Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.

PURPOSE: A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non-small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. PATIENTS AND METHODS: Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. RESULTS: Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0-1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P =.0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P =.0003) and complete resection (hazard ratio, 0.26; P =.0006) as strongly prognostic for increased survival. CONCLUSION: Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.     

Accelerated neoadjuvant chemotherapy of non-small cell lung cancer (NSCLC)

Thirty patients with marginally resectable stage IIIA or stage IIIB NSCLC were treated with cisplatin (80 mg/ m(2)/i.v./dl), ifosfamide (4,000 mg/m(2)/i.v./dl) and vinorelbine (30 mg/m(2)/i.v./dl) plus G-CSF 300 mu g/s.c. on days 7-12 every 14 days for three cycles before surgery. In 26 evaluable patients, the radiographically assessed response rate to chemotherapy was 77% (8% complete). Three septic deaths (10%) occurred in spite of G-CSF and 1 patient refused to continue after the first cycle. Thoracothomy was performed in 23 patients including 19 complete resections. At 15 months median follow-up (range 10-22+), 11/19 (57%) completely resected patients relapsed. The overall median time to treatment failure was 11 months (range 0-17). Actuarial survival probability at 12, 18 and 24 months are 56%, 43% and 36%, respectively. In conclusion, the combination of cisplatin, ifosfamide and vinorelbine in full doses at a 14 day interval (accelerated chemotherapy) was very effective in neoadjuvant NSCLC setting. Nevertheless, relevant toxicity was demonstrated with a 10% death rate probably due to the overlapping toxicity of chemotherapy cycles, suggesting the need for a more intense supportive care or longer interval between cycles.     

Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study

The aim was to investigate the efficacy of neoadjuvant docetaxel-cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m-2 (day 1) plus cisplatin 40 or 50 mg m-2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel-cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.     

Post-operative Treatment with Cisplatin and Vinorelbine in Chinese Patients with Non-small Cell Lung Cancer: A Clinical Prospective Analysis of 451 Patients

Purpose: To determine the efficacy of post-operative chemotherapy with cisplatin plus vinorelbine (NP) inChinese patients with non-small cell lung cancer (NSCLC). Methods: A total of 451 patients with NSCLCs atstages I, II, and IIIA after surgical resection were treated with cisplatin plus vinorelbine for 4 cycles or volunteersobserved between January 2002 and November 2004 and were followed for five years. The therapeutic efficacywas evaluated with reference to overall survival (OS) and disease-free survival (DFS), and adverse effects werealso recorded. Potential factors affecting the lengths of OS and DFS were analyzed by multivariate analysis.Results: Most patients (86.7%) completed at least 4 cycles of treatment. Patients with chemotherapy survivedsignificantly longer than those in the observation group (p<0.001). The absolute improvements in the 2 and 5-yearOS were 3.8% [hazard ratio (HR) =0.674, 95% confidence interval (CI): 0.554-0.820, P<0.0001] and 13.0%(HR=0.732, 95% CI: 0.579-0.926, P=0.009), respectively. The improvement at 4-year DFS was 2.1% (HR=0.327,95% CI: 0.214-0.500, P<0.0001). Stratification analysis revealed that older age, histological type, pathologicaldegree, but not the gender and smoking status, are independent factors affecting the length of survival in thispopulation. Many patients (63.3%) had grade 1-III tolerable adverse effects, and there was no treatment-relateddeath. Conclusions: Post-operative chemotherapy with NP regimen is effective and tolerable in Chinese patientswith NSCLC.     

Neoadjuvant nivolumab plus chemotherapy in resectable non-small-cell lung cancer in Japanese patients from CheckMate 816

In the open-label, phase III CheckMate 816 study (NCT02998528), neoadjuvant nivolumab plus chemotherapy demonstrated statistically significant improvements in event-free survival (EFS) and pathological complete response (pCR) versus chemotherapy alone in patients with resectable non-small-cell lung cancer (NSCLC). Here we report efficacy and safety outcomes in the Japanese subpopulation. Patients with stage IB–IIIA, resectable NSCLC were randomized 1:1 to nivolumab plus chemotherapy or chemotherapy alone for three cycles before undergoing definitive surgery within 6 weeks of completing neoadjuvant treatment. The primary end-points (EFS and pCR) and safety were assessed in patients enrolled at 16 centers in Japan. Of the Japanese patients randomized, 93.9% (31/33) in the nivolumab plus chemotherapy arm and 82.9% (29/35) in the chemotherapy arm underwent surgery. At 21.5 months' minimum follow-up, median EFS was 30.6 months (95% confidence interval [CI], 16.8–not reached [NR]) with nivolumab plus chemotherapy versus 19.6 months (95% CI, 8.5–NR) with chemotherapy; hazard ratio, 0.60 (95% CI, 0.30–1.24). The pCR rate was 30.3% (95% CI, 15.6–48.7) versus 5.7% (95% CI, 0.7–19.2), respectively; odds ratio, 7.17 (95% CI, 1.44–35.85). Grade 3/4 treatment-related adverse events were reported in 59.4% versus 42.9% of patients, respectively, with no new safety signals identified. Neoadjuvant nivolumab plus chemotherapy resulted in longer EFS and a higher pCR rate versus chemotherapy alone in Japanese patients, consistent with findings in the global population. These data support nivolumab plus chemotherapy as a neoadjuvant treatment option in Japanese patients with resectable NSCLC.     

Radiotherapy versus chemotherapy plus radiotherapy in surgically treated IIIA N2 non-small-cell lung cancer

Preoperative chemotherapy in patients with stage III non-small-cell lung cancer (NSCLC) remains controversial. Phase II trials utilizing preoperative chemotherapy in selected patients have achieved complete resection rates of 50%-70% with 3-5 year failure-free survival rates of 15%-33%. Between October 1992 and November 1994, 57 adults (50 of whom were evaluable) with surgically staged IIIA NSCLC and pathologically documented ipsilateral mediastinal nodal involvement (N2) were enrolled in a Cancer and Leukemia Group B randomized trial. Preoperative therapy was thought to be critical to facilitating surgical resectability. For patients randomized to the radiotherapy/surgery/radiotherapy (RSR) arm (n = 24), treatment consisted of preoperative radiation therapy (RT) at 40 Gy, surgery, and then additional RT at 14-20 Gy. For patients randomized to the chemotherapy/surgery/chemotherapy/radiotherapy (CSCR) arm (n = 26), treatment consisted of 2 cycles of cisplatin/etoposide with filgrastim support (PE) followed by surgery, 2 more cycles of PE, then RT 54-60 Gy. The total dose of RT on either arm was 54 Gy if completely resected or 60 Gy if incompletely resected or unresected. Clinical characteristics were well balanced between the two arms. Thoracotomy was performed in 42 patients (84%), 28 (67%) of whom had complete resection. The median failure-free and overall survival rates were 12 months (95% confidence interval [CI], 9-23 months) and 23 months (95% CI, 19 months-infinity) for the RSR arm and 11 months (95% CI, 5-20 months) and 18 months (95% CI, 12-32 months) for the CSCR arm. The rates of overall and complete surgical resection, downstaging of nodal involvement, and failure-free (P = 0.92) and overall survival (P = 0.41) did not differ between the two treatment arms. Moreover, in this trial, the chemotherapy regimen was sufficiently toxic to have had a lower completion rate of prescribed therapy in the CSCR arm than in the RSR arm.     

Long term analysis of survival in the European randomized trial comparing vinorelbine/cisplatin to vindesine/cisplatin and vinorelbine alone in advanced non-small cell lung cancer

In the period 1989-1991, 612 patients with inoperable stage IIIA/B and IV non-small cell lung cancer (NSCLC) were randomized in a phase III trial comparing three chemotherapy regimens. Survival data at five and six years of follow-up confirm the overall benefit of treatment with a combination of vinorelbine and cisplatin compared to vindesine plus cisplatin or vinorelbine alone. Of the 612 patients randomized at the start of the study, 17 have survived beyond five years. Of these patients, eight had entered the trial with metastatic disease. Multivariate analysis to detect prognostic factors suggested a possible interaction between the effect of having cisplatin in the chemotherapy received and baseline performance status. Subgroup analysis subsequently confirmed that the survival benefit of the vinorelbine plus chemotherapy regimen is evident only in patients with initial World Health Organization performance status (PS) of 0-1. Among these patients, the one-year survival rate is 38% for the vinorelbine/cisplatin arm, 29% for vindesine/cisplatin and 34% for vinorelbine alone. The corresponding figures for median survival are 43, 33 and 36 weeks. Among inoperable NSCLC patients with a PS of 2, who appear from this trial not to have benefited from the presence of cisplatin in their chemotherapy, use of single agent vinorelbine is an appropriate treatment option.     

Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial

BACKGROUND: Whether adjuvant chemotherapy improves survival of patients with non-small-cell lung cancer (NSCLC) is not known. We aimed to compare the effect of adjuvant vinorelbine plus cisplatin versus observation on survival in patients with completely resected NSCLC. METHODS: 840 patients with stage IB-IIIA NSCLC from 101 centres in 14 countries were randomly assigned to observation (n=433) or to 30 mg/m(2) vinorelbine plus 100 mg/m(2) cisplatin (n=407). Postoperative radiotherapy was not mandatory and was undertaken according to every centre's policy. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN95053737. FINDINGS: 367 patients in the chemotherapy group and 431 in the control group received their assigned treatment. 301 (36%) patients had stage IB disease, 203 (24%) had stage II disease, and 325 (39%) had stage IIIA disease. Tolerance to chemotherapy mainly included neutropenia in 335 (92%) patients and febrile neutropenia in 34 (9%); seven (2%) toxic deaths were also recorded. Compliance was greater with cisplatin than with vinorelbine (median dose intensity 89% [range 17-108] vs 59% [17-100]). After a median follow-up of 76 months (range 43-116), median survival was 65.7 months (95% CI 47.9-88.5) in the chemotherapy group and 43.7 (35.7-52.3) months in the observation group. Adjusted risk for death was significantly reduced in patients assigned chemotherapy compared with controls (hazard ratio 0.80 [95% CI 0.66-0.96]; p=0.017). Overall survival at 5 years with chemotherapy improved by 8.6%, which was maintained at 7 years (8.4%). INTERPRETATION: Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, better defining indication of adjuvant chemotherapy.     

Is trimodality approach better then bimodality in stage IIIA, N2 positive non-small cell lung cancer?

BACKGROUND: Neoadjuvant treatment followed by surgery is currently being investigated for locally advanced non-small cell lung cancer (NSCLC). This study reports efficacy, toxicity and feasibility of neoadjuvant chemotherapy with concurrent radiotherapy (CCRT) in stage IIIA, N2 positive NSCLC. METHODS: From March 2001 to February 2004, 52 patients with histologically confirmed stage IIIA, N2 positive NSCLC were registered. Patients received preoperative CCRT that consisted of weekly paclitaxel plus platinum chemotherapy and concurrent radiotherapy followed by surgery. RESULTS: Overall response rate was 76.9% (95% CI, 64-88%). The major grade 3-4 toxicities were radiation esophagitis (15.4%) and neutropenia (11.5%), and treatment-related mortality rate was 1.9%. Forty-two of 52 patients (80.8%) subsequently underwent surgical resection and 35 of 52 patients (67.3%) underwent complete resection. Among them, pathological complete response was obtained in 4.8%. Pathological downstaging rate to N0-1 and stage 0-II at surgery were 69.0% and 66.7%, respectively. The perioperative major morbidity rate was 23.8% and perioperative mortality was 2.4%. At a median follow-up of 33.9 months (range: 16.4-49.9), the median progression-free survival and overall survival were 16.5 months (95% CI, 6.2-26.8) and 25.6 months (95% CI, 14.6-36.6), respectively. Multivariate analyses identified that patients achieved mediastinal nodal clearance (downstage to pathological N0 or N1) after CCRT (p=0.02) and age at diagnosis<60 years (p=0.01) showed significantly improved survival. CONCLUSION: Neoadjuvant CCRT showed a high overall response rate with tolerable toxicity profile. Downstaging after CCRT may increase the rate of complete tumor resection and result in survival benefit in stage IIIA, N2 positive NSCLC patients.     

Sequential combined modality therapy for stage III non-small cell lung cancer

These pilot trials clearly demonstrate the feasibility of administering neoadjuvant chemotherapy to patients with stage III NSCLC. Response rates in most of these trials reach or exceed 50%, indicating increased activity of chemotherapy in NSCLC when used at an earlier time in the natural history of the disease, as has been shown in other diseases. In addition, histologic confirmation of complete response can occasionally be achieved. Most of the studies reviewed here have included patients with unresectable disease, who would now frequently be classified as stage IIIB. For these patient cohorts the survival data reported are frequently disappointing, suggesting that the high response rates to neoadjuvant chemotherapy do not necessarily translate into improved survival of the patients. On the other hand, where patients with stage IIIA disease were treated and surgery was included in the overall treatment plan, the survival data are more encouraging. Although most chemotherapy regimens have included cisplatin, it is not clear which combination of drugs and which schedules are superior. Clinical research, therefore, clearly needs to continue to focus on the development of innovative drug combinations and the evaluation of new drugs in NSCLC in an attempt to further increase overall and complete response rates to neoadjuvant chemotherapy. At the same time, randomized studies are needed to unequivocally establish whether the addition of neoadjuvant chemotherapy to standard therapy improves survival for stage IIIA and/or stage IIIB NSCLC as compared with standard therapy alone. Results from one such randomized study, which was conducted by the Cancer and Leukemia Group B (CALGB), have recently been reported. One-hundred and eighty patients with unresectable NSCLC were randomized to receive radiotherapy alone or two cycles of cisplatin and vinblastine followed by radiotherapy. One-hundred and fifty-five eligible patients were analyzed for response. Of 77 patients receiving radiotherapy alone, 43% responded, including 16% with a complete response. Of 78 patients receiving neoadjuvant chemotherapy, 56% responded to both treatment modalities, including 19% with complete response. With a median follow-up of 19 months, the median survival was 16.5 months for patients receiving combined modality therapy and 8.5 months for patients receiving radiotherapy alone. The pattern of relapse was identical in both study arms, showing a predominance of local recurrence or of combined local and distant recurrence, whereas few patients experienced distant disease progression alone.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of Neoadjuvant Chemotherapy on Improvement of Surgical Resectibility and Survival of Patients with Stage ⅢA Non Small Cell Lung Cancer

Objective To assess the effect of neoadjuvant chemotherapy on surgical resectibility and surival in patients with stage III A non small cell lung cancer (NSCLC). Methods 42 patients with stage III A NSCLC were randomized to receive either two cycles chemotherapy followed by surgery (neoadjuvant chemotherapy group) or surgery alone (surgery alone group). All patients received four cycles chemotherapy after surgery. Results The overall response to chemotherapy was 42.9% (38.1% partial response and 4.8% complete response). Toxicity of chemotherapy was minor and consisted mainly of gastroenterological side effects and myelosuppression. Patients treated with neoadjuvant chemotherapy had estimated surgical resection rate of 95.2% (n=20) and a complete resection rate in 52.4% (n=11) compared to 66.7% (n=14) and 28.6% (n=6) respectively, for patients with surgery alone (P<0.05). None of the patients died from the operation. The median survival was 24.6 months in the neoadjuvant chemotherapy group as compared to only 10.8 months in the surgery alone group (P<0.05). The 2-year survival rate was 57.1% in the chemotherapy group as compared to 28.6% in the surgery alone group (P<0.05). Conclusion Neoadjuvant chemotherapy improves the surgical resectibility and increases the median survival and 2-year survival rate of patients with stage III A NSCLC. This study was supported by the Jiangsu Provincial Scientific and Technology Committee (BS200376).     

Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer.

BACKGROUND: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. PATIENTS AND METHODS: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m(2), day 1) and vinorelbine (25 mg/m(2) on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m(2), followed by 250 mg/m(2) weekly thereafter). RESULTS: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. CONCLUSION: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone.     

Induction chemotherapy with cisplatin, vinorelbine, and mitomycin-C followed by surgery for patients with pathologic N2 non-small-cell lung cancer

PURPOSE: The treatment strategy for patients with non-small-cell lung cancer (NSCLC) involving ipsilateral mediastinal lymph nodes is still controversial. We performed a phase II feasibility study of induction chemotherapy followed by surgery for patients with pathologic N2 NSCLC. PATIENTS AND METHODS: Patients with mediastinoscopy- positive stage IIIA N2 NSCLC received 2 cycles of cisplatin 80 mg/m2, vinorelbine 25 mg/m2, and mitomycin-C 8 mg/m2. Patients without progressive disease underwent thoracotomy and lobectomy with lymph node dissections 2-4 weeks later. RESULTS: From January 2000 to July 2004, 24 eligible patients (15 men, 9 women) were enrolled. Induction chemotherapy was completed as planned in 23 patients (95.8%). Hematological toxicity was the primary grade 3/4 toxicity. Twelve (50%) patients achieved a partial response. Twenty-three patients underwent surgical resection, and complete resection was achieved in 22 patients (95.7%). There were no surgery-related deaths. Pathologic complete response in metastatic lymph nodes was achieved in 5 patients. With a median follow-up of 5.4 years (range, 2.88-7.7 years), the estimated 5-year survival was 51.8% (95% CI, 41.3-62.3) and progression-free survival was 46.6% (95% CI, 36-57.2). CONCLUSION: Induction chemotherapy followed by surgery for patients with pathologic N2 NSCLC was feasible and associated with high response to lymph node metastasis and good survival.     

Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage III unresectable non-small-cell lung cancer: results of the Toronto Phase II Trial.

PURPOSE: The 5-year survival rates with surgical resection for preoperatively identified stage IIIA N2 non-small-cell lung cancer (NSCLC) are less than 10%. A pilot study of mitomycin, vindesine, and cisplatin (MVP) induction chemotherapy was undertaken in an attempt to improve the curative potential of surgery in this group of patients. PATIENTS AND METHODS: Thirty-nine patients with mediastinoscopy stage IIIA N2 NSCLC received two cycles of MVP. Responding patients underwent thoracotomy for resection and two further courses of MVP. RESULTS: The overall response rate was 64% (25 of 39) with three complete and 22 partial responses. Twenty-two patients were resected, which included a radical mediastinal node dissection. Eighteen resections were complete and four were incomplete. Pathologically, three patients (7.7%) had no tumor remaining. Toxicity included two postoperative deaths secondary to a bronchopleural (BP) fistula, mitomycin pulmonary toxicity in two patients, and septic deaths in four patients. Twenty-eight patients have died; 20 have recurrent or progressive disease. Eight of the 18 patients completely resected have recurred, with a median time to recurrence of 20.6 months. Sites of recurrence include two locoregional, five distant (two in brain), and one in both. Median survival of all 39 patients is 18.6 months, with a 3-year survival of 26%. The median survival for those patients completely resected was 29.7 months with a 3-year survival of 40%. CONCLUSIONS: We conclude (1) that MVP is an effective but toxic chemotherapeutic regimen for limited NSCLC; (2) the median survival seems to be prolonged; and (3) the role of induction chemotherapy followed by surgery in stage IIIA N2 NSCLC requires a phase III randomized trial to compare it with other treatment modalities.     

Paclitaxel/Platinum-based perioperative chemotherapy and surgery in stage IIIA non-small cell lung cancer

OBJECTIVE: The objectives of the present study were to assess the efficacy and tolerability of perioperative paclitaxel/platinum-based chemotherapy and surgery in patients with stage IIIA clinical N2 (cN2) non-small cell lung cancer (NSCLC). METHODS: Clinical N2 was defined as either >15 mm or >10 mm and multiple nodes on computed tomography (CT) scan. Thirty-four chemotherapy-naive patients with stage IIIA cN2 received preoperative paclitaxel/cisplatin for two cycles and then underwent surgery. The treatment with paclitaxel/carboplatin was repeated for three cycles after the operation. RESULTS: Of the 34 patients, none achieved a complete response (CR) and 22 achieved a partial response (PR), resulting in a response rate of 65%. Among 29 patients (85%) who had received thoracotomy, 25 (74%) underwent complete resection. Two pathological CRs were observed and mediastinal nodes were free of tumor in 21%. Grade 3-4 toxicity was uncommon and treatment-related mortality was not observed. The median time to progression (TTP) was 12.1 months [95% confidence interval (CI) 8.3-15.9 months] and median overall survival (OS) was 23.6 months (95% CI 17.7-30.2 months). CONCLUSIONS: Paclitaxel/platinum-based perioperative chemotherapy and surgery for patients with stage IIIA cN2 NSCLC is effective and well tolerated.     

不可切除Ⅲ A(N2)期非小细胞肺癌的术前化疗

目的探讨不能切除的ⅢA（N2）期非小细胞肺癌（NSCLC）的治疗方法。方法1999年1月至2002年12月,76例不可切除ⅢA（N2）期NSCLC患者接受诺维苯（NVB,25mg／m^23,第1,5天）加卡铂（300mg／m^2,第1天）2个周期的化疗,第二周期化疗后3周重新评估能否手术切除。对化疗效果达到部分有效（PR）或完全有效（CR）、估计能完全切除的64例患者行剖胸探查术;对化疗后评价为稳定（SD）和进展（PD）的12例患者行放疗。64例手术患者中,完全切除（肺叶或全肺切除加纵隔淋巴结清扫术,至少达到R3水平）56例,术后继续给予诺维苯加卡铂化疗2个周期;不完全切除8例,另加局部放疗。结果76例不可切除的ⅢA（N2）期NSCLC经诱导化疗后手术或放疗,中位生存期为18．6个月,1,2,3年生存率分别为64．2％、39．4％和25．6％。其中完全切除患者的中位生存期为28．2个月,1,2,3年生存率分别为70．4％、52．5％和38．6％。结论对不可切除的局部晚期NSCLC,如诱导化疗后可以手术,应首选外科治疗。     

A randomized phase II study of docetaxel or vinorelbine in combination with cisplatin against inoperable, chemo-naïve non-small-cell lung cancer in Taiwan

Cisplatin plus a third-generation anti-cancer drug, such as vinorelbine, gemcitabine, or the taxanes, are the standard regimen used in the first-line treatment of advanced non-small-cell lung cancer (NSCLC), and there is no significant difference in efficacy among the different regimens. Our aim was to evaluate the efficacy of docetaxel plus cisplatin (DC) versus vinorelbine plus cisplatin (VC) in chemo-na?ve NSCLC patients. From December 2003 to May 2005, 94 patients were enrolled. The treatment dose was D 60 mg/m2 and C 60 mg/m2 intravenous infusion (IV) on day 1, or V 25 mg/m2 IV on days 1 and 8, and C 60 mg/m2 IV on day 1, every 3 weeks. In all, 209 cycles of DC and 230 cycles of VC were given to the patients in the DC (median five cycles) and VC (median five cycles) arms, respectively. There were 19 partial responses and one complete response (overall 43.5%) in the DC arm, and no complete responses, but 22 partial responses (overall 45.8%), in the VC arm. Myelosuppression was the major toxicity occurring in both arms, with grades 3 or 4 neutropenia occurring in 72.9% and 71.7% of patients, respectively. Except for alopecia (p=0.005) and diarrhea (p<0.001), which were more common in the DC arm, no significant differences in toxicity profiles were found between the two treatment arms. The median time to disease progression was 4.7 months in the DC arm and 6.3 months in the VC arm (p=0.7355). Median survival time was 13 months in the DC arm and 13.8 months in the VC arm (p=0.9656). The 1-year survival rate was 55.5% and 51.7%, respectively. After treatment, the Lung Cancer Symptom Scales showed no significant difference between the two treatment arms. We concluded that both DC and VC are appropriate regimens for use in the first-line treatment of Chinese NSCLC patients. Asthenia, one of the major side effects of docetaxel, was not a major problem in the present study. Although both regimens produced a high incidence of severe neutropenia, the majority of patients recovered rapidly without sequelae; and VC treatment is still a standard chemotherapy for Chinese NSCLC patients in Taiwan.     

A phase III study of surgical resection and paclitaxel/carboplatin chemotherapy with or without adjuvant radiation therapy for resected stage III non-small-cell lung cancer: Cancer and Leukemia Group B 9734

PURPOSE: Patients with completely resected stage IIIA (N2) non-small-cell lung cancer (NSCLC) are at substantial risk for locoregional and systemic recurrence. Adjuvant chemotherapy has recently improved overall control for these patients. We added adjuvant chemotherapy to control presumed micrometastatic disease and then randomized patients to receive radiation therapy (RT) or observation to determine the benefit of local radiation consolidation. PATIENTS AND METHODS: Patient eligibility required histologically documented stage IIIA (radiographically occult N2) NSCLC that was completely resected, with no known residual disease, surgical staging per protocol requirements, Cancer and Leukemia Group B performance status of 0/1, no previous chemotherapy or RT, and minimal laboratory values. All eligible patients received 4 cycles of paclitaxel 200 mg/m2 over 3 hours with carboplatin at an area under the curve of 6 on days 1, 22, 43, and 64 beginning 4-8 weeks after surgery. Two to 4 weeks after chemotherapy, patients were randomized to receive RT as 5000 cGy in 25 fractions over 5 weeks or observation. RESULTS: The study closed after 2 years because of slow accrual. Forty-four patients entered the study; 2 were ineligible, and 5 were not randomized because of progression, adverse reaction, or patient withdrawal. Thirty-seven patients were the basis of this analysis. Median failure-free survival was 16.8 months on the observation arm and 33.7 months on the RT arm, with a 1-year survival rate of 72% on the observation arm and 74% on the RT arm. There were no statistical differences between the observation and RT arms for failure-free survival or overall survival. CONCLUSION: In this small study, consolidation RT after complete resection and adjuvant chemotherapy in stage IIIA NSCLC did not significantly improve outcome for this high-risk population.     

Neoadjuvant chemotherapy with cyclophosphamide, mitoxantrone, and 5-fluorouracil in locally advanced breast cancer

OBJECTIVES: Our primary objective was to determine the response rate; secondary objectives were to assess the toxicity rate, and disease-free and overall survival rates in patients with locally advanced breast cancer (LABC) receiving a cyclophosphamide (500 mg/m2), mitoxantrone (12 mg/m2) and 5-fluorouracil (500 mg/m2) (CMF) chemotherapy regimen. PATIENTS AND METHODS: The data from 74 patients with LABC with neoadjuvant CMF chemotherapy were analyzed retrospectively. Preoperatively, all patients received 3 cycles of CMF on day 1, repeated every 21 days. In 3 (4.1%) patients, breast-conserving surgery was given and in 71 (95.9%) modified radical mastectomy. All patients received radiotherapy and 3 additional cycles of CMF chemotherapy after surgery. RESULTS: Median age of the patients was 47 years (range: 17-74). 43 patients were premenopausal, whereas 31 were postmenopausal. 54 patients were in stage IIIA, and 20 were in stage IIIB. The overall clinical response rate was 88%; 11 (14.9%) had a complete response, 54 (73%) had a partial response, and 2 (2.8%) had progression. 14 (18.9%) had a pathological complete response. The median follow-up was 62 months. The median disease-free survival was 64.9 months, and the median overall survival was 97.5 months. The 5-year disease-free and overall survival rates were 52% and 79.9%, respectively. Most frequent side-effects were nausea/vomiting, mucositis, alopecia and leukopenia. CONCLUSION: The CMF regimen has a high overall response rate and an acceptable side effect profile in the treatment of locally advanced breast cancer. Further studies are needed to evaluate its effectiveness in breast-conserving strategies.     

A 3-week schedule of gemcitabine plus cisplatin as induction chemotherapy for Stage III non-small cell lung cancer

BACKGROUND: Our aim was to explore the activity and feasibility of gemcitabine plus cisplatin as induction chemotherapy in patients with Stage IIIA N(2) and selected IIIB non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From September 1997 to July 2000, 70 chemonaive patients with Stage III NSCLC, median age of 64 years, World Health Organization performance status 0, 1, or 2, and the ability to tolerate a pneumonectomy entered the study and received gemcitabine 1250 mg/m(2) on days 1 and 8 and cisplatin 70 mg/m(2) on day 2 every 3 weeks. After three cycles of induction chemotherapy, patients underwent resection or radiotherapy. RESULTS: Responses were seen in 40 of the 69 assessable patients, for an intent-to treat overall response rate of 57.1% (95% confidence interval, 45-62%), with 4.2% complete response. Response rates were 68 and 35% in patients with Stage IIIA and IIIB disease, respectively. The overall pathological CR rate after induction chemotherapy was 3%, with an overall pathological downstaging rate of 20%. Median survival for all patients was 14.5 months, with an estimated 1-year survival rate of 67% (95% CI, 54.3-79.5%). The estimated time to treatment failure was 12.6 months. Grade 3/4 thrombocytopenia was the main hematologic toxicity, occurring in 26% of patients, but was not associated with life-threatening bleeding. Febrile neutropenia was rare and other severe non-hematologic toxicities were uncommon. CONCLUSIONS: The 3-week schedule of gemcitabine plus cisplatin is highly active as induction chemotherapy in Stage IIIA N(2) unresectable NSCLC. This suggests a need for a multimodality approach upfront, such as concurrent chemoradiation therapy, particularly in patients with Stage IIIB disease.