State-of-the art treatment of locally advanced and metastatic non-small cell lung cancer

Despite the poor mortality figures from lung cancer, advances have been observed in the treatment of advanced (stages IIIB and IV) non-small cell lung cancer (NSCLC). In the first instance, such advances have been achieved thanks to chemotherapy (CT) consisting of platinum-based compounds (results demonstrated in several phase III studies) and then thanks to newer cytotoxic agents such as gemcitabine. Used as monotherapy, gemcitabine provides a marked benefit compared to the standard treatment consisting of etoposide/cisplatin (EC) (21% objective response, 39% survival at 1 year). A good efficacy profile of this agent in combination with platinum analogs was also observed in randomized phase III studies, confirming the significant higher survival obtained with the gemcitabine/cisplatin (GC) combination (in GC versus C protocols and that comparing four doublets of CT). Results observed with G without platinum analogs are comparable to those of treatment with a platinum agent. Other studies conducted with triplets of CT need to be confirmed. Newer non-cytotoxic agents have also been studied: the anti-vascular endothelial growth factor monoclonal antibody with or without CT may prolong survival; docetaxel improves overall survival outcomes compared to palliative therapy. In locally advanced stages, advances have been made possible by radiochemotherapy (RT/CT): several phase II and phase III studies using EC and RT have been conducted. Lastly, in induction treatments, CT appears to provide improvement.     

Neoadjuvant chemotherapy in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a systemic illness. More than half of those patients who present with stage I-IIIA disease and are resected will experience distant relapse. Postoperative adjuvant chemotherapy has been evaluated in several randomized trials but the results of these trials have been inconclusive with increased survival reported in few trials. In resectable stage IIIA NSCLC the findings of three randomized trials have indicated that the survival of these patients is better with neoadjuvant chemotherapy plus surgical resection than with resection alone. Phase II trials using preoperative concurrent chemoradiotherapy have been carried out with encouraging results. The majority of patients with stage IIIA NSCLC require multimodality therapy if they are to achieve a 5-year survival. Combined modality treatment in locally advanced NSCLC continues to evolve and is a subject of ongoing research. One focus for present research is to integrate new active agents into the neoadjuvant setting. Another challenge is to find better treatment approaches in earlier stages of disease. Some data suggest that induction chemotherapy in stage I-II is feasible, does not appear to compromise surgery and yields high response rates. A further aim is to use molecular biological markers of malignancy to identify patients at highest risk of metastatic relapse.     

Role of gemcitabine in the treatment of advanced non-small cell lung cancer: review of the main phase II and phase III trials

Marked advances in the treatment of non-small cell lung cancer (NSCLC) have been made thanks to new agents. Among these agents, gemcitabine appears to be a major compound in advanced stage NSCLC chemotherapy. To start with, several phase III trials (conducted in Europe and in the USA) studied the gemcitabine/cisplatin combination (GC): US study protocois compared GC to cisplatin alone, to the standard treatment (etoposide/cisplatin) or to platinum/taxane doublets; in these studies, as a result of treatment with GC, a higher survival rate was observed. A study conducted in Italy, which is undergoing analysis, observes GC versus paclitaxel/carboplatin versus cisplatin/vinorelbine. In addition, in newer clinical protocols, it was observed that gemcitabine combined with taxanes or with vinorelbine demonstrated efficacy at least equal to that of combinations with platinum analogs. Newer agents acting on epithelial growth factor are also undergoing evaluation.     

Neoadjuvant strategies in the treatment of non-small cell lung cancer

The prognosis of patients with resectable non-small cell lung cancer (NSCLC), other than stage IA disease, remains disappointing, with 5 year survival rates ranging from 40-55%. For the past 15-20 years, several phase II trials have investigated the efficacy of chemotherapy and chemoradiotherapy prior to surgery in the management of stage IIIA NSCLC, with encouraging results. Phase III trials comparing surgery alone with chemotherapy plus surgery have confirmed the efficacy of this multimodality approach. Gemcitabine, one of the new agents with significant activity against NSCLC, has undergone extensive clinical testing in combination with cisplatin in this setting. In 47 patients with stage IIIA disease, induction with gemcitabine/cisplatin was well tolerated and yielded a response rate of >70%. Downstaging of the mediastinal lymph nodes occurred in 53% of patients. Preliminary data from another study employing mitomycin C, ifosfamide and cisplatin in resectable NSCLC suggest that there are favourable effects of induction treatment, especially in early-stage disease. With the availability of chemotherapeutic combinations such as gemcitabine/cisplatin, which are both effective and well tolerated, combination therapy is likely to become a major advance in the treatment of patients with early-stage (IB, II) NSCLC.     

Real life adjuvant chemotherapy uptake and survival in patients with non-small cell lung cancer after complete resection

Objectives: Adjuvant chemotherapy (AC) in non-small cell lung cancer (NSCLC) has become a standard of care in patients with stages IIA, IIB, and IIIA after complete tumor resection. Utilization and outcome of AC in routine practice is described in a few studies, with non-conclusive results.

Materials and methods: This retrospective study included consecutive patients with NSCLC who underwent curative-intent surgery. Data of AC uptake in stages IB (tumor of ≥4?cm in diameter), II, and IIIA, and reasons of AC omission were evaluated according to medical records. Mortality risk among patients treated with surgery (only) and different types of AC in routine practice was compared.

Results: AC was applied to 79% of patients with stages IB (tumor of ≥4?cm in diameter), II, and IIIA, and was associated with an improved median of overall survival (HR?=?0.69; 95% CI?=?0.44–1.06). Significantly longer survival was achieved in the sub-group treated with platinum and oral vinorelbine (HR?=?0.575, 95% CI?=?0.339–0.974), and the longest survival was among patients treated with oral vinorelbine and cisplatin (HR?=?0.371, 95% CI?=?0.168–0.820).

Conclusions: AC utilization should be based on co-operation between surgeons, pneumo-oncologists, and patients. Rational use of AC offers better survival in routine practice.     

Adjuvant chemotherapy for non-small cell lung cancer: a New Zealand perspective

This article reviews recent developments with the use of adjuvant chemotherapy for resected early-stage non-small cell lung cancer (NSCLC) and the implications of these developments for healthcare in New Zealand (NZ). Non-small cell lung cancer is a major cause of mortality and morbidity in NZ, and is greatly over-represented among Maori and socioeconomically deprived populations. Early-stage NSCLC is potentially curable by surgery, but long-term outcome after surgical resection is limited by disease recurrence locally or at sites distant from the primary disease. Three recent large randomised controlled phase III trials using modern platinum-based combination chemotherapy protocols have shown significant survival benefits for the use of postoperative adjuvant chemotherapy after resection of early-stage NSCLC. Cisplatin plus vinorelbine was used as the adjuvant chemotherapy regimen in two of these trials resulting in improvements in 5-year survival of 51.2% versus 42.6% (p=0.013) and 69% versus 54% (p=0.03), respectively. In NZ, adjuvant chemotherapy for NSCLC is expected to prevent up to 15 lung cancer deaths each year for relatively low drug expenditure and has the potential to benefit Maori and the economically-deprived disproportionately more than other populations. In conclusion, it is the opinion of this group of NZ lung cancer specialists that adjuvant chemotherapy with cisplatin plus vinorelbine should now be adopted as a standard of care for patients with resected stage II and III NSCLC. For this to occur, current PHARMAC policies preventing its use for these eligible patients will need to be revised.     

Docetaxel (taxotere) in the treatment of non-small cell lung cancer

Docetaxel is a new semi-synthetic anticancer agent derived from bacatin III of the needles of the European yew Taxus baccata. Docetaxel has a novel mechanism of action since it binds to tubulin inducing its polymerization and promoting stable microtubule formation. Several differences exist between docetaxel and paclitaxel: (i) broader activity of docetaxel against freshly explanted human tumors than paclitaxel; (ii) a 2-fold higher affinity than paclitaxel; (iii) 2.5-fold more potent than paclitaxel as an inhibitor of cell replication and (iv) docetaxel acts at the S-phase whereas paclitaxel at the G(2)/M phases of the cell cycle. Preclinical and phase II studies revealed that docetaxel is active against NSCLC. In chemotherapy-na ve patients with NSCLC response rates ranged from 19% to 54% with a median duration of survival ranging from 6.3 months to 11 months, and 1-year survival ranging from 21% to 71%. Docetaxel as single agent provided a survival as well as a clinical benefit over BSC in untreated patients with NSCLC. Docetaxel has been efficiently combined with cisplatin (ORR 33%-46%), carboplatin (ORR 30%-48%), vinorelbine (ORR 20%-51%), gemcitabine (ORR 37%-47%), with a median survival ranging from 5-14 months. A preliminary analysis of a multicenter randomized trial comparing docetaxel/CDDP with docetaxel/gemcitabine revealed that the two regimens had comparable activity in terms, of response rates, duration of response, TTP and overall survival; however, the docetaxel/gemcitabine combination has a most favourable toxicity profile compared to docetaxel/CDDP. Docetaxel has also demonstrated radiosensitizing properties and encouraging results have been achieved in combination with irradiation. Finally, docetaxel has shown an important activity in previously-treated patients with NSCLC with ORR ranging from 16% to 25% with a median survival ranging from 7.2 months to 10.5 months. Randomized trials revealed that second-line docetaxel confers a survival benefit over either BSC or ifosfamide/vinorelbine in pretreated patients with NSCLC.     

Randomized clinical trial of adenosine 5'-triphosphate on tumor growth and survival in advanced lung cancer patients

We recently reported that regular infusions of adenosine 5'-triphosphate (ATP) inhibited loss of body weight and quality of life in patients with non-small cell lung cancer (NSCLC). In the present paper we investigated whether ATP affects tumor growth and survival in the same group of patients. Fifty-eight NSCLC patients (stage IIIB or IV) were randomly assigned to receive either 10 i.v. 30-h ATP infusions every 2-4 weeks over a 24-week period (n = 28) or no ATP (control patients, n = 30). ATP was given for a median of 6.5 infusions. Differences in time to progression and survival between patients in both groups were tested by means of the log-rank test and Cox regression analysis. Forty-nine patients were evaluable for tumor response. None of the evaluable patients showed a complete or partial response. Median time to progression was 3.9 months [95% confidence interval (CI) = 2.3-5.5] in the ATP group compared to 3.0 months (95% CI = 2.4-3.7) in the control group (p = 0.71). Median survival was 5.6 months (95% CI = 1.1-10.1) for the ATP group and 4.7 months (95% CI = 2.6-6.8) for the control group (p = 0.68). ATP treatment was associated with a significant increase in survival in the subgroup of weight-losing patients with stage IIIB NSCLC: in this subgroup, median survival was 9.3 months (95% CI = 2.1-16.5) for ATP-treated patients versus 3.5 months (95% CI = 2.3-4.7) for control patients (between-group difference: p = 0.009). No significant effect of ATP was observed for weight-losing patients with stage IV NSCLC or for weight-stable NSCLC patients. Although ATP as a single therapy does not lead to tumor regression or increased survival in patients with advanced lung cancer, it may prolong survival in weight-losing patients with stage IIIB lung cancer. The latter finding is intriguing, but requires confirmation in larger clinical trials.     

Neoadjuvant chemotherapy with gemcitabine and cisplatin in stage IIIA/B non-small cell lung cancer

Purpose. We studied cisplatin plusgemcitabine as induction (neoadjuvant)therapy in patients with stage IIInon-small cell lung cancer (NSCLC) toassess its objective remission rate,resectability, survival, and toxicity. Patients and methods. Patients with stageIII NSCLC received 2 cycles of gemcitabine1250 mg/m² on days 1, 8, and 15,plus cisplatin 100 mg/m² on day 2.Subsequently, patients were assigned tolocal therapy – surgery or radiotherapy. Results. Twenty-nine eligiblepatients (male/female: 21/8) with a medianage of 59 years (range, 43–71 years) wereenrolled between October 1996 and February1999. A total of 80 cycles were given,with a median of 3 per patient (range, 1–4cycles). Overall, toxicities were mild;only one patient had febrile neutropenia,and there were no grade 4 non-hematologicaltoxicities. There was one toxic deathfollowing afebrile grade 4 neutropenia.Overall clinical response rate (2 completeresponses [CRs] + 16 partial responses[PRs]) was 62% (95% CI, 45%–79%);10 patients had stable disease and noneprogressed; one patient was not evaluable.Eight of the 18 operated patients hadpathological response: 1 CR and 7downstagings to N(–); 14 patients wereresected. Median survival was 17 months(95% CI, 13–21 months), with 1-year and2-year actuarial survival rates of 61%and 29%, respectively. Conclusions. Gemcitabine pluscisplatin is a very active andwell-tolerated induction regimen in stageIII NSCLC. Comparative studies with otherstandard regimens are warranted.     

Phase II study of S-1 monotherapy as a first-line treatment for elderly patients with advanced nonsmall-cell lung cancer: the Central Japan Lung Study Group trial 0404

Although S-1 has been shown to have activity against advanced nonsmall-cell lung cancer (NSCLC), its efficacy for elderly patients remains unclear. This phase II study evaluated the efficacy and safety of S-1 as a first-line treatment for elderly patients. Chemotherapy-na?ve patients aged 70 years or older with stages IIIB to IV or postoperative NSCLC and performance status 1 or lower were eligible. Patients received S-1 approximately equivalent to 80 mg/m/day for 2 weeks followed by a 1-week rest period every 3 weeks. The primary end point was the response rate. Secondary end points were toxicity, disease control rate, progression-free survival, and overall survival. Twenty-nine patients were eligible. The median age was 78 years (range, 70-85 years). The overall response rate and the disease control rate were 27.6 [95% confidence interval (CI), 11.3-43.9%] and 65.5% (95% CI: 48.2-82.8%), respectively. The median progression-free survival time was 4.0 months (95% CI: 4.0-9.8 months). The median overall survival was 12.1 months (95% CI: 13.8-25.5 months) and the 1-year survival rate was 53.6%. No grade 4 toxicities were observed. The only hematological toxicity of grade 3 was anemia in 6.9% of patients. The grade 3 nonhematological toxicities included hyponatremia, anorexia, nausea, oral mucositis, and diarrhea in 3.4% of patients and infection in 6.9% of patients. S-1 monotherapy was effective and well tolerated as a first-line treatment for elderly patients with advanced NSCLC. The results of this study warrant further investigations of this regimen, including a randomized controlled trial.     

评估吉非替尼交替化疗对比化疗治疗Ⅳ期非小细胞肺癌的疗效及安全性

目的:比较吉非替尼交替化疗与单纯化疗在Ⅳ期非小细胞肺癌(Non-small cell lung cancer,NSCLC)患者治疗中的疗效和安全性。方法:回顾分析2013年9月-2014年9月Ⅳ期表皮生长因子受体(Epidermal growth factor receptor, EGFR)突变阳性NSCLC患者病历59例,依治疗方案分为2组:对照组(n=30):培美曲塞 (500 mg·m^-2,iv,d1),顺铂 (75 mg·m^-2,iv,d1),21 d为1个周期,治疗4~6个周期;观察组(n=29):化疗方案同对照组,加用吉非替尼(250 mg,po,d2~15),比较2组的客观缓解率(ORR)、疾病控制率(DCR)、中位无进展生存期(PFS)及药物不良反应(ADR)。结果:观察组和对照组的ORR分别为51.7%、16.7%(P=0.004),DCR分别为93.1%和86.7%(P=0.413),中位PFS分别为15.5个月和8.0个月(P=0.001);观察组外显子19 LREA缺失的患者疗效及耐受性优于21 L858R突变的患者,患者突变位点不同,ADR临床表现存在较大差异,严重ADR的发生率为13.79%。结论:吉非替尼交替化疗较单纯化疗对EGFR突变阳性的Ⅳ期NSCLC患者的疗效更好,其中对外显子19 LREA 缺失疗效最优。     

Neoadjuvant therapy for non-small cell lung cancer

Clinical trials evaluating neoadjuvant or preoperative therapy for locally advanced non-small cell lung cancer (NSCLC) have demonstrated the feasibility, tolerability and activity of this approach. Three randomized trials have reported improved survival in patients with stage III NSCLC treated with preoperative chemotherapy followed by surgical resection compared to surgery alone. Combinations of neoadjuvant chemotherapy plus thoracic radiotherapy have also been investigated, generally resulting in higher rates of pathologic response, but higher toxicity rates as well. The best approach to neoadjuvant therapy remains to be determined and may well be substage dependent. In bulky stage III NSCLC, the role of surgery itself remains unclear and is the subject of an ongoing intergroup trial in the US. Regardless, neoadjuvant therapy has emerged as an important paradigm for clinical research since it serves as an in vivo test of chemosensitivity in patients, and represents a 'window of opportunity' for testing new chemotherapeutic agents and novel strategies. Among the new chemotherapeutic agents being investigated in this setting is docetaxel, one of the most active agents in first- and second-line chemotherapy of NSCLC, and a potent radiosensitizer. Preliminary studies have confirmed the feasibility of integrating docetaxel into neoadjuvant treatment strategies and encouraging results have been reported.     

The role of tegafur/uracil in pulmonary malignancy

Tegafur/uracil (UFT) is an oral fluorinated pyrimidine composed of a combination of uracil and tegafur in a 4:1 molar ratio. When given on a continuous basis, it yields a fluorouracil area under the concentration-time curve identical to that achieved with isomolar concentrations of fluorouracil administered by continuous infusion. Its 8.7% response rate in advanced non-small cell lung cancer (NSCLC) is modest, but it has demonstrated synergy with cisplatin in human solid tumour xenografts. In combination with cisplatin in patients with advanced NSCLC, response rates of 29 to 43% were observed with acceptable toxicity. Researchers in Japan have demonstrated the utility of this agent as adjuvant therapy after surgical resection, either alone or in combination with cisplatin and vindesine versus observation; long term survival rates exceed 60%, compared with 49% for the control group. Efforts in the US will assess the role of this agent as non-cross-resistant consolidation therapy after a plateau in response has been obtained with platinum-based therapy in advanced disease. They will also recapitulate the Japanese studies, assessing their utility as adjuvant therapy in NSCLC patients who have undergone resection. Finally, ongoing phase I studies are combining this agent with paclitaxel and other systemic agents.     

Gastro-oesophageal malignancy in New Zealand: 1995-97

AIM: To assess the incidence, treatment and survival of patients with oesophago-gastric carcinoma in New Zealand. METHODS: All cases of oesophageal or gastric carcinoma diagnosed in 1995-97 were retrieved from the national cancer registry. Linked data describing all episodes of inpatient treatment for these patients were obtained from the New Zealand Health Information System. An analysis of demographics, treatment and survival was performed. RESULTS: A total of 1791 cases were recorded (616 oesophageal, 1175 gastric). Carcinomas of the gastrooesophageal junction made up the majority of cases. 1138 were male. The median age was 71 years. 78.6% were of European descent, 10.4% Maori, 3.6% Pacific Islanders and 7.4% of other ethnic backgrounds. There were a total of 3403 hospital admissions (median 1.0 per patient). Overall, 29% underwent a surgical resection (15% oesophageal, 36% gastric). Exploratory surgery alone was performed in 14% operated on for oesophageal cancer and 12.3% for gastric neoplasms. Following resection 90 day mortality was 11.8% (10.5% oesophageal, 12% gastric). Overall median survival was 6.3 months (5.8 months oesophageal, 6.6 months gastric) with 16.7% of patients alive at three years. Following resection median survival was 17.8 months ( 16.2 months oesophageal, 18.1 months gastric) with 35.8% of patients alive at three years (34.7% oesophageal, 36% gastric). CONCLUSIONS: These data provide a baseline for future studies of the evaluation and treatment of gastrooesophageal malignancy in New Zealand.     

Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer

Our objective was to evaluate gefitinib (IRESSA), an epidermal growth factor receptor tyrosine kinase inhibitor, versus docetaxel as second-line monotherapy for advanced non-small-cell lung cancer (NSCLC). SIGN (Second-line Indication of Gefitinib in NSCLC; code 1839IL/0503) was a multicenter, randomized, parallel-group, open-label, phase II trial that investigated oral gefitinib (250 mg/day) or i.v. docetaxel (75 mg/m2 every 3 weeks) in patients with advanced NSCLC who had previously received one chemotherapy regimen. The primary objective was assessment of symptom improvement (using the FACT-L Lung Cancer Subscale). Secondary objectives included quality of life (FACT-L total score), response rate (using RECIST), overall survival and safety. This trial recruited 141 patients (68 to gefitinib and 73 to docetaxel) who received treatment for a median duration of 3.0 (gefitinib) and 2.8 (docetaxel) months. Similar efficacy was observed with gefitinib and docetaxel, 36.8 and 26.0% symptom improvement rates, 33.8 and 26.0% quality-of-life improvement rates, 13.2 and 13.7% objective response rates, and 7.5 and 7.1 months median overall survival, respectively. Fewer drug-related adverse events were observed with gefitinib compared with docetaxel (all grades: 51.5 versus 78.9%; Common Toxicity Criteria grade 3/4: 8.8 versus 25.4%). There were no withdrawals or deaths due to drug-related adverse events with gefitinib, while three patients withdrew and three died due to adverse events in the docetaxel group that were possibly drug related. We conclude efficacy with gefitinib was similar to docetaxel, but with a more favorable tolerability profile, in the second-line treatment of advanced NSCLC. These results support further investigation of gefitinib in this disease setting.     

Combined treatment in advanced stages (IIIb-IV) of non-small cell lung cancer

Chemotherapy regimens based on platinum represent the reference standards in Non-Small Cell Lung Cancer (NSCLC) and when it is associated with radiotherapy and/or surgery (combined treatment) it improves survival of patients. Aim of this study was to estimate the efficacy of chemotherapy, based on high-dose epirubicin plus cisplatin, associated with surgery and/or radiotherapy. Twenty-four inoperable NSCLC patients (15 pts in stage IIIb and 9 in stage IV) were treated with epirubicin (120 mg/m2) plus cisplatin (60 mg/m2), every three weeks for at least 3 cycles up to a maximum of 6. A total of 109 treatment cycles (epirubicin plus cisplatin) were administered and two of 24 patients achieved full response (CR), 9 showed partial response (PR), for an overall response rate of 45.8%, 8 patients (33.4%) achieved stable disease (SD) and 5 (20.8%) progressive disease (PD). Leukopenia aroses in 81.9% of the cycles, anaemia in 36.6% and thrombocytopenia in 14%. After chemotherapy, nausea/vomiting was present in 33.3% of patients, while in a small number of cases there were also mucositis, diarrhea, fever, phlebitis, transaminase increase and electrocardiographic anomalies. Upon entry, at the end of therapy patients underwent restaging (CT, bronchoscopy, bone scintiscan) to evaluate the possibility of surgical resection; 15 out of 24 patients completed treatment with radiotherapy (40-60 Gy) and then were re-evaluated for surgery. Five patients underwent complete surgical resection of the neoplasia (4 after chemotherapy and one after radiotherapy). After 1 year survival was 66.6% for all patients. Combined treatment in advanced NSCLC showed a good response and survival after 1 year.     

Gefitinib in non-small cell lung cancer

Gefitinib (Iressa), an orally-active tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is the first approved molecular-targeted drug for the management of patients with advanced non-small cell lung cancer (NSCLC). Two Phase II trials (IDEAL [Iressa Dose Evaluation in Advanced Lung Cancer]-1 and -2), evaluated the efficacy of gefitinib in advanced NSCLC patients who received < or = 2 (IDEAL1) or > or = 2 (IDEAL2) previous chemotherapy regimens. The response rate and disease control rate in IDEAL1 and -2 was 18/12% and 54/42%, respectively. The median survival time and one-year survival rate in both studies were approximately 7 months and 30%, respectively. As gefitinib has demonstrated antitumour activity and an acceptable tolerability profile not typically associated with cytotoxic adverse events, such as hematological toxicities, combinations with cytotoxic drugs have been evaluated. Disappointingly, in chemotherapy-naive patients with advanced NSCLC, gefitinib 250 and 500 mg/day combined with platinum-based chemotherapy (gemcitabine/cisplatin or paclitaxel/carboplatin) did not produce prolonged survival, compared with chemotherapy alone in two large, randomised, placebo-controlled, multi-centre Phase III trials (INTACT [Iressa NSCLC Trial Assessing Combination Treatment]-1 and -2). Furthermore, in a recent randomised, placebo-controlled, Phase III trial (ISEL: IRESSA Survival Evaluation in Lung cancer), gefitinib failed to prolong survival compared with placebo in patients with advanced NSCLC who had failed one or more lines of chemotherapy. Subgroup analysis of ISEL suggested improved survival in patients of Asian origin and non-smokers. In addition, subset analyses of IDEAL and several retrospective studies have indicated that female gender, adenocarcinoma histology (especially bronchial alveolar carcinoma), non-smoker status and Asian ethnicity are factors which predict to response to gefitinib. Two types of somatic mutation clustered around the ATP binding pocket in the tyrosine kinase domain of the EGFR gene have been reported as possible surrogate biological markers for predicting response to gefitinib. Appropriate patient selection by clinical characteristics or genetical information is needed, both for future clinical trials of gefitinib and its routine use in the clinic among patients with advanced NSCLC.     

Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis

Vandetanib (ZD6474; ZACTIMA, AstraZeneca) is a once-daily, orally available agent with potential for use in a number of solid tumor types. Vandetanib targets key signaling pathways in cancer by inhibiting VEGFR-dependent tumor angiogenesis, and EGFR- and RET-dependent tumor cell proliferation and survival. Phase I studies showed vandetanib to be generally well tolerated at doses of < or = 300 mg/day, with a pharmacokinetic profile that supports once-daily oral administration. Phase II evaluation of vandetanib in patients with advanced refractory NSCLC has demonstrated improvements in progression-free survival both as monotherapy (versus gefitinib) and in combination with docetaxel (versus docetaxel alone). These positive outcomes have led to the initiation of Phase III trials of vandetanib in advanced NSCLC. Clinical development is also ongoing in other tumor types and encouraging evidence of antitumor activity has been reported in patients with metastatic hereditary medullary thyroid cancer.     

Gefitinib in non-small cell lung cancer

Gefitinib (Iressa^TM), an orally-active tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is the first approved molecular-targeted drug for the management of patients with advanced non-small cell lung cancer (NSCLC). Two Phase II trials (IDEAL [Iressa Dose Evaluation in Advanced Lung Cancer]-1 and -2), evaluated the efficacy of gefitinib in advanced NSCLC patients who received ≤ 2 (IDEAL1) or ≥ 2 (IDEAL2) previous chemotherapy regimens. The response rate and disease control rate in IDEAL1 and -2 was 18/12% and 54/42%, respectively. The median survival time and one-year survival rate in both studies were ~ 7 months and 30%, respectively. As gefitinib has demonstrated antitumour activity and an acceptable tolerability profile not typically associated with cytotoxic adverse events, such as hematological toxicities, combinations with cytotoxic drugs have been evaluated. Disappointingly, in chemotherapy-naive patients with advanced NSCLC, gefitinib 250 and 500 mg/day combined with platinum-based chemotherapy (gemcitabine/cisplatin or paclitaxel/carboplatin) did not produce prolonged survival, compared with chemotherapy alone in two large, randomised, placebo-controlled, multi-centre Phase III trials (INTACT [Iressa NSCLC Trial Assessing Combination Treatment]-1 and -2). Furthermore, in a recent randomised, placebo-controlled, Phase III trial (ISEL: IRESSA Survival Evaluation in Lung cancer), gefitinib failed to prolong survival compared with placebo in patients with advanced NSCLC who had failed one or more lines of chemotherapy. Subgroup analysis of ISEL suggested improved survival in patients of Asian origin and non-smokers. In addition, subset analyses of IDEAL and several retrospective studies have indicated that female gender, adenocarcinoma histology (especially bronchial alveolar carcinoma), non-smoker status and Asian ethnicity are factors which predict to response to gefitinib. Two types of somatic mutation clustered around the ATP binding pocket in the tyrosine kinase domain of the EGFR gene have been reported as possible surrogate biological markers for predicting response to gefitinib. Appropriate patient selection by clinical characteristics or genetical information is needed, both for future clinical trials of gefitinib and its routine use in the clinic among patients with advanced NSCLC.     

The importance of surgery as the first step in multimodality treatment of small cell bronchial carcinoma. The ISC Lung Cancer Study Group

For patients with small cell lung cancer (SCLC) in their early stages (TNM I, II), surgery for cure was used to eliminate the primary tumour and its regional lymph-nodes followed by intermittent chemotherapy and radiotherapy within the first six postoperative months. After the pathohistological examination of the operation-specimen a two-arm-randomization was performed: standard chemotherapy (1000 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine) compared with sequential chemotherapy using three different drug-combinations (A: 1500 mg/m2 cyclophosphamide, 100 mg/m2 lomustine, 15 mg/m2 methotrexate; B: 1000 mg/m2 cyclophosphamide, 40 mg/m2 doxorubicin, 1 mg/m2 vincristine; C: 5 x 1.6 g/m2 ifosfamide plus mesna, 5 x 120 mg/m2 etopside). Thereafter disease-free patients only received prophylactic cranial irradiation (PCI: administering 3600 TD Gy/18 fractions) according to the protocols of the International Society of Chemotherapy Studies I and II. Preliminary evaluations in March 1990 of 170 patients from 24 cooperating departments for thoracic surgery showed that the projected life-table four-year-survival rate of 63 patients with SCLC at pTNM-stage I was 61%, of 54 patients at pTNM-stage II was 35%, of 13 patients at stage pT3, 4 NO, 1 MO was 59% and of 40 patients at stage pT N2 MO was 35%. The indication for surgery is emphasized for pTNM-stages I + II. For N2-lesions surgery would not be recommended in general, but the survival rate seems to indicate that this treatment was not detrimental, being rather more favourable compared with chemotherapy or radiotherapy alone. The continuation and enlargement of these studies seem not only justified, but emphatically indicated.(ABSTRACT TRUNCATED AT 250 WORDS)