Stage IIIB Non-small Cell Lung Research Articles

P-606 Neoadjuvant chemo- and radiotherapy for stage IIIB non-small cell lung cancer (NSCLC). A prospective multicenter trial by the Swiss group for clinical cancer research (SAKK)

P-606 Neoadjuvant chemo- and radiotherapy for stage IIIB non-small cell lung cancer (NSCLC). A prospective multicenter trial by the Swiss group for clinical cancer research (SAKK)

P-248 Induction chemoradiotherapy and surgical resection for selected stage IIIB non-small cell lung cancer

P-248 Induction chemoradiotherapy and surgical resection for selected stage IIIB non-small cell lung cancer

P-236 Induction chemotherapy (CT) with gemcitabine (G), paclitaxel (T), and cisplatin (P) and subsequent radiotherapy (TRT) with concomitant G for stage IIIB non-small cell lung cancer (NSCLC): results of a multicenter phase II study

P-236 Induction chemotherapy (CT) with gemcitabine (G), paclitaxel (T), and cisplatin (P) and subsequent radiotherapy (TRT) with concomitant G for stage IIIB non-small cell lung cancer (NSCLC): results of a multicenter phase II study

Guidelines on Treatment of Stage IIIB Non-small Cell Lung Cancer

Stage IIIB includes patients with T4, any N, M0, and any T, N3, M0. Surgery may be indicated only for carefully selected T4N0M0 patients with or without neoadjuvant chemotherapy or chemoradiotherapy. Patients with N3 lymph node involvement are not considered as surgical candidates. For patients with unresectable disease, good performance score, and minimal weight loss, treatment with combined chemotherapy and radiotherapy has resulted in better survival than treatment with radiotherapy alone. Multiple daily fractions of radiotherapy have not resulted in improved survival compared with standard fractionation once daily. Concurrent chemoradiotherapy appears to be associated with improved survival compared with sequential chemotherapy and radiotherapy. Treatment of stage IIIB due to malignant pleural effusion is addressed in the section that deals with stage IV disease.

Venous thromboembolism among patients with advanced lung cancer randomized to prinomastat or placebo, plus chemotherapy

Two clinical trials have suggested that the combination of vascular endothelial growth factor inhibitor with chemotherapy is associated with venous thromboembolism (VTE). This retrospective cohort study investigates whether a similar association exists when matrix metalloproteinase inhibitor (prinomastat) is combined with chemotherapy. Patients (n=1,023) with stage IIIB, IV, or recurrent non-small cell lung cancer (NSCLC) were followed during 2 randomized, double-blind trials of prinomastat versus placebo orally bid, plus gemcitabine/cisplatin (GC) or paclitaxel/carboplatin (PC). VTE included deep venous thrombosis (DVT) or pulmonary embolism (PE) confirmed by imaging or autopsy. Risks identified in univariate analysis (incidence densities compared by t test) were confirmed in multivariate analysis (proportional hazards model). During 7,500.3 patient-months, 58 VTE (31 PE, 27 isolated DVT) were confirmed in 54 patients. On univariate analysis, VTE was associated with central venous catheter placed within 3 months, 15 mg prinomastat plus GC, and to a lesser extent, 15 mg prinomastat plus PC, baseline performance status, and histologic type. VTE incidence was not increased by 15 mg prinomastat alone (post-discontinuation of chemotherapy), by chemotherapy plus placebo, or by 5 or 10 mg prinomastat plus chemotherapy. On multivariate analysis,VTE hazards (95% confidence interval) were 5.69 (2.61, 12.40) with recently placed central catheter, 2.78 (1.42, 5.43) with 15 mg prinomastat plus GC, and 2.06 (0.98, 4.31) with 15 mg prinomastat plus PC; performance status and histology were nonsignificant. We can conclude that combined treatment with 15 mg prinomastat plus chemotherapy approximately doubles the hazard of VTE among patients with advanced NSCLC.

Neoadjuvant therapy in non-small cell lung cancer. Prognostic impact of "mediastinal downstaging"

In the course of a prospective multicenter study, 40 (26 squamous cell and 14 adenocarcinomas) patients with stage IIIA and IIIB non-small cell lung cancer (NSCLC) were submitted to surgery after neoadjuvant radiochemotherapy. Pretherapeutic clinical lymph node status was compared to the lymph node involvement established in the resection specimens. Therapy-induced tumor regression was classified according to a three-step tumor regression grading system. In 29 patients (72.5%) a downward shift in lymph node involvement could be established,whereas in 27.5% ( n=11) pretherapeutic lymph node status was maintained. Of 26 patients with post-therapeutic N0 or N1 status, 21 revealed less than 10% vital tumor tissue in the resection specimens (regression grades IIb or III). Patients with post-therapeutic N0 or N1 lymph node status were found to have a survival benefit compared to patients with N2 lymph node involvement, though this difference was not statistically significant (p=0.27). On the other hand, tumor regression showed a significant correlation to the overall survival period (p=0.02). Thus, therapy-induced tumor regression grading seems to be a more precise method to predict the outcome of the disease.

Escalated hyperfractionated accelerated radiation therapy combined with chemotherapy for stage IIIB non-small cell lung cancer

To evaluate the therapeutic effect and acute side-effect of escalated hyperfractionated accelerated radiation therapy (EHART) combined with chemotherapy for stage IIIB non-small cell lung cancer (NSCLC). From Aug. 1998 to Aug. 2001, a prospective trial for NSCLC was carried out in 112 patients with stage IIIB. These patients were nonrandomly divided into 2 groups: conventional fractionated radiation therapy group (CFRT 65 cases) and EHART group (47 cases). The CFRT patients were treated by 1.8-2 Gy/fraction per day, 5 treatment days per week; the total doses received in center of tumor were 54-70 Gy /27-40 fractions/37-85 days, the median was 60 Gy/30 factions/43 days. The EHART patients were treated by escalated doses: In the first and second weeks, 1.2 Gy/fraction twice a day was given, then 1.3 Gy , 1.4 Gy , and 1.5 Gy from third to fifth weeks respectively, twice fractions a day (over 6 hours interval), 5 treatment days each week, the total doses were 60-66 Gy/46-50 fractions/30-45 days, the median was 66 Gy /50 fractions/34 days. Radiation fields just covered the tumor mass which were determined by thoracic CT with 1.5 cm margins. A total of 4-6 cycles chemotherapy with MVP regimen mostly was delivered before (1-2 cycles) and after (3-5 cycles) radiotherapy. Each patient was followed up for 1 year. Seven cases were excluded from EHART, twelve from CFRT. There were 93 patients to be evaluated. The immediate response rate of tumor by EHART and CFRT was 72.5% and 64.2% respectively (Chi-square=1.02, P=0.346). The 1-year survival rate was 60.0% and 47.2% respectively (Chi-square=2.56, P=0.107), and the local control rate was 67.5% and 52.8% respectively (Chi-square=3.01, P=0.085). The incidence and degree of acute radiation esophagitis in EHART were more severe than that in CFRT (Chi-square=5.02, P=0.025). The treatment effect by EHART for stage IIIB NSCLC is encouraging and its toxicities could be tolerated by most of patients. It is worthy of further study on survival rate and late complications in long term.

91 A comparison of intensity modulated and three dimensional conformal radiotherapy plans in RTOG 93-11 patients with stage IIIB non-small Cell Lung cancer

91 A comparison of intensity modulated and three dimensional conformal radiotherapy plans in RTOG 93-11 patients with stage IIIB non-small Cell Lung cancer

Concurrent administration of Docetaxel and Stealth® liposomal doxorubicin with radiotherapy in non-small cell lung cancer : excellent tolerance using subcutaneous amifostine for cytoprotection

The substantial augmentation of the radiation sequelae during chemo–radiotherapy with novel drugs masks the real potential of such regimens. In this study we examined whether subcutaneous administration of amifostine can reduce the toxicity of a highly aggressive chemo–radiotherapy scheme with Stealth® liposomal doxorubicin (Caelyx®) and Docetaxel (Taxotere®) in non-small cell lung cancer. Twenty-five patients with stage IIIb non-small cell lung cancer were recruited in a phase I/II dose escalation trial. The starting dose of Taxotere® was 20 mg m−2 week and of Caelyx® was 15 mg m−2 every two weeks, during conventionally fractionated radiotherapy (total dose of 64 Gy). The dose of Taxotere®/Caelyx® was, thereafter, increased to 20/25 (five patients) and 30/25 mg m−2 (15 patients). Amifostine 500 mg was given subcutaneously before each radiotherapy fraction, while an i.v. amifostine dose of 1000 mg preceded the infusion of docetaxel. The ‘in-field’ radiation toxicity was low. Grade 3 esophagitis occurred in 9 out of 25 (36%) patients. Apart from a marked reduction of the lymphocyte counts, the regimen was deprived from any haematological toxicity higher than grade 1. No other systemic toxicity was noted. The CR and CR/PR rates in 15 patients treated at the highest dose level was 40% (6 out of 15) and 87% (13 out of 15) respectively. It is concluded that the subcutaneous administration of amifostine during high dose Taxotere®/Caelyx® chemo–radiotherapy is a simple and effective way to render this aggressive regimen perfectly well tolerated, by reducing the systemic and the ‘in-field’ toxicity to the levels expected from simple conventional radiotherapy. The impressive tolerance and the high CR rate obtained encourages the conduct of a relevant randomized trial to assess an eventual survival benefit in patients with non-small cell lung cancer.British Journal of Cancer (2002) 87, 385–392. doi:10.1038/sj.bjc.6600486 www.bjcancer.com© 2002 Cancer Research UK

Dose-intensified accelerated vindesine–ifosfamide–cisplatin (VIP) chemotherapy followed by high-dose accelerated hyperfractionated radiotherapy in patients with pathologically proven stage IIIB non-small cell lung cancer: a feasibility study

This study shows the feasibility of accelerated vindesine–ifosfamide–cisplatin chemotherapy, immediately followed by intensive radiotherapy to the residual tumour in responding patients, in 16 patients with pathologically proven stage IIIB non-small lung cancer. All toxicities were reversible, with only two of ten patients experiencing grade 3 oesophagitis, no treatment-related deaths and no serious late effects.

Surgery as part of combined modality treatment in stage IIIB non-small cell lung cancer

Background. The role of surgery after neoadjuvant chemotherapy in patients with stage IIIB non-small cell lung cancer (NSCLC) remains unclear. Methods. A prospective multicenter trial of neoadjuvant chemotherapy followed by surgery or radiotherapy or both was conducted with 41 patients with stage IIIB NSCLC. End points were toxicity, response, downstaging, complete resectability, and survival. The diagnostic value of repeat mediastinoscopy after neoadjuvant chemotherapy (three courses of gemcitabine/cisplatin) was also studied. Results. Response rate after neoadjuvant chemotherapy was 66% (27 of 41). Fifteen patients underwent repeat mediastinoscopy, which proved to be inadequate in 6 patients. Two repeat mediastinoscopies were false negative. Resection was performed in 18 patients, of which 10 proved to be radical. Hospital mortality was 2.4% (n = 1). Major complications occurred in 6 patients (fistula, empyema, hemorrhage). Histopathologically proven downstaging was seen in 16 patients (39%). Twenty-five patients underwent radiotherapy of whom 14 were diagnosed with stable/progressive disease and 9 with partial/complete response. Median survival for all patients was 15.1 months, for nonresponders 8.4 months and for responders 16.8 months ( p = 0.11). Patients with partial/complete response had a mean survival of 21.5 months after resection and 13.0 months after radiotherapy ( p = 0.0003). Conclusions. Radical surgery can be performed in 37% (10 of 27) of the responders resulting in a prolonged survival. Surgery as part of combined modality treatment is feasible in stage IIIB NSCLC. Results of a repeat mediastinoscopy are disappointing and proved to be a not-so-effective restaging tool because of the high number of incomplete procedures and because it yields false negative results.

Is lung cancer surgery justified in patients with direct mediastinal invasion?

To assess the results of the surgical treatment of patients with stage IIIB non-small cell lung carcinoma (NSCLC) invading the mediastinum (T4). Twenty-nine patients were operated on from 1986 to 1999. Histology was squamous cell carcinoma in 17 patients, adenocarcinoma in eight, large cell carcinoma in two and neuroendocrinal carcinoma in two. Three patients received a preoperative chemotherapy (n = 2) or radiochemotherapy (n = 1). The lung resection consisted of a pneumonectomy in 25 patients and a lobectomy in four. The procedure was extended to one of the following structures: superior vena cava (SVC) (n = 17), aorta (n = 1), left atrium (n = 5) and carina (n = 6). Seventeen patients had a postoperative regimen including radiochemotherapy (n = 12), radiotherapy (n = 4), or chemotherapy (n = 1). Complete R0 resection was achieved in 25 patients, whereas four patients had a microscopically (n = 1) or macroscopically (n = 3) residual disease. The operative mortality rate was 7% (n = 2). Non-fatal major complications occurred in eight patients (28%). Overall 5-year survival rate was 28% (median 11 months), including the operative mortality. The median survival of the 18 patients with an N0 or N1 disease was 16 months whereas the median survival of the 11 patients with an N2 disease was 9 months. At completion of the study, 22 patients have died, two postoperatively and 10 from pulmonary causes without evidence of cancer. Surgical management of T4 NSC lung cancer invading the mediastinum should be considered, in the absence of N2 disease, when a complete resection is achievable.

A phase II trial of preoperative chemoradiotherapy using uft in clinical stage IIIb non-small cell lung cancer

A phase II trial of preoperative chemoradiotherapy using uft in clinical stage IIIb non-small cell lung cancer

Pathologic stage IIIb non-small cell lung cancer (NSCLC): Prolonged survival with consoloidation Docetaxel following concurrent chemoradiotherapy (SWOG 9504)

Pathologic stage IIIb non-small cell lung cancer (NSCLC): Prolonged survival with consoloidation Docetaxel following concurrent chemoradiotherapy (SWOG 9504)

Curative radiation therapy after VIP, a cisplatin-based chemotherapy, in stage IIIB non-small cell lung cancer (NSCLC): A phase II study

Curative radiation therapy after VIP, a cisplatin-based chemotherapy, in stage IIIB non-small cell lung cancer (NSCLC): A phase II study

Definitive concurrent chemoradiotherapy for stage IIIB non-small cell lung cancer

Definitive concurrent chemoradiotherapy for stage IIIB non-small cell lung cancer

Vindesine with cyclophosphamide-epirubicin-cisplatin in the treatment locally advanced non-small cell lung cancer

Objective: To evaluate the addition of vindesine to a cyclophosphamide-epirubicin-cisplatin (CAP) regimen for treating the patients with locally advanced non-small cell lung cancer (NSCLC). Methods: From May 1994 to August 1998, 59 previously untreated patients with stage IIIa and IIIb non-small cell lung cancer were enrolled into this trial. Patients characteristics were the following: the median age was 52 years; the median performance status was 1; there were 19 stage IIIa and 40 stage IIIb; there were 47 adenocarcinoma, 10 squamous cell carcinoma and 2 large cell carcinoma. All patients were treated with vindesine (2 mg/m2, on day 1 and day 8), cyclophosphamide (0.6/m2, on day 1), epirubicin (40 mg/m2, on day 1) and cisplatin (60 mg/m2, on day 1) every 3 or 4 weeks. Results: Four achieved a complete response (6.8%), 29 achieved a partial response (49.2%), 15 had stable disease, and 10 had progressive disease. A clinical improvement was in 45 of 59 patients (76.3%). The most frequent major toxic effects were myelosuppression, nausea and vomiting. Conclusion: The vindesine with CAP regimen was active combination chemotherapy in patients with locally advanced NSCLC accompanied by the limited side effects.

Neoadjuvant Etoposide, Ifosfamide, and Cisplatin Followed by Concomitant Thoracic Radiotherapy and Continuous Cisplatin Infusion in Stage IIIb Non-small Cell Lung Cancer

To determine the applicability and safety of an ifosfamide, cisplatin, and etoposide (VIP) regimen as a neoadjuvant chemotherapy to a concomitant thoracic radiotherapy and cisplatin continuous infusion in locally advanced non-small cell lung cancer (NSCLC). Forty-four patients (stage IIIb in 43 and stage IIIa in 1) entered a study of VIP, followed by concomitant thoracic radiotherapy and cisplatin continuous infusion. Chemotherapy consisted of three courses of cisplatin 25 mg/m2, ifosfamide 1.5 g/m2 (with uroprotection), and etoposide 100 mg/m2 given on days 1 to 4 of a 21-day cycle with hematopoietic support using recombinant human methionyl granulocyte colony stimulating factor. Patients who achieved a response or a stabilization were planned to receive a split-course normofractionated thoracic radiotherapy (first course: 30 Gy/10; 4-week rest period; second course: 25 Gy/10). A continuous cisplatin infusion of 6 mg/m2 daily was administered using an autonomous chemotherapy delivery device. Total plasma platinum titration was performed daily during the two courses in five of the patients. Analyses were done on an intent-to-treat basis. Thirty-nine of the 44 patients received the three-cycle chemotherapy program. Received dose intensity was 82%. Thirty-eight patients received the radiotherapy and, among them, 35 received the complete concomitant continuous cisplatin infusion. Objective (complete) response rates were 48% (7%) at the end of chemotherapy and increased up to 61% (16%) by the end of radiotherapy. At the end of the first radiotherapy cycle, the mean total plasma platinum concentration was twice as high as that of the residual postinduction chemotherapy concentration. During induction chemotherapy, myelosuppression was the limiting toxicity requiring hospital readmission in 23 patients. During radiotherapy, the main toxicity was acute esophagitis. A relatively high rate of pulmonary fibrosis was observed using the subjective objective management analytic--late effects of normal tissue score without life-threatening pulmonary function impairment. None of the patients died from toxic reactions. Probability of survival at 1, 2, and 3 years was 49%, 19%, and 5%, respectively. Primary cause of failure was a local relapse in 63% of the patients, brain metastases in 24%, and hematogeneous metastases to other sites in 13%. Neoadjuvant VIP followed by concomitant radiotherapy-chemotherapy is feasible, but the split-course radiotherapy did not prevent a high rate of local recurrences. The high rate of toxic reactions requiring hospital readmission limits further development of such an aggressive regimen in NSCLC.

Sequential treatment with vindesine–ifosfamide–platinum (VIP) chemotherapy followed by platinum sensitized radiotherapy in stage IIIB non-small cell lung cancer: A phase II trial

Purpose: Daily administration of cisplatin concomitant with radiotherapy improved the overall survival in inoperable non-small cell lung cancer (NSCLC) in one EORTC study. In this study, we prospectively investigated the efficacy and toxicity of a sequential treatment with three cycles of vindesine–ifosfamide–platinum (VIP) induction chemotherapy, followed by daily cisplatin-sensitized radiotherapy. Methods: Between June 1993 and June 1995, 23 previously untreated patients with stage IIIB NSCLC with World Health Organization performance status 0 or 1 were included. Chemotherapy consisted of platinum 30 mg/m 2 and ifosfamide 1200 mg/m 2 i.v. on days 1, 2 and 3, and vindesine 3 mg/m 2 i.v. on days 1 and 8, every 4 weeks. After three cycles and at least stable disease, radiotherapy was started (30 Gy in 10 fractions, followed by a boost of 22 Gy in 10 fractions). Each fraction was preceded by Platinum 6 mg/m 2 i.v. Results: Nineteen patients completed the sequential therapy. One patient died from neutropenic sepsis during the first cycle of chemotherapy, and three patients had progressive disease after chemotherapy. The overall response rate after sequential therapy was 47% (95% confidence interval 24–80), median survival was 10.6 months, 1- and 2-year survival rates were 47 and 16%, respectively. Major toxicity consisted of neurotoxicity grade III–IV in 18% and of leukopenia grade III–IV in 22% of the patients. Acute radiation pneumonitis grade III occurred in 11% of the patients. Conclusion: Three-drug VIP induction chemotherapy followed by cisplatin-sensitized radiotherapy is feasible, with acceptable, albeit substantial, toxicity. In spite of the theoretically promising sequence of therapies, survival results remain disappointingly low.

Vinorelbine (VNR)-cisplatin (C) combination neoadjuvant chemotherapy in stage IIIB non-small cell lung cancer (NSCLC): results after 2 years

Vinorelbine (VNR)-cisplatin (C) combination neoadjuvant chemotherapy in stage IIIB non-small cell lung cancer (NSCLC): results after 2 years