteristics such as gender , age , histology , and tumor size . Mediastinoscopy and /or mediastinotomy ( Chamberlain procedure ) with a biopsy was performed in all patients with N2 stage detected by CT scan of the chest ( 83 % of the patients in the preresectional chemotherapy arm and 63 % of those in the surgery arm ) . In eight of the 25 patients ( 32 % ) who had mediastinoscopy in the preresectional chemotherapy arm , the initially positive mediastinal lymph nodes were downstaged . For the 30 patients who received preresectional chemotherapy , overall median survival was 22 months ( 95 % CI , 13.4 30.6 ) . Of the 30 patients who received surgery alone , overall median survival was 10 months ( 95 % CI , 7.4 - 12.6 ; P = 0.005 by the log rank test ) . Up date d survival data reveals a plateau in the preresectional chemotherapy group , and this still significant long-term survival benefit prompts us to hypothesize that even with short-term preresectional chemotherapy , the natural history of still resectable CT-visible N2 non-small cell lung cancer is favorably altered . The results of our study mirror the long-term survival recently reported in the MD And erson r and omized study The role of neoadjuvant chemotherapy in stage IIIa non-small cell lung cancer remains undefined . Since 1987 , 27 patients with non-small cell lung cancer , all with histologically confirmed metastases to the ipsilateral mediastinal lymph nodes , have been enrolled in an ongoing prospect i ve , r and omized trial at our institution . Thirteen patients have been r and omized to preoperative etoposide-platinum ( EP ) chemotherapy-surgery-postoperative EP , and 14 other patients have been r and omized to surgery-postoperative mediastinal irradiation ( SRT ) .  Both groups are similar in sex , age , weight loss , tumor location , preoperative pulmonary function , physiologic grade , and tumor histology . Eight of the 13 EP patients have responded as evidence d by a 50 % or greater radiographic tumor shrinkage after two cycles . Complete tumor and nodal resection rates were similar : 11/13 EP patients versus 12/14 SRT patients . There was no operative mortality for the 27 patients . Median potential follow-up is 29.9 months for the EP group and 34.9 months for the SRT group . Preliminary results suggest a trend toward increased survival time for the EP group ( median , 28.7 months ) versus the SRT group ( median , 15.6 months ) ( p2 = 0.095 ) . Eleven of 12 resected SRT patients have had recurrence versus 8 of 11 resected EP patients . Time to recurrence reveals no significant differences between the two groups but a trend toward increased disease-free interval in the EP group ( 12.7 months versus 5.8 months , EP versus SRT ) . This interim analysis demonstrates the feasibility of such a trial ; however , despite the trends , definitive conclusions await further accrual and study maturation BACKGROUND Patients with resectable stage IIIA non-small-cell lung cancer have a low survival rate following st and ard surgical treatment . Nonr and omized trials in which induction chemotherapy or a combination of chemotherapy and radiation prior to surgery were used to treat patients with regionally advanced primary cancers have suggested that survival is improved when compared with treatment by surgery alone . PURPOSE We performed a prospect i ve , r and omized study of patients with previously untreated , potentially resectable clinical stage IIIA non-small-cell lung cancer to compare the results of perioperative chemotherapy and surgery with those of surgery alone . METHODS This trial was design ed to test the null hypothesis that the proportion of patients surviving 3 years is 12 % for either treatment group against the alternate hypothesis that the 3-year survival rate would be 12 % in the surgery alone group and 32 % in the perioperative chemotherapy group . The estimated required sample size was 65 patients in each group . The trial was terminated at an early time according to the method of O'Brien and Fleming following a single unplanned interim analysis . The decision to terminate the trial was based on ethical considerations , the magnitude of the treatment effect , and the high degree of statistical significance attained . In total , 60 patients were r and omly assigned between 1987 and 1993 to receive either six cycles of perioperative chemotherapy ( cyclophosphamide , etoposide , and cisplatin ) and surgery ( 28 patients ) or surgery alone ( 32 patients ) . For patients in the former group , tumor measurements were made before each course of chemotherapy and the clinical tumor response was evaluated after three cycles of chemotherapy ; they then underwent surgical resection . Patients who had documented tumor regression after preoperative chemotherapy received three additional cycles of chemotherapy after surgery . RESULTS After three cycles of preoperative chemotherapy , the rate of clinical major response was 35 % . Patients treated with perioperative chemotherapy and surgery had an estimated median survival of 64 months compared with 11 months for patients who had surgery alone ( P < .008 by log-rank test ; P < .018 by Wilcoxon test ) . The estimated 2- and 3-year survival rates were 60 % and 56 % for the perioperative chemotherapy patients and 25 % and 15 % for those who had surgery alone , respectively . CONCLUSIONS In this trial , the treatment strategy using perioperative chemotherapy and surgery was more effective than surgery alone . IMPLICATION S This clinical trial strengthens the validity of using perioperative chemotherapy in the management of patients with resectable stage IIIA non-small-cell lung cancer . Further investigation of the perioperative chemotherapy strategy in earlier stage lung cancer is warranted
INTRODUCTION The survival effectiveness of neoadjuvant chemotherapy in non-small cell lung cancer ( NSCLC ) is still unclear based on the study of most up-to- date literature s. This article contributes to this problem by conducting an up date d meta- analysis .