Does chemotherapy have a role as palliative therapy for unfit or elderly patients with non-small-cell lung cancer?

Elderly patients and younger "unfit" patients with poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) (> or = 2) suffering from advanced non-small-cell lung cancer (NSCLC) are two different populations--both of which require palliative treatments. Elderly patients frequently experience progressive decline of organ function and multiple comorbidities, which need to be considered when choosing therapy. ECOG 1594 showed that advanced NSCLC patients with an ECOG PS of 2 did not tolerate platinum-based chemotherapy (cisplatin/paclitaxel, carboplatin/paclitaxel, cisplatin/docetaxel, carboplatin/paclitaxel). These data confirm that treatments designed specifically for this patient subset are needed. Single-agent chemotherapy seems to be a reasonable approach, and non-platinum-based combination chemotherapy should also be investigated. The oncology community has become increasingly aware of the magnitude of the problem of cancer in the elderly. More than 30% of lung cancers arise in patients > or = 70 years old. Elderly patients tolerate chemotherapy poorly, according to the few published papers, and are not considered eligible for aggressive cisplatin-based chemotherapy in clinical practice. A phase III randomized trial (ELVIS [Elderly Lung Cancer Vinorelbine Italian Study]) demonstrated survival and quality-of-life benefits with single-agent vinorelbine versus best supportive care. Among the newer drugs, gemcitabine has demonstrated activity and low toxicity in phase II studies. With this background, we performed a randomized, multicenter phase III trial (MILES [Multicenter Italian Lung Cancer in the Elderly Study]) in 707 advanced NSCLC elderly patients. The MILES study compared single-agent chemotherapy with vinorelbine or gemcitabine versus polychemotherapy with gemcitabine plus vinorelbine. Results showed no benefit in response rate, time to progression, survival, and quality of life for the combination. Single-agent chemotherapy remains the standard treatment approach for elderly NSCLC patients with advanced disease.     

Combination treatment with weekly docetaxel and gemcitabine for advanced non-small-cell lung cancer in elderly patients and patients with poor performance status: results of a Minnie Pearl Cancer Research Network phase II trial

The purpose of this study was to evaluate the feasibility, toxicity, and efficacy of the combination of weekly docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC) who are either elderly or have poor performance status (PS). Patients with stage IIIB or IV NSCLC who had received no previous chemotherapy and were = 70 years of age were eligible for this clinical trial. Patients < 70 years of age were also eligible if they had poor PS or were considered poor candidates for standard platinum-based combination chemotherapy regimens. All patients received chemotherapy with gemcitabine 800 mg/m2 and docetaxel 30 mg/m2, both drugs administered by 30-minute intravenous infusions on days 1, 8, and 15. Treatment courses were repeated every 28 days. Patients were reevaluated after completion of 2 treatment courses; responding patients continued treatment until disease progression or for a maximum of 6 courses. Between August 1999 and June 2000, 64 patients (73% with stage IV disease) were treated at 17 participating sites in the Minnie Pearl Cancer Research Network. Eighteen of 64 patients enrolled (28%) had objective response to treatment; an additional 25 patients (39%) had stable disease. Median survival was 7 months, with 1- and 2-year survival rates of 30% and 17%, respectively. Treatment was well tolerated by most patients. Grade 3/4 leukopenia occurred in 7 patients (11%), but no patient required hospitalization for neutropenia/fever. One patient developed fatal bilateral pneumonitis, which was possibly treatment-related. The combination of weekly docetaxel/gemcitabine is active and relatively well tolerated in most patients with advanced age or poor PS with advanced NSCLC. A randomized comparison of this regimen versus single-agent weekly docetaxel is in progress.     

Optimizing first-line treatment options for patients with advanced NSCLC

The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor, despite years of research into new chemotherapy combinations. Platinum-based chemotherapy has long been the standard of care for the initial treatment of advanced NSCLC. While no one particular platinum-based chemotherapy regimen is definitely superior to the others (as demonstrated in the Eastern Cooperative Oncology Group's E1594 trial), three randomized phase III trials (the Southwest Oncology Group 9509, Italian Lung Cancer Project, and TAX326 trials) have recently demonstrated that taxane-platinum doublets are better tolerated than a combination of vinorelbine and cisplatin (VC). Moreover, a combination of docetaxel and cisplatin produced superior survival and quality of life than VC in the TAX326 study. Nonplatinum combinations, such as a taxane-gemcitabine doublet, appear promising and better tolerated than their platinum-based comparators in other studies. Efforts to evaluate chemotherapy specifically in elderly patients and in those with poor performance status (PS) have increased. Single-agent chemotherapy has been safely administered to these populations, but platinum-based doublet therapy may also be feasible in both elderly patients and patients with PS scores of 2. The addition of the monoclonal antibody against vascular endothelial growth factor, bevacizumab, to standard chemotherapy for patients with non-squamous cell advanced NSCLC significantly extended median survival in the E4599 randomized trial. Each incremental advance demonstrates that progress can be made in first-line treatment of advanced NSCLC.     

Weekly docetaxel in the treatment of elderly patients with advanced nonsmall cell lung carcinoma. A Minnie Pearl Cancer Research Network Phase II Trial

BACKGROUND: Weekly administration of docetaxel was found to reduce myelosuppression and other nonhematologic toxicities when compared with administration every 3 weeks. In the current Phase II trial, the authors evaluated the feasibility, toxicity, and efficacy of weekly docetaxel in the treatment of elderly patients with newly diagnosed advanced nonsmall cell lung carcinoma. METHODS: Thirty-nine patients with advanced, previously untreated nonsmall cell lung carcinoma entered this Phase II trial between February 1998 and January 1999. Patients were required either to be age >/= 65 years or to be poor candidates for combination chemotherapy due to coexistent medical illnesses. All patients received docetaxel, 36 mg/m(2), administered weekly for 6 consecutive weeks, followed by 2 weeks without treatment. Patients were reevaluated after 8 weeks of treatment; responding patients continued weekly docetaxel for a maximum of 32 weeks or until disease progression. RESULTS: Weekly docetaxel was well tolerated by this elderly group of patients with nonsmall cell lung carcinoma. Grade 3 leukopenia was noted in only 3 patients (8%), and no patient developed Grade 4 myelosuppression. Grade 3/4 nonhematologic toxicity also was uncommon; fatigue/asthenia was reported in 4 patients (10%). Seven of 38 evaluable patients (18%) had objective responses to weekly docetaxel whereas an additional 13 patients (34%) had a minor response or stable disease at first reevaluation. The median survival in this group of elderly patients was 5 months, with a 1-year actuarial survival rate of 27%. CONCLUSIONS: The results of the current study show that weekly docetaxel is active and well tolerated in elderly patients with advanced nonsmall cell lung carcinoma and provides an additional treatment option for these patients, who often tolerate combination chemotherapy regimens poorly.     

Challenging the platinum combinations in the chemotherapy of NSCLC

In previously untreated patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) the combination of docetaxel and gemcitabine is active and well tolerated. In the phase II setting using a 3-week schedule, response rates (RR) ranged from 25 to 50%, and median survival from 11 to 13 months. Preliminary data with weekly and bi-weekly schedules indicate maintained efficacy while reducing the risk of neutropenia. A randomized phase III trial has shown that the combination of docetaxel and gemcitabine is as active as docetaxel plus cisplatin, achieving a 1-year survival rate of 39%, with significantly less neutropenia and gastro-intestinal toxicity. The combination of docetaxel with vinorelbine is equally active and the associated toxicities are manageable. In phase II studies the average response rate is 40%, and in one study using a 2-week schedule the 1-year survival rate was 60%. With this combination neutropenia is the commonest adverse event while clinically significant neuropathy is infrequent. In a randomized phase II trial, docetaxel plus cisplatin was compared to docetaxel plus irinotecan. The non-platinum doublet achieved comparable levels of activity, though with a different toxicity profile (more diarrhea but less nausea and vomiting). The combination of docetaxel with irinotecan and carboplatin has achieved 1-year survival of 55%. All three docetaxel combinations (gemcitabine, vinorelbine, and irinotecan) could provide a valuable alternative to platinum-based chemotherapy and should be further evaluated in phase III setting.     

The role of weekly docetaxel in the treatment of advanced non-small-cell lung cancer

Docetaxel is one of the most active single agents in the treatment of advanced non-small-cell lung cancer (NSCLC). Weekly administration of docetaxel markedly reduces myelosuppression and also reduces nonhematologic toxicity. Phase II trials with single-agent weekly docetaxel have been completed in first- and second-line treatment of advanced NSCLC; preliminary results of treatment with weekly docetaxel-based combination regimens are also available. In patients who were elderly or had poor performance status, weekly docetaxel produced a 19% response rate, 28% 1-year survival, and was well tolerated. As second-line therapy, response rates to weekly docetaxel were similar to results with administration every 3 weeks, although no direct comparisons exist. Combination regimens, particularly weekly docetaxel/gemcitabine, also appear active and well tolerated and should be further evaluated. Addition of various targeted agents (eg, epidermal growth factor receptor inhibitors, antiangiogenesis agents) also merits evaluation.     

Activity and toxicity of gemcitabine and gemcitabine + vinorelbine in advanced non-small-cell lung cancer elderly patients: Phase II data from the Multicenter Italian Lung Cancer in the Elderly Study (MILES) randomized trial

BACKGROUND: Following the demonstration that vinorelbine improves survival and quality of life compared with best supportive care in elderly patients with advanced non-small-cell lung cancer (NSCLC), we started the three-arm prospective Multicenter Italian Lung Cancer in the Elderly Study (MILES) trial of vinorelbine, gemcitabine and gemcitabine + vinorelbine. DESIGN: Within the randomized phase 3 trial, pilot single-stage phase 2 studies were planned for gemcitabine and for gemcitabine + vinorelbine. Eligible patients are aged 70 or more, with stage IV or IIIb (with metastatic supraclavear nodes or malignant pleural effusion) NSCLC. Single-agent gemcitabine is given at 1200 mg/m(2) on days 1 and 8; in the combination, gemcitabine is given at 1000 mg/m(2) and vinorelbine at 25 mg/m(2), both on days 1 and 8, every 3 weeks. RESULTS: As planned 49 patients were enrolled in each group. Median age was 74 in both groups. Two-thirds of patients had stage IV disease. The response rate was 18.4% (95% exact CI 8.8-32.0) with both treatments. With single-agent gemcitabine main toxicities were grade 4 thrombocytopenia and grade 2 hepatic toxicity, in one patient each, and grade 2 pulmonary toxicity in two patients. With gemcitabine + vinorelbine combination there were grade 4 neutropenia and thrombocytopenia (one patient each), grade 3 anemia requiring red blood cell transfusion (two patients), and grade 4 fever in two patients. Four patients, with severe cardiac comorbidities, suffered grade 3 heart toxicity with atrial flutter or fibrillation, followed by congestive heart failure responsive to treatment. CONCLUSION: Both single-agent gemcitabine and the gemcitabine + vinorelbine combination are sufficiently active and tolerable to allow continuation of the MILES study.     

Management of advanced non-small-cell lung cancer in elderly populations

Elderly patients, defined as those >or= 70 years of age, represent approximately 40% of all patients diagnosed with non-small-cell lung cancer in the United States. Nonetheless, elderly patients have been underrepresented in national cooperative group trials, and many do not receive appropriate treatment. Whereas the benefit of systemic chemotherapy in younger patients is accepted by most clinicians, there remains a great deal of skepticism with respect to older patients, who are often labeled unfit for chemotherapy. More recent studies with a special focus on elderly patients demonstrate that these patients indeed benefit from chemotherapy. The landmark Elderly Lung Cancer Vinorelbine Italian Study Group trial and the Multicentre Italian Lung Cancer in the Elderly Study clarified the role of vinorelbine in the treatment of elderly patients. Retrospective and prospective subgroup analyses from selected North American trials suggested that elderly patients also benefit from platinum-based combinations. Whether elderly patients should be treated with single-agent versus combination chemotherapy is discussed in this review. The available data suggest that patients should be evaluated for chemotherapy based on their performance status and comorbidities rather than age alone. For elderly patients judged fit to receive combination chemotherapy, carboplatin-based regimens are a reasonable option. In elderly patients with less than optimal performance status or significant comorbid conditions, single-agent therapy may be more appropriate.     

Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl Cancer Research Network phase II trial.

PURPOSE: To evaluate the efficacy and toxicity of docetaxel administered weekly to elderly or poor-performance status patients with advanced breast cancer. PATIENTS AND METHODS: Forty-one patients with advanced breast cancer who were either over the age of 65 or considered to be poor candidates for combination chemotherapy received docetaxel 36 mg/m2 weekly for 6 consecutive weeks, followed by 2 weeks without treatment. The median age of patients in this trial was 74 years, and 73% of patients had one or more visceral sites of metastases. Seventy-five percent of patients received weekly docetaxel as first-line treatment for metastatic breast cancer, and the other 25% received it as second-line treatment. Thirty-six patients were assessable for efficacy, and all patients were assessed for toxicity. RESULTS: A total of 448 doses of weekly docetaxel were administered to 41 patients. Thirteen patients (36%) had objective responses to treatment, and an additional 13 patients (36%) had stable disease or minor response. Median time to progression for responding and stable patients was 7 months (range, 3 to 27 months). Median survival for the entire group was 13 months, with 1- and 2-year actuarial survival rates of 61% and 29%, respectively. Severe neutropenia occurred in only 0.4% of courses, and no other hematologic toxicity was observed. Grade 3/4 fatigue was the most common toxicity, occurring in 20% of patients. CONCLUSION: Weekly docetaxel therapy is active and well tolerated by elderly and/or poor-performance status patients with advanced breast cancer. This treatment can be administered with minimal myelosuppression. Weekly docetaxel provides an additional option for treatment in this difficult subgroup of patients with metastatic breast cancer. Well-tolerated combination regimens containing weekly docetaxel merit evaluation for this patient population.     

Second-line chemotherapy for recurrent non-small cell lung cancer: do new agents make a difference?

After a certain degree of nihilism, chemotherapy has become the standard treatment for advanced and metastatic non-small cell lung cancer (NSCLC). The new chemotherapeutic drugs (vinorelbine, taxanes, gemcitabine, and irinotecan) and their associations with cisplatin have shown better response rates and survival in comparison with the standard regimens. This increase of survival is the main motive of the possible consideration of a second-line therapy in NSCLC patients. To this regard, the most promising drug may be docetaxel that, in a randomized trial comprising a best supportive care arm (BSC), documented a response rate of 7.6%, a longer median survival (31 weeks versus 21 of BSC), and a statistically better quality life. Other phase II studies obtained a response rate of 20% and 1-year survival of 40% using docetaxel. Also gemcitabine has shown interesting results in this setting, with a 19% response rate and a median and 1-year survival rate of 34 weeks and 45%, respectively. The activity of paclitaxel is not well defined because of conflicting results and deserves further investigations, while the efficacy of vinorelbine and irinotecan has been dismal. Large randomized trials comparing the treatment arm with best supportive care and a careful analysis of quality of life and cost-effectiveness will be needed to clarify the role of second-line therapy in advanced NSCLC.     

Weekly docetaxel plus gemcitabine or vinorelbine in refractory advanced breast cancer patients: A parallel dose-finding study

Purpose:The objective of this study was to determine thedocetaxel MTD when combined with gemcitabine or vinorelbine in advanced breastcancer patients who had received previous anthracycline-based chemotherapy foradvanced disease. Patients and methods:Advanced breast cancer patients aged between18 and 70 with ECOG PS 0–2 who had not responded to, or had relapsedafter, first-line anthracycline-based chemotherapy, were randomized to receiveeither gemcitabine 1000 mg/m² or vinorelbine 25 mg/m²in combination with escalating doses of docetaxel (starting from 30mg/m²), all on days 1 and 8 every three weeks. Escalation wasstopped if >33% of patients treated at a given dose level showed DLTat the first cycle. Results:A total of 34 patients with locally advanced (8) ormetastatic disease (26) were treated, for a total of 94 cycles delivered.Nineteen patients received docetaxel in combination with gemcitabine and 15with vinorelbine. All patients had been pretreated with anthracyclines, and24 of 34 had also received weekly dose-dense paclitaxel. A docetaxel dose of40/m² proved to be safe when combined on days 1 and 8 withgemcitabine, while a dose of 35 mg/m² was tolerated in combinationwith vinorelbine. Overall, nine episodes of DLT, all of them neutropenia,occurred at the first cycle. Considering all 94 cyles, grades 3 or 4neutropenia and thrombocytopenia occurred in 15 (44%), and 7(20%) patients. Non-hematologic toxicity was mild, except for threecases of grade 2 peripheral neuropathy. All patients were assessed forresponse on an 'intent-to-treat' basis. Overall, five partial responses wererecorded (docetaxel + gemcitabine = 3 and docetaxel + vinorelbine = 2), fora 15% (95% CI: 5%–31%) overall responserate. Only 1 of 24 (4%) patients who had received weekly dose-densepaclitaxel responded to treatment. Conclusions:The weekly docetaxel administration in combinationwith either gemcitabine or vinorelbine is a well-tolerated treatment forheavily pretreated advanced breast cancer patients. This approach, althoughsometimes capable of achieving a major response, does not seem advisable inadvanced breast cancer patients refractory to both anthracyclines andpaclitaxel.     

New drugs in the palliative chemotherapy of advanced non-small-cell lung cancer.

In inoperable advanced non-small-cell lung cancer (NSCLC), palliative chemotherapy is established and aims at palliation of symptoms, improvement of quality of life and prolongation of survival. In the last years, several new drugs with enhanced activity towards NSCLC and improved toxicity profile have been characterised, for example vinorelbine, gemcitabine, paclitaxel and docetaxel. Data from randomised trials suggest that regimens containing new drugs are more active than older combinations. Platin-based combinations of either vinorelbine, gemcitabine or paclitaxel have resulted in better outcome than cisplatin alone and new drugs in combination with platins are more active than the corresponding single agent. Non-platin-based combinations must be considered investigational until their non-inferiority to platin-based protocols has been proven in randomised trials on large patient populations. Patients with good performance status and adequate organ function should receive platin-based chemotherapy that includes the new drugs (vinorelbine, gemcitabine, paclitaxel or docetaxel). New drugs without platins are suitable for elderly patients and patients with poor performance status. Second-line chemotherapy prolongs survival in selected patients and should be particularly offered to patients with good performance status.     

Combination second-line chemotherapy with gemcitabine and docetaxel for recurrent non-small-cell lung cancer after platinum-containing chemotherapy: a phase I/II trial

PURPOSE: In a randomized trial, docetaxel monotherapy yielded longer survival than the best supportive care in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy, and combination chemotherapy regimens containing docetaxel have been assessed to enhance the efficacy of second-line chemotherapy. We conducted a phase I/II trial of gemcitabine and docetaxel in patients with recurrent NSCLC after platinum-based chemotherapy and with an ECOG performance status (PS) of 0 or 1. PATIENTS AND METHODS: Docetaxel administration was fixed at a dosage of 60 mg/m(2) on day 8, and gemcitabine was administered on days 1 and 8. The starting dose level of gemcitabine was 800 mg/m(2) (level 0), and the subsequent dose level of gemcitabine was 1000 mg/m(2) (level +1). Treatment was repeated every 3 weeks. RESULTS: In the phase I study, 13 patients were enrolled, and in the phase II study, 29 patients were enrolled. Neutropenic fever and omission of treatment on day 8 due to leukopenia (leukocyte count less than 3000/mm(3)) were dose-limiting toxicities (DLTs). Three of six patients experienced DLTs at level +1, which was the maximum tolerated dose. Gemcitabine 800 mg/m(2) on days 1 and 8 plus docetaxel 60 mg/m(2) on day 8 (level 0) was recommended for the phase II study. An objective response was observed in 8 (28%) of the 29 patients. The median time to disease progression was 4.2 months (95% CI 0.9-7.7 months). The median survival time was 11.1 months (95% CI 9.9-12.4 months), and the 1-year survival rate was 41%. The most common toxicity, though mild, was hematologic, and consisted of grade 4 neutropenia (18%), grade 3 febrile neutropenia (11%), and grade 3 thrombocytopenia (11%). There were no toxic deaths. Grade 3 non-hematologic toxicities included nausea (4%) and rash (4%). CONCLUSIONS: The combination chemotherapy of gemcitabine and docetaxel is active and well tolerated in patients with recurrent NSCLC after platinum-based chemotherapy and with a good PS.     

Lung cancer

Aging society is coming now, the ratio of elderly patients among all lung cancer patients has currently been increasing. It is necessary for elderly patients who are under-represented in clinical trials to study their suitable regimen. Thus, phase II and III clinical trials have been performed specifically for elderly non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients all over the world. As for single agent chemotherapy, there is a strong rationale for docetaxel and vinorelbine in elderly patients with advanced NSCLC. Recently, there are phase I and II clinical trial for CPT-11 monotherapy, and gefitinib and TS-1 are reasonable options for elderly patients. Alimta is tolerable for elderly, and subset analysis is performed for the elderly with recurrent NSCLC. As platinum-based chemotherapy, there are several elderly subset analyses and JCOG 0207, which is a phase III trial now in progress comparing weekly cisplatin+weekly docetaxel and weekly docetaxel. In SCLC, there is no evidence of single agent chemotherapy but combination chemotherapy such as carboplatin+etoposide is recommended. A phase III study of carboplatin+etoposide versus amrubicin under way. These studies should aim to optimize several agents for elderly patients and prolong survival, palliative care.     

Highlights from the Tenth World Conference on Lung Cancer

Should adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC) be the standard of care? That question has been much debated since the presentation of results from the International Adjuvant Lung Cancer Trial (IALT) in May 2003 at the plenary session of the American Society of Clinical Oncology annual meeting. The IALT study showed a statistically significant survival advantage for patients treated with cisplatin-based adjuvant chemotherapy. The topic of adjuvant chemotherapy permeated the Tenth World Conference on Lung Cancer held from August 10-14, 2003 in Vancouver, Canada. Updated results of the IALT study were presented along with results from the Big Lung Trial from the United Kingdom and the Adjuvant Lung Project Italy trial, neither of which showed a significant survival benefit for adjuvant chemotherapy. How to put the IALT data into practice remains controversial, and leading lung cancer experts have not reached a consensus. Platinum-based doublets that include a taxane, vinorelbine, or gemcitabine remain the standard of care for the first-line treatment of metastatic NSCLC. However, there may soon be a new option for second-line treatment. A randomized study of pemetrexed in the second-line setting found efficacy similar to that of docetaxel given every 3 weeks, with less toxicity. Gefitinib was recently approved by the U.S. Food and Drug Administration for the treatment of advanced NSCLC following platinum-based chemotherapy and docetaxel. However, concerns have arisen about toxicity due to reports of interstitial pneumonitis from Japan. The observed incidence of interstitial pneumonitis from the data available to date is approximately 1%. Which patients derive the most benefit from gefitinib? It appears that lifetime nonsmokers and patients with bronchioloalveolar histology have the highest probability of disease response.     

Phase I study of vinorelbine plus gemcitabine as third-line chemotherapy for refractory non-small cell lung cancer

For non-small cell lung cancer (NSCLC), which is refractory for both platinum-based chemotherapy and docetaxel, no standard regimen has yet been established. We conducted a phase I study of a combination of vinorelbine and gemcitabine as third-line chemotherapy for refractory NSCLC to determine both the maximum tolerated dose (MTD) and the recommended dose (RD). Twenty patients with NSCLC refractory for both platinum and docetaxel were enrolled, and all patients were eligible for this phase I study. Cohorts of three to seven patients received vinorelbine at doses ranging from 20 to 25 mg/m(2), and gemcitabine at doses ranging from 600 to 1000 mg/m(2), on days 1 and 8 every 3 weeks. The dose-limiting toxicities were treatment delay, serum gammaGTP elevation, diarrhea and cerebral infarction, which were resolved without serious sequela, and there was no treatment-related death. The MTD was vinorelbine at 25 mg/m(2) and gemcitabine at 1000 mg/m(2) and the RD was vinorelbine at 25 mg/m(2) and gemcitabine at 800 mg/m(2). The median overall survival time was 6.8 months for all 20 patients eligible. As third-line chemotherapy, the combination of vinorelbine and gemcitabine was feasible and promising for NSCLC which is refractory for both platinum and docetaxel.     

Indications for chemotherapy in stage IV non-small cell lung cancer

Treatment of stage IV NSCLC has been a controversial issue during the last decade. However, there is now clear evidence that cisplatin-containing chemotherapy regimens lead to prolonged survival with an increase of the 1-year survival rates at about 10%. New drugs like gemcitabine, the taxanes (paclitaxel, docetaxel), and vinorelbine have shown very promising single-agent activity and have been included into modern combination chemotherapy regimens achieving response rates of 40 to 50% and 1-year survival rates of between 30 and 40%. In comparison to single-agent cisplatin or cisplatin/etoposide as 'standard treatment approaches', most of these modern combinations could demonstrate advantages in terms of response, survival and improved QOL. Patients with favourable prognostic factors are at the moment frequently treated with platinum-based combination chemotherapy often including one of these newer active drugs. Patients with adverse prognostic factors such as elderly or stage IV patients with a reduced performance status are preferably treated with single agents such as gemcitabine, paclitaxel or vinorelbine.     

Overview of chemoradiation clinical trials for locally advanced non-small cell lung cancer in Japan

The standard of care for unresectable stage III non-small cell lung cancer (NSCLC) is combined-modality therapy with both chemotherapy and thoracic radiation therapy (TRT). A phase III trial by the West Japan Lung Cancer Group revealed that the combination of mitomycin, vindesine, and cisplatin (MVP) with concurrent TRT yielded a median survival time of 16.6 months and a 5-year survival rate of 16% in patients with unresectable stage III NSCLC. Although evidence indicates that concurrent chemotherapy and TRT (chemoradiation) increases survival to a moderately greater extent than sequential therapeutic approaches, the optimal strategies for such concurrent treatment remain to be defined, and differ between full-dose systemic and low-dose radio-enhancing protocols. Two phase III trials have been initiated in Japan to address these issues and they have recently reported preliminary data. Early results of the Okayama Lung Cancer Study Group (OLCSG) trial, comparing chemoradiation based on divided docetaxel and cisplatin chemotherapy with MVP-based chemoradiation, have been reported. The West Japan Oncology Group (WJOG) is comparing the efficacy and toxicity of TRT and concurrent chemotherapy with either carboplatin-paclitaxel or carboplatin-irinotecan, followed by full-dose consolidation chemotherapy, with the efficacy and toxicity of MVP-based chemoradiation. Several phase I/II studies to test the optimal use of new agents such as S-1 (an oral anticancer drug combining tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate) and gefitinib (an inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor) are also ongoing. In addition, radiation dose intensification with three-dimensional planning approaches is currently under evaluation. A phase I clinical trial by WJOG to establish, prospectively, the maximum tolerated dose of three-dimensional hyperfractionated radiotherapy with concurrent weekly chemotherapy (carboplatin-paclitaxel) is thus currently under way. This overview of ongoing trials highlights new directions in the treatment of locally advanced NSCLC.     

Weekly combination chemotherapy with docetaxel and gemcitabine as first-line treatment for elderly patients and patients with poor performance status who have extensive-stage small cell lung carcinoma: a Minnie Pearl Cancer Research Network phase II trial

BACKGROUND: The goal of the current study was to evaluate the feasibility, toxicity, and efficacy of a novel combination of weekly docetaxel and gemcitabine for elderly patients and patients with poor performance status who had advanced-stage small cell lung carcinoma (SCLC). METHODS: Previously untreated patients with advanced-stage SCLC were eligible for the current clinical trial. In addition, patients were required to be age > 65 years or to have poor performance status (Eastern Cooperative Oncology Group 2). All patients received 800 mg/m2 gemcitabine and 30 mg/m2 docetaxel intravenously on Days 1, 8, and 15. Courses were repeated at 28-day intervals. RESULTS: Forty patients were enrolled in the current multicenter, community-based trial. Nine patients (23%) had partial responses to treatment. The median survival for the entire group was 4 months. Fourteen percent of patients were alive at 1 year. Myelosuppression was mild to moderate, with no episodes of neutropenia and fever. Grade 3/4 fatigue (25%) was the only common nonhematologic toxicity. CONCLUSIONS: Although relatively well tolerated, the weekly regimen of gemcitabine and docetaxel possessed only modest activity in this group of patients with unfavorable prognosis. The regimen offered no potential advantages over standard treatment approaches and is not recommended for further development.     

Medical treatment of advanced non-small cell lung cancer in elderly patients: A review of the role of chemotherapy and targeted agents

Lung cancer is the leading cause of cancer related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all cases. Half of the patients at diagnosis of NSCLC are over seventy years old; therefore, the elderly represent a large subgroup of patients affected by advanced NSCLC in our clinical practice. Nevertheless, the elderly are under-represented in clinical trials. Given the fact that old age is frequently associated with several comorbidities, poor general conditions and physiologic reduction in organ function, clinicians must carefully choose the best treatment option for elderly patients with advanced NSCLC, always taking into account the expected risks and benefits. In this paper we perform a review of literature evidence regarding the medical treatment of elderly patients affected by advanced NSCLC, encompassing single-agent chemotherapy, doublet chemotherapy and targeted agents. We conclude that single-agent chemotherapy with a third generation agent (vinorelbine, taxanes, gemcitabine) represents a valid treatment option for elderly patients who are not eligible for a combination chemotherapy due to clinical features such as comorbidities, poor performance status and inadequate organ function. Platinum-based doublet chemotherapy shows similar efficacy in elderly patients as compared to their younger counterpart, despite greater treatment related toxicity and it is indicated in elderly patients with ECOG PS: 0–2, adequate organ function and no major comorbidities. Elderly patients affected by epidermal growth factor receptor (EGFR) mutated NSCLC benefit mostly from a tyrosine kinase inhibitor of EGFR (erlotinib, gefitinib) which is associated with a good toxicity profile. Currently there are no available data to strongly support the use of bevacizumab in combination with first line chemotherapy in the treatment of older adults. Elderly patients affected by NSCLC harboring the EML4-ALK translocation could benefit mostly from a treatment with an oral inhibitor of such a rearrangement (crizotinib).