Safety and efficacy of gefitinib treatment in elderly patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience

We evaluated the safety and efficacy of gefitinib treatment in elderly patients with non-small-cell lung cancer (NSCLC). We retrospectively compared toxicity, response and survival outcomes for gefitinib in patients aged 75 years or older (elderly group) with the same outcomes in patients aged younger than 75 years. In total, 350 patients were eligible for this analysis, of whom 92 were in the elderly group and 258 in the non-elderly group. In the elderly group, adverse events were generally mild to moderate and grade 3-4 adverse events were observed in 8 (9%) patients. The objective response rate (17 vs. 21% for elderly vs. non-elderly, respectively) and median survival time (7.6 vs. 9.3 months) were also similar in the two groups. Multivariate analysis revealed elderly patients with lower Brinkman index tended to be more sensitive to gefitinib (odds ratio: 4.57, 95% confidence interval: 0.91-22.72, p = 0.0642). In this study, treatment with gefitinib appeared to be as safe and effective in elderly patients (aged 75 or older) with NSCLC as in non-elderly patients.     

Prognostic factors in patients with resected stage I non-small cell lung cancer. A report from the Lung Cancer Study Group

The authors present prognostic information on recurrence and survival for resected Stage I lung cancer patients with squamous cell carcinoma, adenocarcinoma or large cell carcinoma. The data derive from 392 carefully staged patients and include results from the history and physical examination, preoperative laboratory tests, nature of the surgery, complications, initial pathologic findings following surgical resection, and final pathologic review. A simple multivariate model of recurrence, which is used to classify patients into low, intermediate, and high-risk groups, is based on tumor size and location (T1, T2), histologic type (squamous, nonsquamous/mixed) and nodal status (N0, N1). To model survival, the performance status and the presence of empyema, pneumonia, or wound infection were added to the previous factors. Not all factors associated with increased mortality are associated with increased risk of recurrence, and, in particular, postoperative empyema, pneumonia or wound infections carry an increased risk of death only. Serial measurements of performance status and leukocyte count have the potential for monitoring for increased risk of recurrence and death.     

Factor associated with failure to administer subsequent treatment after progression in the first-line chemotherapy in EGFR-mutant non-small cell lung cancer: Okayama Lung Cancer Study Group experience

Purpose

Early administration of both epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy and cytotoxic chemotherapy is crucial for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. We investigated the effect of first-line administration of these therapies on subsequent therapy in NSCLC patients.

Methods

This study enrolled 63 consecutive patients with advanced EGFR-mutant NSCLC and good performance status (PS) and who underwent first-line EGFR-TKI therapy or standard cytotoxic chemotherapy and then had progressive disease, from 2007 to 2011. The ability of each patient to receive the other therapy after first-line treatment failure was assessed.

Results

In the first-line setting, 23 and 40 patients received EGFR-TKI therapy and cytotoxic chemotherapy, respectively. At relapse, the EGFR-TKI therapy group showed more frequent PS deterioration (p = 0.042) and greater likelihood of symptomatic central nervous system (CNS) relapse (p = 0.093) compared with the cytotoxic chemotherapy group. Nine (39 %) of 23 patients initially receiving EGFR-TKI therapy could not receive standard cytotoxic therapy after progression mainly due to symptomatic CNS relapse. Only one (3 %) of 40 initially treated with cytotoxic chemotherapy failed to receive subsequent EGFR-TKI therapy (p < 0.001). Multivariate analysis revealed a correlation between the first-line therapy and the failure to switch to the other therapy after disease progression (OR 48.605, p = 0.005).

Conclusion

In this study, patients who could not receive both EGFR-TKI therapy and cytotoxic chemotherapy in the early-line setting were included more in the first-line EGFR-TKI group, suggesting a potential risk associated with missing the timing of administration of subsequent therapy. Further investigation is warranted to detect their pretreatment clinical or molecular characteristics for development of a new treatment strategy specific for such subpopulation.     

非小细胞肺癌脑膜转移的诊疗进展

脑膜转移是非小细胞肺癌的严重并发症,其临床表现不特异,主要包括脑实质受累、颅神经及脊髓、脊神经根刺激症状。诊断主要依据肿瘤病史、临床表现、影像学及脑脊液检测。EGFR-TKIs等靶向治疗药物应用于选择人群可能存在生存获益,但目前其总体治疗效果仍不满意,预后差。本文就非小细胞肺癌脑膜转移的流行病学、病理生理、临床表现、诊断方法及治疗疗效的研究进展进行综述。     

Continued gefitinib treatment after disease stabilisation prolongs survival of Japanese patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience.

BACKGROUND: This study aimed to investigate the survival outcome of patients with non-small-cell lung cancer (NSCLC) who had obtained disease stabilisation with gefitinib treatment and to clarify the effect of continued treatment with gefitinib on prognosis. PATIENTS AND METHODS: We reviewed the clinical records of 365 Japanese patients with NSCLC who received gefitinib (250 mg/day). RESULTS: Of 324 (89%) patients assessable for response, 147 (45%) obtained disease stabilisation and 71 (22%) patients achieved an objective response. Overall survival in patients obtaining disease stabilisation was significantly longer than in patients with progressive disease (median survival time 12.1 versus 4.4 months; P <0.0001). In patients obtaining disease stabilisation, those who continued gefitinib treatment until disease progression tended to have longer overall and progression-free survival compared with those discontinuing gefitinib treatment (1-year survival rate 52.1% versus 36.6%, P = 0.08; 1-year progression-free survival rate 31.8% versus 5.2%, P = 0.001). Multivariate analysis showed discontinuing gefitinib was an independent risk factor for progression-free survival (hazard ratio 1.66; 95% confidence interval 1.07-2.56; P = 0.022) but not for overall survival. CONCLUSIONS: Our findings indicate the importance of achieving disease stabilisation with gefitinib treatment and continued gefitinib treatment in Japanese patients with disease stabilisation, although further studies are required to confirm these findings.     

吉非替尼(Gefitinib)对非小细胞肺癌的脑部转移具有疗效

目的 比较分析吉非替尼对不同体能表现、既往不同化疗次数、有或无脑部转移病灶的非小细胞肺癌患者的治疗结果。方法 总共有76例患者参加试验。结果 患者的疾病控制率为63．2％(95％CI为52．1％～74．3％)．无疾病恶化牛存期的中位数为5．0个月(95％CI为3．5～6．6个月)，整体生存期的中位数为9．9个月(95％CI为4．9～14．8个月)。其中具有可测量病灶的57例患者的客观反应率为33．3％(95％CI为20．7％～46．0％)。76例患者中有21例患者同时具有可评估的颅内及颅外病灶，其中17例(81．0％)对吉非替尼有相同的颅内及颅外肿瘤反应．而出现脑部转移并不影响患者的生存期。药物引起的副作用大部分是中等反应．仅5例患者发生不可耐受的毒性，其中1例(5．8％)为间质性肺炎。结论 吉非替尼对非小细胞肺癌的脑部转移有疗效．值得进一步没计随机临床试验观察单剂吉非替尼治疗或加上其它形式的治疗在脑部转移的非小细胞肺癌患者中所扮演的角色。     

Short-term low-volume hydration in cisplatin-based chemotherapy for patients with lung cancer: the second prospective feasibility study in the Okayama Lung Cancer Study Group Trial 1201

Objective

We previously reported the feasibility of short-term low-volume hydration in patients with advanced lung cancer who received cisplatin-based chemotherapy (Jpn J Clin Oncol 2013). We sought to determine the clinical usefulness of a more convenient hydration method, evaluating the safety and efficacy of shorter-term and lower-volume hydration.

Method

Chemonaïve patients with advanced lung cancer who were ≤75 years and reserved an adequate renal function for cisplatin use (≥60 mg/m²) were eligible. An intravenously administered hydration of 1700 ml in ~3.5 h with 1500 ml of orally administered hydration was investigated. The primary endpoint was the proportion of patients without grade 2 or worse renal toxicity in the first cycle.

Results

A total of 45 patients were registered, all of whom were evaluable for renal toxicity. The median baseline creatinine score was 0.70 mg/dl, and the median cisplatin dose on day 1 was 75 mg/m². In the first cycle, one patient (2 %) developed grade 2 creatinine toxicity, and thus, the proportion of patients with less than grade 2 was 98 % (the lower limit of 95 % confidence interval; 93 %), which met the primary endpoint. Five patients (11 %) had grade 1 or greater nephrotoxicity, three of whom successfully recovered. The objective response rate was 24 % and median progression-free survival 5.8 months.

Conclusion

This prospective study demonstrated the safety and efficacy of shorter-term lower-volume hydration.

     

A phase II study of irinotecan combined with cisplatin in non-small cell lung cancer. CPT-11 Lung Cancer Study Group

Based upon the results of phase I study of irinotecan (CPT-11) combined with cisplatin (CDDP) on non-small cell lung cancer (NSCLC), a combination phase II study on NSCLC was carried out from Feb., 1992 to Sep., 1992. CPT-11 (60 mg/m2) and CDDP (80 mg/m2) were administered by i.v. drip infusion, with administration schedules of Days 1, 8, 15 and only Day 1, respectively. This therapy course was repeated every 4 weeks. Subjects were NSCLC patients of stage III B or IV disease. Those without prior chemotherapy (Group A) and those with prior therapy (Group B) were enrolled separately. Seventy patients were entered into Group A and 32 patients into Group B. One of the patients of Group A was ineligible. The characteristics of the eligible cases of Group A were: male/female, 51/18; median age, 61 years old; PS 0/1/2, 18/39/12; stage IIIB/IV, 26/43; and adeno/squamous/large, 51/15/3. Those of group B were: male/female, 20/12; median age, 62 years old; PS 0/1/2, 5/18/9; stage I/IIIB/IV, 1/7/24, adeno/squamous/large/ad-sq, 28/2/1/1. Thirty-three patients (47.8%) responded in Group A and B patients (25.0%) responded in Group B. Major adverse reactions (grade 3 or higher) of Group A/Group B were neutropenia (80.3%/73.3%), anemia (35.3%/34.4%), diarrhea (18.8%/28.1%) and nausea/vomiting (34.8%/34.4%). Median survival times for Group A and Group B were 308 and 295 days, respectively. CPT-11 in combination with CDDP is effective against NSCLC, suggesting that further studies are needed to determine the usefulness of this therapy.     

肺癌纵膈淋巴结转移与血行转移相关性的临床研究

目的探讨非小细胞肺癌(NSCLC)纵隔淋巴结转移(N2)与血行转移的相关性,为对手术后的N2肺癌采取有针对性的辅助治疗措施提供依据.方法对96例根治性切除术后病理诊断为纵隔淋巴结转移(pN2)的NSCLC患者进行回顾性研究,选择无淋巴结转移(pN0)的NSCLC患者作为对照组,与pN2患者配对.术后两年内每6个月对患者进行随访复查一次,监测血行转移.计算两组患者血行转移的发生率,应用x2检验比较发生率的差别.结果pN2组患者手术后两年内血行转移的发生率为29.17%,多数为脑和肺转移(64.29%);pN0组患者血行转移的发生率为13.54%,两者的差别非常显著(P＜0.01).pN2肺癌患者术后发生血行转移的概率大约是pN0患者的3倍(OR=3.14).结论肺癌根治切除术后血行转移的发生与纵隔淋巴结转移有关,有纵隔淋巴结转移的患者血行转移的发生率增高.     

Clinical features and outcome of leptomeningeal metastasis in patients with breast cancer: a single center experience

Background

Leptomeningeal metastasis (LM) is one of the major problems in the management of metastatic breast cancer; typically, LM has a devastating prognosis and often represents a terminal event. The present study analyzed the clinical features and outcome of LM in patients with breast cancer.

Methods

The medical records of patients diagnosed with LM from breast cancer at Asan Medical Center, between 2002 and 2012, were reviewed retrospectively.

Results

Of 95 LM patients, 38 (40 %) had an ECOG performance status (PS) ≤ 2, and the median age was 47 years (range 26–72 years). At the time of LM diagnosis, 46 patients (48.4 %) presented with coincidental failure of systemic disease control. Seventy-eight patients (82.1 %) underwent intrathecal (IT) chemotherapy, resulting in cytologic negative conversion in 26 patients, and 46 patients (48.4 %) received systemic chemotherapy. The median overall survival (OS) time was 3.3 months, and 7.8 % of the patients survived for more than 1 year. OS tended to be higher in patients who achieved cytologic negative conversion from IT chemotherapy than in those who did not (4.5 vs. 2.4 months, P = 0.088). Multivariate analysis demonstrated that ECOG PS ≤ 2, controlled extracranial disease at the time of LM diagnosis, and systemic chemotherapy after LM diagnosis were independent factors associated with survival.

Conclusions

The prognosis of patients with LM from breast cancer is poor. Systemic chemotherapy, in addition to intrathecal chemotherapy, might confer a survival benefit, even after the detection of LM.     

非小细胞肺癌脑转移治疗进展

非小细胞肺癌(NSCLC)脑转移的治疗方法包括激素、抗惊厥药物治疗、手术、放疗、化疗.近年来分子靶向治疗如表皮生长因子(EGFR)酪氨酸激酶抑制剂(TKI)成为NSCLC脑转移的新的治疗选择.     

First-line gefitinib therapy for elderly patients with non-small cell lung cancer harboring EGFR mutation: Central Japan Lung Study Group 0901

Purpose

Icotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, has proved effectiveness in xenografted nude mice. Purpose of the present studies was to investigate tolerability and pharmacokinetics of Icotinib in healthy subjects for the first time, including dose proportionality, food effect, and tolerability.

Methods

Two studies were conducted in total of 22 healthy subjects: a randomized, two-Latin-square crossover, dose proportional study (n = 12) and a randomized two-way crossover food-effect study (n = 10).

Results

Plasma concentration of Icotinib reached peak at a median T_max of 0.75–3.5 h after single dose and then declined with a mean t_1/2β of 6.02–7.83 h. Over the dose range of 100–600 mg, AUC values were proportional to dose and C_max showed a slight saturation when dose increases. Only 0.2 % of the dose was excreted through kidney in unchanged Icotinib. After dosing 400 mg of Icotinib with high-fat and high-calorie meal, mean C_max and AUC were significantly increased by 59 and 79 %, respectively. Three subjects experienced four adverse events (rash, increase in AST and ALT, and external injury). Rash and increased levels of AST and ALT were considered as drug-related. No serious adverse events were reported.

Conclusion

The current work demonstrated that Icotinib was well tolerated in healthy male subjects (n = 22) over the dose range of 100–600 mg with or without food. Icotinib exposure, expressed in AUC, was proportionally increased with dose over the above dose range. Food intake significantly increased the absorption and exposure of Icotinib in healthy subjects.