Jen Fu Shih

Phase II randomized trial of erlotinib or vinorelbine in chemonaive, advanced, non-small cell lung cancer patients aged 70 years or older

Introduction: The primary objective of this study was to compare the response rates of elderly, chemonaive patients with advanced non-small cell lung cancer (NSCLC) treated with daily oral erlotinib versus oral vinorelbine. Methods: Chemonaive Taiwanese patients aged 70 years or older who had advanced NSCLC were randomized to receive either oral erlotinib 150 mg (E) daily or oral vinorelbine 60 mg/m2 (V) on days 1 and 8 every 3 weeks. Results: From February 2007 to July 2008, 116 patients were enrolled and 113 were included in the intent-to-treat population: 57 patients in the E group and 56 patients in the V group. Objective response rates were 22.8% (13 of 57) in E and 8.9% (5 of 56) in V (p = 0.0388). Median progression-free survival (PFS) was 4.57 months in E and 2.53 months in V (p = 0.0287), with an 80.6% increase in median PFS for E compared with V. Median survival time was 11.67 months in E and 9.3 months in V (p = 0.6975). Toxicities were generally mild in both groups. Median PFS was longest for epidermal growth factor receptor gene (EGFR)-mutated patients in the E group, followed by EGFR-mutated patients in V, EGFR wild type in E, and EGFR wild type in V (p = 0.0034). Overall survival was longer for EGFR-mutated patients than for EGFR wild-type patients (p < 0.0001). Conclusions: Erlotinib is highly effective compared with oral vinorelbine in elderly, chemonaive, Taiwanese patients with NSCLC. EGFR-mutated patients had better survival than those with EGFR wild-type disease, regardless of the treatment received.

A phase II randomized trial of gefitinib alone or with Tegafur/uracil treatment in patients with pulmonary adenocarcinoma who had failed previous chemotherapy

Background: Tegafur/uracil (UFT) is suitable for metronomic chemotherapy because of its underlying antiangiogenesis mechanism. This study aimed to assess the efficacy of adding daily oral UFT to gefitinib treatment in patients with pulmonary adenocarcinoma who had failed previous chemotherapy. Methods: Taiwanese patients who had adenocarcinoma of the lung and failed previous chemotherapy were randomized into gefitinib 250 mg daily alone (G) or plus daily oral UFT (GU). From November 2005 to August 2009, 115 patients were enrolled. Results: There were 58 patients in the G arm and 57 in the GU arm. One-year progression-free survival (PFS) was 18% in the G arm and 36.7% in the GU arm (p = 0.03). Fifty-four patients had tissue samples available for tumor epidermal growth factor receptor (EGFR) sequence analysis: 16 classical mutations and 8 wild types in the G arm, and 20 classical mutations and 10 wild-types in the GU arm. The addition of UFT significantly improved PFS in patients with EGFR mutations (14.4 versus 7.6 months, p = 0.0061). Forty-three patients underwent tumor tissue microvessel density measurement, and a trend favoring the addition of UFT to gefitinib treatment was found in those with low microvessel density (median PFS: 11.8 versus 2.8 months, p = 0.0536). The median survival time was 18.3 months in the G arm and 23.6 months in the GU arm (p = 0.381). Conclusion: Gefitinib plus UFT treatment had better PFS than gefitinib alone treatment. Gefitinib is effective in patients with EGFR mutations, and the addition of UFT treatment produced better PFS in these patients with mutations.

A phase II randomized study of vinorelbine alone or with cisplatin against chemo-naïve inoperable non-small cell lung cancer in the elderly

PURPOSEnOur aim here was to determine whether or not the addition of cisplatin into vinorelbine (V) treatment is an appropriate regimen for physically fit chemo-naïve non-small cell lung cancer (NSCLC) patients aged 70 or older.nnnPATIENTS AND METHODSnPatients were randomized into vinorelbine (V) or vinorelbine plus cisplatin (VP) treatment arms. Treatment consisted of vinorelbine 25 mg/m(2) intravenous infusion (i.v.) on days 1 and 8 every 3 weeks (V arm), or vinorelbine 22.5 mg/m(2) i.v. on days 1 and 8 plus cisplatin 50 mg/m(2) i.v. on day 1 every 3 weeks (VP arm).nnnRESULTSnSixty-five patients were enrolled from May 2005 to December 2006, including 31 who received V treatment and 34 who received VP treatment. Objective response rates were 16.1% in V and 32.4% in VP (p=0.009). Control rates were 51.6% in V and 82.4% in VP (p=0.008). Myelosuppression was more common and severe in the VP arm. Any grade of anemia and neutropenia was significantly higher in the VP arm (p=0.001 and 0.009, respectively). Fatigue sensation was more common and severe in the VP arm (p=0.032). Median time to disease progression was 3.1 months in the V arm and 5.2 months in the VP arm (p=0.0303). The 1-year survival rate was 50.9% in the V arm and 47.2% in the VP arm.nnnCONCLUSIONSnAdding cisplatin to vinorelbine treatment is feasible in elderly patients, and has a better response rate and longer median time to disease progression. However, both statistically significantly higher toxicity and no survival advantage for the combination treatment was observed.

Third-line or fourth-line chemotherapy in non-small-cell lung cancer patients with relatively good performance status.

Background: Our aim here was to explore treatment efficacy of pemetrexed and docetaxel in non‐small‐cell lung cancer patients who had failed previous chemotherapy and epidermal growth factor receptor‐tyrosine kinase inhibitor therapy. Methods: We retrospectively reviewed clinical data of our non‐small‐cell lung cancer patients who received third‐ or fourth‐line chemotherapy with pemetrexed or docetaxel in our institution from January 2006 to December 2009. Results: One hundred and twenty‐three patients received treatment, including 85 patients with pemetrexed treatment and 38 patients with docetaxel treatment. There was no difference in tumor response rate and toxicity profiles when using pemetrexed as third‐ or fourth‐line treatment, neither was there difference in docetaxel treatment of third‐ versus fourth‐line treatment. There was also no difference between docetaxel and pemetrexed in response rate and control rate when they were used as fourth‐line treatment. However, docetaxel used in fourth‐line treatment had higher incidence of neutropenia and more frequent need of granulocyte colony‐stimulating factor support compared with pemetrexed in fourth‐line treatment. Median progression‐free survivals (PFSs) were 2.6 months and 3.8 months when using pemetrexed as third‐ and fourth‐line treatment, respectively (p = 0.417). Median PFSs were 3.8 months and 4.8 months when using docetaxel as third‐ and fourth‐line treatment, respectively (p = 0.882). There was also no difference in PFS between pemetrexed and docetaxel, both in third‐ and fourth‐line treatment. Median survivals were 13.4, 12.2, 13.2, and 13 months for pemetrexed in third‐line, fourth‐line, and docetaxel in third‐line and fourth‐line treatment, respectively. Conclusion: This retrospective study of pemetrexed and docetaxel showed relatively safe toxicity profile, reasonable response rate, and long survival when used as third‐ and fourth‐line chemotherapy. Thus, it is reasonable to give good performance status patients third‐ and fourth‐line chemotherapy. A phase III randomized trial is needed for better clarification of these issues.

Salvage Therapy for Chinese Non-small Cell Lung Cancer Patients Who Failed Previous Chemotherapy

Our aim was to determine the appropriate salvage regimen for Chinese non-small cell lung cancer (NSCLC) patients who failed previous chemotherapy. We retrospectively analyzed data from our seven clinical trials, including single-agent gemcitabine, gefitinib, docetaxel with a different schedule, vinorelbine plus cisplatin, vinorelbine plus gemcitabine, docetaxel plus gemcitabine, and docetaxel plus ifosfamide, with a total of 342 cases (including 314 patients, of which 28 entered two different trials due to different salvage line settings), and compared these data with those of other studies, addressing the efficacy and toxicity of salvage therapy in patients who failed previous chemotherapy to analyze choosing of an appropriate salvage regimen. Of the 342 cases receiving salvage treatment, 71.1% were in second-line treatment, and 28.9% in third-line or later treatment. The response rate to our salvage therapy ranged widely, from 6.1% to 36.1%. Median survival was between 5.7 and 8.4 months when different salvage chemotherapy regimens were used, whereas it was 9.3 months in those who received gefitinib treatment. Similarly, 1-year survival ranged between 19.7% and 40% in a chemotherapy setting, and 40.8% for gefitinib treatment. Those who received gefitinib had better toxicity profiles than those who received other regimens. Febrile neutropenia occurred in 19 patients who received a chemotherapy agent (6.2%), and four patients died despite granulocyte colony-stimulating factor and antibiotic treatment. Grade 3 or 4 interstitial pneumonitis occurred in 14 of 247 patients (5.7%) who received docetaxel with/without another agent, and 10 patients died. Grade 3 interstitial pneumonitis occurred in one patient who received gefitinib treatment and recovered. In conclusion, both chemotherapeutic agents, such as docetaxel alone or gemcitabine plus vinorelbine, and gefitinib, are probably appropriate salvage regimens for Chinese NSCLC patients who have failed previous chemotherapy. However, gefitinib has a better safety profile and probably better survival than the chemotherapeutic agents and would be an appropriate alternative choice for salvage chemotherapy, even in a second-line setting for Chinese patients.

The epidermal growth factor receptor-tyrosine kinase inhibitor era has changed the causes of death of patients with advanced non-small-cell lung cancer

Background: Epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) are effective against tumor EGFR‐mutated non‐small cell lung cancer (NSCLC). Patients with the tumor EGFR‐activating mutation (EGFRmu) had superior survival, compared to patients with EGFR wild‐type tumors (EGFRwt). Many patients with the EGFRmu have had disease progression with EGFR‐TKI treatment because of central nervous system (CNS) metastases. The objective of this retrospective study was to compare the causes of death in patients with a known tumor EGFR mutation status who had been treated with EGFR‐TKIs. Methods: We retrospectively reviewed the chart records of our patients with advanced NSCLC who had received diagnosis, treatment, and supportive and hospice care in our hospital between July 2005 and June 2010. The tumor EGFR mutation status was analyzed by using a DNA sequence method. All enrolled patients had a documented cause of death. Results: Ninety‐four patients had documented tumor EGFR data, had received EGFR‐TKI treatment (either erlotinib or gefitinib), and were with or without previous or salvage systemic chemotherapy. Of the 94 patients, 36 patients had EGFRwt and 58 patients had EGFRmu. The overall patient survival after starting EGFR‐TKI treatment was significantly longer in the EGFRmu patients (median 17.2 months) than in the EGFRwt patients (median 11.6 months; p = 0.0058). Twenty‐nine patients died of CNS metastases and 65 died of organ failure (other than the CNS). Patients who died of CNS metastases had undergone EGFR‐TKI treatment significantly longer than patients who died of other organ failure (median, 8 months vs. 1.9 months; p = 0.0003) with a hazard ratio of 2.308 [95% confidence interval (C.I.), 1.452–3.668; p = 0.0004]. A significantly higher proportion of EGFRmu patients (26 of 58 patients; 44.8%) than EGFRwt patients (3 of 36 patients; 8.3%) (p < 0.001) died of CNS metastases. Conclusion: The EGFRmu NSCLC patients survived longer and had a significantly higher probability of mortality due to CNS metastases, compared to the EGFRwt patients. This change in the causes of death was noted after the era of EGFR‐TKI treatment, and will have an important impact on the strategies and management of supportive and hospice care for patients.