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Data from adjuvant trials clearly indicate that one of the most important problems in patients with resected non-small-cell lung cancer (NSCLC) is compliance to chemotherapy. In the postoperative setting, significant comorbidities and incomplete recovery after surgery often make it difficult for patients to tolerate or comply with systemic therapy. Therefore, it may be preferable to deliver chemotherapy before surgery as "neoadjuvant" or "induction" chemotherapy. The rationale for using induction chemotherapy is based on evidence that chemotherapy might reduce tumor burden and possess activity against micrometastases, resulting in improved results by surgery, radiotherapy, or a combination. Moreover, induction therapy facilitates in vivo assessment of tumor response or resistance. Potential drawbacks include the risk of perioperative complications, and the possibility that the tumor mass may become unresectable due to disease progression. During the past decade, four phase III randomized trials evaluated the role of induction chemotherapy in stage IIIA NSCLC. The first three studies consistently showed that induction chemotherapy improves survival compared with surgery alone. More recently, a large phase III trial performed by French investigators suggested a survival benefit in stage I/II patients, but not stage IIIA. The high activity of new platinum-based chemotherapy--based on response rate and 1-year survival in advanced disease--reinforces the rationale for the use of these new combinations in early-stage NSCLC, especially for a subset of patients traditionally treated with surgery alone. Several phase III trials are currently evaluating the role of new doublets as induction chemotherapy; these are discussed in the article. The results of these ongoing phase III trials should help clarify the role of induction chemotherapy in early-stage disease.

Purpose: Our objective was to determine the activity in terms of response rate, surgical resectability, and the tolerability of the new three-drug combination gemcitabine-cisplatin-paclitaxel (GCP) in unresectable stage IIIA(N2) and IIIB non-small cell lung cancer (NSCLC)., Patient and Methods: Forty-two chemo-naive patients with stage IIIA(N2)-IIIB NSCLC, median age of 59 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and the ability to tolerate pneumectomy, received gemcitabine (Gem) 1000 mg/m(2) IV days 1 and 8, cisplatin (CDDP) 50 mg/m(2) IV days 1 and 8, paclitaxel 125 mg/m(2) 1h infusion IV days 1 and 8, every 21 days for 3 cycles. After induction chemotherapy, patients were evaluated for surgery or definitive radiotherapy., Results: Grade 3-4 neutropenia was the main hematologic toxicity, occurring in 28% of patients. Grade 3-4 thrombocytopenia was observed in only 11% of cases. No neutropenic fever or bleeding episodes were recorded. Severe non-hematologic toxicity was uncommon. Thirty (71%, 95% CI: 57.2-84.7%) of the 42 eligible patients had objective responses (1 complete and 29 partial responses). After induction chemotherapy, 21 patients (50%) went to surgery. Complete resection was obtained in 16 patients (38%). Viable tumor was present in 18 of 21 resection specimens. In three cases only necrotic tumor cells were identified, for a pathological complete response of 7%. With a median follow-up of 13.9 months, median time to progression was 17.4 months, median survival 21.7 months and estimated 1-year survival 92%., Conclusions: GCP combination is active and well tolerated in locally-advanced, non-resectable NSCLC. The activity profile, in terms of response and surgical resection rate, is comparable to that obtained with standard doublets.

Background: Surgery is the primary treatment for patients with stage I, II, or IIIA non-small-cell lung cancer (NSCLC). However, long-term survival of NSCLC patients after surgery alone is largely unsatisfactory, and the role of adjuvant chemotherapy in patient survival has not yet been established., Methods: Between January 1994 and January 1999, 1209 patients with stage I, II, or IIIA NSCLC were randomly assigned to receive mitomycin C (8 mg/m2 on day 1), vindesine (3 mg/m2 on days 1 and 8), and cisplatin (100 mg/m2 on day 1) every 3 weeks for three cycles (MVP group; n = 606) or no treatment (control group; n = 603) after complete resection. Randomization was stratified by investigational center, tumor size, lymph-node involvement, and the intention to perform radiotherapy. The primary endpoint was overall survival and secondary endpoints were progression-free survival and toxicity associated with adjuvant treatment. Survival curves were analyzed using the log-rank test. All statistical tests were two-sided., Results: After a median follow-up time of 64.5 months, there was no statistically significant difference between the two patient groups in overall survival (hazard ratio = 0.96, 95% confidence interval = 0.81 to 1.13; P =.589) or progression-free survival (hazard ratio = 0.89, 95% confidence interval = 0.76 to 1.03; P =.128). Only 69% of patients received the three planned cycles of MVP. Grades 3 and 4 neutropenia occurred in 16% and 12%, respectively, of patients in the MVP arm. Radiotherapy was completed by 65% of patients in the MVP arm and by 82% of patients in the control group. In the multivariable analysis, only disease stage and sex were associated with survival., Conclusion: This randomized trial failed to prospectively confirm a statistically significant role for adjuvant chemotherapy in completely resected NSCLC. Given the poor compliance with the MVP regimen used in this study, future studies should explore more effective treatments.

A significant number of small cell lung carcinomas shows overexpression of the proto-oncogene c-kit product, a tyrosine kinase known as Kit or CD117. This molecular pathway seems somewhat implicated in promoting the neoplastic growth of small cell lung carcinoma. The current pharmacological availability of its selective inhibitor, together with the promising clinical results in the management of CD117-positive neoplasms such as advanced gastrointestinal stromal tumors, aroused great interest among oncologists in also adopting this therapeutic strategy in other CD117-positive tumors. We evaluated a series of 27 small cell lung carcinomas, comparing the expression of CD117 of the primary naïve tumor (before first-line chemotherapy) with the expression of the same neoplasm after postchemotherapy relapse. All the patients underwent similar chemotherapeutic regimens (cisplatin/carboplatin plus etoposide). At diagnosis, 21 of 27 cases (78%) showed strong immunoreactivity for CD117. Among these 21 originally positive tumors, CD117 remained overexpressed in 10 after relapse (48%), whereas the other 11 cases became negative. No originally CD117-negative small cell carcinomas displayed immunoreactivity after chemotherapy. CD117 expression was not statistically correlated with overall survival, occurrence of chemoresistance, or clinical response to chemotherapy. We also evaluated CD117 expression in a series of 46 surgically resected non-small cell lung carcinomas (8 squamous cell carcinomas, 10 adenocarcinomas, 5 pleomorphic carcinomas, 10 typical and 3 atypical carcinoids, and 10 large cell neuroendocrine carcinomas). Apart from small cell carcinomas, CD117 overexpression was observed in 6 of 10 large cell neuroendocrine carcinomas, whereas all the other histotypes resulted unstained. We speculate that loss of CD117 expression after chemotherapy in a high proportion of SCLC indicates that in this tumor, Kit unlikely represents the product of a constitutive mutation, as instead shown in gastrointestinal stromal tumors. Keeping this finding in mind, oncologists could re-test CD117 expression in relapsing small cell lung carcinomas in order to establish the best candidates for enrollment in ongoing clinical trials with Kit inhibitors. Practically speaking, CD117 may be helpful in discriminating between pulmonary high-grade neuroendocrine tumors and other histotypes, but pathologists should be aware that treated small cell lung carcinomas may remain unstained in a not insignificant number of cases.

Purpose: We report four cases of Brain Metastases (BM) from non-small cell lung cancer (NSCLC) responding to ZD 1839 therapy after standard therapy failure., Patients and Methods: Four patients with BM from NSCLC, pretreated with two or more lines of chemotherapy, received ZD 1839 (Iressa), on a compassionate use basis, at the daily dose of 250 mg until disease progression. Three patients received Iressa after whole brain radiotherapy (WBRT) failure., Results: After 3 months of ZD 1839 therapy, one patient had complete response on the brain with stabilization of extracranial disease, while the other three patients had partial response both on the brain and on extracranial sites. At the time of this analysis, two patients discontinued the treatment after 5 and 7 months for disease progression, while two patients are still on treatment with no evidence of treatment failure after 3+ and 12+ months. ZD 1839 was generally well tolerated, with skin toxicity recorded in two patients., Conclusion: ZD 1839 may be effective in NSCLC patients with pretreated BM. Large and prospective trials need to clarify the role of ZD 1839 in the treatment of BM from NSCLC.

Background: The objective of this trial was to evaluate the activity and safety of one of the newer platinum-based doublets as a neoadjuvant regimen in patients with unresectable Stage IIIA-bulky N2 and Stage IIIB nonsmall cell lung carcinoma (NSCLC)., Methods: From June 1996 to April 2000, 129 consecutive patients with locally advanced NSCLC were treated with gemcitabine, 1000 mg/m(2) on Days 1 and 8 and cisplatin, 70 mg/m(2) on Day 2 (GC) of a 21-day treatment cycle, for 4 cycles, as part of a combined-modality approach., Results: After induction chemotherapy, 80 patients (62%; 95% confidence interval, 53.6-70.4%) achieved a partial response, 43 patients (33%) had stable disease, and 6 patients (5%) had disease progression during chemotherapy. Forty patients (31%), were considered resectable and underwent thoracotomy. Complete resectability was obtained in 38 patients (29%), with 2% of patients achieving a pathologic complete response. After surgery, 9 patients with Mountain Classification Stage IIIA NSCLC and 9 patients with Stage IIIB NSCLC received definitive adjuvant radiotherapy. Forty-six of 52 patients with Stage IIIB disease and 24 of 37 patients with Stage IIIA disease who were not considered suitable for surgery received definitive radiotherapy. The median time to disease progression was 11.4 months, the median survival was 19.4 months (range, 1.2-55.2 + months), and the 1-year survival rate was 74%. The lungs (33%) and the brain (21%) were the main sites of recurrence. Major toxicity was comprised of Grade 3-4 thrombocytopenia, which occurred in 34 patients (27%)., Conclusions: GC administered according to a 3-week schedule was a highly active and safe regimen in patients with primary, unresectable, locally advanced NSCLC., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11460)

Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. The identification and implementation of predictive genetic markers of response-specific cytotoxic drugs is a priority of current research and future trials. In this study, we have used quantitative PCR to analyse expression of beta-tubulin III, stathmin, RRM1, COX-2 and GSTP1 in mRNA isolated from paraffin-embedded tumor biopsies of 75 nonsmall-cell lung cancer patients treated as part of a large randomized trial. In total, 22 patients were treated with gemcitabine/cisplatin, 25 with vinorelbine/cisplatin and 28 with paclitaxel/carboplatin. There were no differences in clinical characteristics and transcript levels in the pretreatment biopsies according to treatment arm. Patients with low beta-tubulin III levels had better response in the paclitaxel/carboplatin arm (P=0.05), and those with low RRM1 levels showed a tendency to better response in the gemcitabine/cisplatin arm. Time to progression was influenced by beta-tubulin III (P=0.03) and stathmin (P=0.05) levels in the vinorelbine/cisplatin arm, and there was a tendency toward correlation between beta-tubulin III levels and time to progression in the paclitaxel/carboplatin arm. RRM1 levels influenced time to progression (P=0.05) and even more so, survival (P=0.0028) in the gemcitabine/cisplatin arm. The predictive value of beta-tubulin III, stathmin and RRM1 should be tested in prospective customized chemotherapy trials, the results of which will help tailor chemotherapy to improve patient survival.

Lung cancer is the leading cause of cancer death in the world. Therapeutic improvements caused by recent cytotoxic agents seem to have reached a plateau. New therapeutic strategies are, therefore, necessary to improve the cure rate. These include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, cyclooxygenase-2 (COX-2) inhibitors, gene therapy and vaccines. The antiepidermal growth factor receptor (EGFR) group includes compounds acting on the extracellular domain of EGFR, such as IMC-C225 and trastuzumab; small molecules inhibiting EGFR phosphorylation, such as ZD 1839 and OSI-774; or compounds that interfere with one of the downstream steps, such as mitogen-activated protein kinase kinase (MEK) inhibitors. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumour activity. Antiangiogenesis inhibitors include matrix metalloprotease inhibitors (MMPIs), suchs as marimastat, AG3340, BAY 12-9566, BMS-275291 and Col-3. Antiangiogenic agents offer great potential for the treatment of lung cancer, as shown in preclinical models, whereas emerging data suggest that there are limits to their use as monotherapy in advanced disease. Molecules targeting vascular endothelial growth factor (VEGF) or its receptor (VEGFR) also seem to control tumour progression and may prolong survival. COX-2 inhibitors are another class of agents currently under evaluation in clinical trials for their chemoprevention role in subjects at high lung cancer risk, and also in patients with non-small cell lung cancer (NSCLC) in combination with standard chemotherapeutics. Genetic and immunologic therapies represent two additional promising modalities. All of these therapies are in different phases of clinical testing and have shown encouraging activity alone or in combination with chemotherapy drugs.

Lung cancer accounts for about 28% of all cancer-related deaths. Non-small cell lung cancer (NSCLC) constitutes 80% of all lung cancer cases, and in 70% of patients, the disease is diagnosed when it is locally advanced or metastatic. In these situations, chemotherapy has played only a minor role in modifying the natural history according to a 1995 meta-analysis. New drugs such as gemcitabine, vinorelbine, and the taxanes have been combined with cisplatin and tested in several phase-II and phase-III clinical trials versus cisplatin alone and different cisplatin/new drug combinations. Overall, the data seem to confirm that, despite a possible increase in response rate, no major difference in long-term survival has been achieved. Moreover, toxicity and cost may be significant with some of the combinations and schedules. While the combination of cisplatin and gemcitabine seems to be fairly active and better tolerated, we all look forward to the results of ongoing studies on the association of these regimens with the new biological drugs., (Copyright 2002 Elsevier Science Ireland Ltd.)

Background: Small cell lung cancer (SCLC) is a chemoresponsive tumor but overall survival remains poor even in limited disease (LD). With the aim of eradicating chemoresistant tumor cells and reducing toxicity, we investigated in this phase II trial the feasibility and outcome of a sequential approach of induction chemotherapy (CT) followed, in responding patients with LD-SCLC, by intensified platinum-based CT and concurrent thoracic irradiation (TI)., Materials and Methods: We treated 55 consecutive LD-SCLC patients with three 21-day cycles of cyclophosphamide, epiadriamycin and vincristine (CEV) as induction CT. In 44 (80%) patients there was an objective response and they received treatment intensification consisting of TI and concomitant CT with carboplatin and etoposide plus recombinant granulocite colony stimulating factor. Twenty-five (57%) patients were submitted to twice-daily thoracic irradiation (TDTI; 1.5 Gy per fraction, to a total dose of 45 Gy) and 19 (43%) to once-daily thoracic irradiation (ODTI; 2 Gy per fraction, to a total dose of 50 Gy)., Results: Median follow up was 75 months (range, 42-102). Of 44 patients submitted to intensification with TI plus CT, 32 (73%) had a complete and 12 (27%) a partial response. Median overall survival of all 55 patients was 17 months with actuarial survival probabilities of 2 and 5 years, 32 and 25%, respectively. Analysis of patient sub-groups showed a 5-month median survival in non-responders, 19 in TDTI and 17 in ODTI patients, respectively. Two and 5 year survival probabilities were 0% in non-responders, 40 and 35% in TDTI and 39 and 21% in ODTI patients, respectively. At present, 13 of 44 responders are still alive, of which nine (20%) have been progression-free from 45 to 93 months (median 60). Treatment failure was registered in 31 (70%) of 44 patients who received both induction and intensification treatment. One-half of patients had intrathoracic recurrence, eight of which only local and the remaining seven local and distant. Fourteen (32%) patients had brain metastases. Grade 3-4 neutropenia occurred in 24 (55%) patients with no differences between treatment groups. Grade 3 esophagitis was registered in four (9%) patients: in 3/25 (12%) and 1/19 (5%) of those who received TDTI and ODTI, respectively (P=not significant). Acute radiation pneumonitis occurred in three (12%) patients submitted to TDTI. No clinically debilitating pulmonary fibrosis, permanent esophageal stricture or toxic death was observed., Conclusions: In LD-SCLC patients late concurrent CT plus TI is feasible and effective. Our long-term results are similar to the best reported in the literature. Despite the high incidence of complete response obtained, however, one-half of the patients had intrathoracic relapse and one-third brain metastases.

Gemcitabine is considered to be one of the most active drugs in the treatment of non-small cell lung cancer (NSCLC). When used as a single agent, gemcitabine yielded response rates consistently > 20%, with a uniformly good tolerance profile. Preclinical data indicated synergism between gemcitabine and platinum compounds, such as cisplatin or carboplatin. The gemcitabine-cisplatin combination is considered one of the reference regimens for advanced NSCLC and the recommended schedule is gemcitabine 1000 - 1250 mg/m(2) on days 1 - 8 and cisplatin 70 - 80 mg/m(2) on days 1 or 2. In order to avoid many of the non-haematological toxicities associated with cisplatin, several trials evaluated the gemcitabine-carboplatin combination. Previous trials using the 28-day schedule showed unacceptable haematological toxicity. Recent studies demonstrated the activity and feasibility of gemcitabine-carboplatin combination using a 21-day schedule, with carboplatin administered on day 1 and gemcitabine on days 1 and 8. Gemcitabine can be combined with one of the other new agents, such as the taxanes or vinorelbine, to create novel non-platinum-doublets. Although encouraging, the available data are still conflicting and non-platinum-based combinations are not indicated outside clinical trials. Three-drug combinations increased toxicity and failed to demonstrate any advantage over standard doublets in advanced NSCLC. Gemcitabine is active and well tolerated in elderly patients and represents a reasonable therapeutic option. Although no Phase III trials have been conducted to compare gemcitabine to the best supportive care or docetaxel in pretreated NSCLC, gemcitabine alone or in combination with vinorelbine or one of the taxanes can be considered a valid option for second-line treatment in patients who had a previous response or who achieved stable disease with a platinum-containing regimen. Gemcitabine is considered the most radiopotentiating agent available amongst the newer agents we have in terms of activity and toxicity, but the routine use of gemcitabine in combination with radical thoracic radiotherapy, although promising, is not yet recommended. Further testing of gemcitabine-based combinations with concurrent radiation is underway.

Platinum-based chemotherapy is considered the standard treatment for advanced non-small cell lung cancer (NSCLC). Several phase II trials using cisplatin in combination with new chemotherapeutic agents, such as gemcitabine, the taxanes, vinorelbine, and irinotecan, showed impressive response rates and suggested an improvement in overall survival. Large phase III trials comparing these second-generation cisplatin regimens indicated a substantial equivalence of new combinations, marginally improving the outcome of patients over the first-generation platinum-based regimens. Phase III trials have not yet shown dramatic advantages for either multiple-drug regimens, with nonoverlapping mechanisms of action and toxicity, or nonplatinum doublets, with efficacy and/or toxicity profiles superior to those of platinum-based chemotherapy. Chemotherapy in advanced non-small cell lung cancer has reached a plateau, and it is clear that new approaches are required. These should include prevention, screening, and early detection, and the use of novel treatments based on our understanding of the biology and molecular biology of this disease., (Copyright 2002, Elsevier Science (USA). All rights reserved.)