Response to pemetrexed rechallenge after acquired resistance of EGFR-TKI in a patient with advanced NSCLC

Acquired resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been developed as an important clinical problem though EGFR-TKI such as gefitinib, erlotinib and afatinib 0005 and 0010 has achieved 8–14 months of progression free survival in advanced non-small cell lung cancer (NSCLC) patient with EGFR mutation. We report a case here that an advanced lung adenocarcinoma with L858R mutation responded well to pemetrexed rechallenge after acquired resistance of erlotinib.     

Maintenance chemotherapy in advanced NSCLC: A population-based assessment of eligibility

BackgroundMaintenance chemotherapy has been incorporated into treatment paradigms for advanced NSCLC. Eligibility criteria include stable disease/partial response and PS 0–1 after a first line platinum doublet. In practice, maintenance can be difficult to deliver due to patient factors and preferences. We propose to examine the proportion of patients eligible for maintenance and factors associated with the delivery of subsequent lines of chemotherapy.MethodsThe BC Cancer Agency provides care to a population of 4.5 million. A retrospective review was conducted of all referred Stage IIIB/IV patients in 2009 who received first line systemic therapy. Baseline characteristics, PS and response after first line and subsequent systemic therapy details were recorded. Patients were deemed potentially maintenance eligible or not based on clinical trial criteria; however maintenance therapy was not delivered to these patients as it was not yet available.Results330 patients were identified; 98 were potentially maintenance eligible. The reason for maintenance ineligibility in n = 232; no upfront doublet (n = 41), PS ≥ 2 (n = 38), progressive disease (PD) (n = 53), PS ≥ 2 and PD (n = 62), PS ≥ 2 and unknown response (n = 35), PD and unknown PS (n = 3). Further chemotherapy (2nd line or beyond) was administered in maintenance eligible 68% vs ineligible 56%. Reasons for no further chemotherapy were predominantly decline in PS and brain metastasis. Median OS: 7 m for 1st line only versus 16.8 m for ≥2nd line (p < 0.001).ConclusionsIn our population based study, 30% of advanced NSCLC patients were eligible to receive maintenance chemotherapy based on the clinical trial criteria. Despite a good initial PS and disease control only 68% of maintenance eligible patients received subsequent therapy. A clear survival benefit was seen with ≥2nd line treatment. Maintenance therapy or initiation of early second line therapy should be considered for advanced NSCLC patients to improve survival outcomes.     

含铂两药方案治疗老年晚期非小细胞肺癌的临床分析

目的 评价老年晚期非小细胞肺癌（NSCLC）患者接受以铂类为基础的两药联合化疗的疗效及安全性。方法 回顾性分析2003年1月至2009年12月北京胸科医院肿瘤内科收治的晚期NSCLC患者115例,年龄≥65岁,均接受以铂类为基础的两药联合一线化疗。具体化疗方案为：顺铂50～60mg／m2或卡铂曲线下面积（AUC）4～5静滴,第1天;紫杉醇135～150mg／m2静滴3～4h,第1天;或长春瑞滨25mg／m2静滴6～10min,第1、8天;或吉西他滨1000mg／m2静滴30min,第1、8天。上述方案3～4周为1个周期。观察并随访治疗疗效及主要不良反应。结果 115例患者中,应用铂类联合紫杉醇方案化疗44例（38.3％）,联合吉西他滨方案31例（27.0％）,联合长春瑞滨方案40例（34.7％）。全组患者的有效率（RR）为26.1％,疾病控制率（DCR）为76.5％,中位无进展生存时间（PFS）为5.5个月,中位总生存时间（OS）为14.0个月,1、2年生存率分别为50％和15％。化疗相关不良反应主要为骨髓抑制,包括白细胞及血小板减少,对症处理后可恢复。按照不同年龄、方案、铂类药物及ECOG评分进行亚组分析,其中不同ECOG评分及铂类药物的中位PFS及OS差异有统计学意义（P＜0.05）。结论 以铂类为基础联合第3代细胞毒性药物的两药方案一线治疗一般状态较好的老年晚期NSCLC的疗效较好,毒副反应可以耐受。     

Chemotherapy rechallenge in metastatic colon cancer: A case report and literature review

BACKGROUNDColorectal cancer (CRC) is the third leading cause of cancer-related death in males and females in the United States. Approximately, 20%-22% of patients have metastatic disease at the time of presentation, and 50%-60% will develop metastasis over the course of their disease. Despite advances in systemic therapies, there remains a paucity of effective third- and later-line therapies for patients with ongoing disease progression. However, rechallenging chemo-resistant CRC tumors with previously administered therapies is an emerging concept that may be a life-prolonging option for heavily treated metastatic colorectal cancer (mCRC).CASE SUMMARYA 41-year-old man with no previous medical history initially presented with worsening diffuse abdominal tenderness. Computed tomography was significant for a splenic flexure mass and hepatic lesions concerning for metastatic disease. He underwent a colectomy with anastomosis. Postoperative pathology was diagnostic for moderately to well-differentiated adenocarcinoma (T4bN1bM1a). He received adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), but therapy was discontinued due to the development of atrial fibrillation. Additional workup indicated a carcinoembryonic antigen level of 508.2 ng/mL, and mutational analysis found that the tumor was microsatellite instability-high and KRAS/BRAF wild-type. He was started on irinotecan with oxaliplatin (IROX), and bevacizumab (14 cycles), developed disease progression, was transitioned to FOLFOX and cetuximab, and then eventually three cycles of pembrolizumab. Following disease progression, he was rechallenged with IROX therapy, as he previously responded well to oxaliplatin-based therapy. The IROX rechallenge provided this patient with a ten-month survival benefit, decreased metastatic burden, and marked improvement in his clinical condition.CONCLUSIONRechallenge of previous lines of well-tolerated systemic chemotherapy regimens may be a valuable therapeutic strategy in patients with heavily-treated mCRC.     

A phase I/II trial of Tumor Treating Fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer

Background

Low intensity, intermediate frequency, alternating electric fields (Tumor Treating Fields; TTFields) exhibit anti-mitotic activity in cancer cells. Promising preclinical data have led to a single arm phase I/II trial in NSCLC patients.

Methods

Forty-two inoperable stage IIIB (with pleural effusion) and IV NSCLC patients who had had tumor progression received pemetrexed 500 mg/m² iv q3w together with daily TTFields therapy until disease progression. The primary endpoint was time to “in-field” progression.

Results

Median age for all patients was 63 years, 76% had stage IV disease, 78% had adenocarcinoma and 17% had performance status of 2. The median time to in-field progression was 28 weeks and the median time to systemic progression was 22 weeks. Six patients (14.6%) had a partial remission (PR) and 20 had stable disease (SD) (48.8%). Median overall survival was 13.8 months and 1 year survival rate was 57%. There were no TTFields-related serious adverse events.

Conclusions

The combination of TTFields and pemetrexed as a second line therapy for NSCLC is safe and potentially more effective than pemetrexed alone. TTFields improved disease control within the treatment field and a phase III study is planned to further investigate its role as a novel treatment in NSCLC.     

Overcoming dynamic molecular heterogeneity in metastatic colorectal cancer: Multikinase inhibition with regorafenib and the case of rechallenge with anti-EGFR

In metastatic colorectal cancer (mCRC), fluorouracil-based combination therapy with oxaliplatin or irinotecan is the mainstay of first-line treatment. Patient survival has been significantly improved with the introduction of monoclonal antibodies against VEGF (bevacizumab), VEGFR2 (ramucirumab) or EGFR (cetuximab or panitumumab) in first- and second-line therapies. However, all patients treated with chemotherapy and targeted therapies will eventually relapse, and recently the emergence of alterations in EGFR, RAS, BRAF, ERB-B2, MET and possibly in other genes has been shown to jeopardize response to EGFR blockade. In chemorefractory patients, multikinase inhibition with regorafenib has proved to be effective and rechallenge with chemotherapy or anti-EGFR agents is empirically pursued. This review will critically discuss how the evolving knowledge of mechanisms of resistance driven by intratumoural dynamic molecular heterogeneity can impact on rational choice of treatments in this setting.     

伊立替康联合顺铂一线治疗晚期非小细胞肺癌

目的:观察伊立替康(商品名开普拓)每周给药联合顺铂治疗晚期非小细胞肺癌(NSCLC)的疗效以及不良反应。方法:经病理学或细胞学确诊的初治晚期NSCLC患者13例,男性8例,女性5例,中位年龄48岁,KPS评分>70。接受顺铂60~80mg/m2联合开普拓60mg/m2第1、8、15天静脉滴注,每4周重复。至少2周期以上可评价疗效及不良反应。结果:全组PR3例,SD9例,PD1例,总有效率为23%。中位生存时间12.5个月,1年生存为率70%(7/10)。主要不良反应为延迟性腹泻和粒细胞减少。结论:开普拓每周给药联合顺铂治疗晚期NSCLC疗效确切,不良反应发生率低,耐受性较好。     

Simplified FOLFIRI in pre-treated patients with metastatic gastric cancer

Purpose  Second-line chemotherapy in patients with metastatic gastric cancer (MGC) pre-treated with cisplatin is not a standard option. We studied a combination of irinotecan, fluorouracil and folates. Methods  Patients progressive to cisplatin-based chemotherapy were enrolled. Irinotecan 180 mg/m², folinic acid 200 mg/m², and fluorouracil 400 mg/m² were given on day 1, immediately followed by fluorouracil 2,400 mg/m² 46 h continuous infusion (simplified FOLFIRI), every 2 weeks. Results  Between June 2002 and May 2003, 28 patients were treated. Median age was 57 years (range 38–68). Most patients had a distal primary (90%), and metastatic disease (71%). Partial response was obtained in six patients (21%, 95% CI 8–41) and stable disease in eight (21%, 95% CI 13–41). Among the six responsive patients three were refractory to docetaxel. At a median follow-up of 2.9 years median time to progression was 4 months (95% CI: 2–5), and median overall survival was 5 months (95% CI 4–9). Toxicity was mild, without treatment-related deaths or life-treating adverse events. Conclusions  Simplified FOLFIRI was moderately active and well tolerated in unselected patients with MGC pre-treated with cisplatin-based chemotherapy. Its role in patients refractory to taxanes is promising and warrants further investigation.     

顺铂联合吉西他滨与联合紫杉醇治疗晚期非小细胞肺癌疗效分析

目的:观察顺铂联合吉西他滨以及顺铂联合紫杉醇治疗晚期非小细胞肺癌疗效以及毒副反应。方法:经病理组织学或细胞学证实的200例晚期非小细胞肺癌患者,随机分为吉西他滨组(GP组)与紫杉醇组(TP组)各100例。GP组:吉西他滨1000mg/m2,d1与d8,顺铂50mg/m2,d2-d4,均静脉滴注;TP组:紫杉醇150mg/m2,d1,顺铂60mg/m2,d1-d3。两组患者均每21天为一个周期,连用二个周期以上。结果:TP组总有效率(PR+CR)为50%,1年生存率为41%;GP组总有效率(PR+CR)为30%,1年生存率为36%。两组患者有效率有显著性差异(P=0.035),1年生存率无显著差异(P=0.745)。两组主要毒副反应不同,GP组血小板减少显著高于TP组,而TP组肌肉关节疼痛与呕吐显著高于GP组。结论:顺铂联合紫杉醇方案治疗效果优于顺铂联合吉西他滨方案,但是毒副反应较强。     

Combined VEGF-A and VEGFR-2 concentrations in plasma: diagnostic and prognostic implications in patients with advanced NSCLC

Introduction

The vascular endothelial growth factor (VEGF) family of ligands and receptors (VEGFR) play an important role in tumor angiogenesis. Increased expression of angiogenic factors in tumors or in blood is associated with poor prognosis. The aim of this study was to investigate the role of VEGF-A and soluble VEGFR-2 (sVEGFR-2) as biomarkers in advanced non-small-cell lung cancer (NSCLC).

Methods

We studied 432 patients with advanced NSCLC (stages IIIB-IV) treated with cisplatin and docetaxel and 89 healthy age-matched controls. Blood samples were collected before chemotherapy, and VEGF-A and sVEGFR-2 levels were determined by ELISA.

Results

VEGF-A and sVEGFR-2 levels were higher in NSCLC patients than in the controls, but VEGF-A behaves as a better diagnostic biomarker. There were no significant associations between VEGF-A and sVEGFR-2 concentrations and clinical characteristics, such as ECOG-PS, gender, stage, histology, metastases, and treatment response. A patient subgroup characterized by a combination of high VEGF-A and low sVEGFR-2 levels exhibited the worst patient prognoses in terms of TTP and OS.

Conclusions

VEGF-A and sVEGFR-2 levels were significantly higher in patients than in the controls. A combination of VEGF-A and sVEGFR-2 can be used as an independent prognostic biomarker in advanced NSCLC.     

西妥昔单抗在转移性结直肠癌一线治疗后的后续应用研究进展

表皮生长因子受体（epidermal growth factor receptor，EGFR）单克隆抗体西妥昔单抗联合化疗是RAS野生型转移性结直肠癌（metastatic colorectal cancer，mCRC）患者一线治疗的标准方案，并在后续治疗中也可能有效。一线西妥昔单抗联合化疗后患者病情缓解或稳定，西妥昔单抗继续维持治疗存在很大争议。而当肿瘤对治疗产生耐药性时，就会发生疾病进展。而对于化疗和靶向治疗后疾病进展并不意味着患者对这两类药物同时产生耐药性。多项研究表明，患者可能对化疗药物而不是西妥昔单抗产生耐药性，同时对西妥昔单抗产生耐药性的患者也可能通过化疗转换作用复敏，目前对一线西妥昔单抗联合化疗后进展的RAS野生型患者通过后续使用西妥昔单抗跨线治疗或二线化疗后再挑战治疗能否获益尚无定论。多项研究试图筛选适合于上述治疗策略的优势人群，以期延长这些患者的治疗获益时间，有助于建立其全程治疗策略。就近年来RAS野生型mCRC西妥昔单抗维持、跨线和再挑战治疗方面的研究进展进行综述。     

紫杉醇联合化疗治疗复发的晚期非小细胞肺癌40例临床研究

目的 初步探讨紫杉醇联合化疗治疗复发的晚期非小细胞肺癌的疗效。方法40例复治患者，每周紫杉醇方案4例，紫杉醇60mg／m^2静脉滴注3h，第1、8、15天，顺铂75mg／m^2第2天，每4周为一个周期；常规化疗36例，紫杉醇135mg／m^2静脉滴注311，第1大，顺铂75mg/m^2或卡铂300～350mg/m^2静脉输注第2天，每3～4周为一个周期，进行2～4周期。结果40例患者中3例死亡未评价疗效，1例因毒副反应术完成治疗,总有效率13．9％(5/36)。肿瘤相关症状改善率58．3％(21／36)。随访27例，中位生存期26．4周，1年生存率8％(4/36)。主要毒副反应为骨髓抑制和肌肉、关节疼痛。结论 紫杉醇用于二线治疗有一定疗效并能改善症状，但给药方式及剂量仍需研究，二线治疗的地位尚需明确。     

周剂量紫杉醇治疗晚期高龄非小细胞肺癌的临床研究

目的：探讨周剂量紫杉醇治疗70岁以上晚期高龄非小细胞肺癌的临床疗效和毒副反应.方法：采用紫杉醇60mg/m2/w.连用2w和（或）3w,每3～4周重复,2～4周期化疗后进行评价.结果：全组32例,总有效率37.5%;其中18例初治有效率为44.4%,CR1例,14例复治病例,有效率为35.7%.毒副反应为Ⅰ～Ⅱ度白细胞下降和周围神经毒性及消化道反应.结论：周剂量紫杉醇可作为治疗70岁以上晚期高龄非小细胞肺癌患者的安全有效的化疗方案之一.     

Second primary cancers in patients with nasopharyngeal carcinoma: a pooled analysis of 13 cancer registries

Objective To study the risk of second primary cancers in nasopharyngeal carcinoma (NPC) patients and the risk of NPC as second primary cancer. Methods We used data from the cancer registries from Singapore and from 12 low-incidence areas, including a total of 8,947 first occurring NPC cases, and 167 second occurring cases. We calculated standardized incidence ratios (SIRs) by comparing the second cancer incidence in NPC patients to the first primary cancer incidence in non-cancer population. We also calculated SIRs of second NPC after other primaries. Results In Singapore, the risk of cancers of the lung (SIR = 0.42), stomach (SIR = 0.41), and colon (SIR = 0.23) was significantly decreased after NPC, whereas that of cancer of the tongue (SIR = 11.1) was significantly increased. In Australia, Canada, and Europe, the risk of non-Hodgkin’s lymphoma (NHL) (SIR = 3.06), tongue cancer (SIR = 5.29), brain cancer (SIR = 3.89), myeloid leukemia (SIR = 3.85), and non-melanoma skin cancer (NMSC) (SIR = 3.47) was significantly increased after NPC. Incidences of second occurring NPCs following various primary cancers were not significantly altered compared to the incidence of first occurring NPCs. Conclusions Immune suppression (NHL, NMSC), shared genetic factors (lung cancer, NHL, myeloid leukemia), and shared environmental risk factors (tongue and brain cancers) might explain the associations. Except for NHL, there was no evidence of association with other Epstein-Barr virus-related cancers. Research grant and financial support: Supported by a grant R03 CA101442-02 from the National Cancer Institute (P. Brennan). G. Scélo worked on this study during the tenure of a Special Training Award from the International Agency for Research on Cancer.