Second-line treatment with oxaliplatin + raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorin-based chemotherapy

Background:To evaluate the efficacy and tolerance of combined raltitrexed and oxaliplatin in patients with advanced colorectal cancer pretreated with fluoropyrimidine–leucovorin-based chemotherapy. Patients and methods:Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within six months after withholding palliative chemotherapy with fluoropyrimidines–leucovorin ± irinotecan, participated in this study. Treatment consisted of oxaliplatin 130 mg/m² and raltitrexed 3.0 mg/m² both given on day 1 every three weeks for a total of eight courses unless prior evidence of progressive disease. Results:The overall objective response rate was 33.3% for all 36 evaluable patients (95% confidence interval (CI): 18.6%–51%). Seventeen additional patients (47.2%) had stable disease, and only seven (19.5%) progressed. The median progression-free survival was 6.5 months (range 1.2–14.0). After a median follow-up time of 12 months, 23 patients (63.8%) are still alive. The tolerance of treatment was acceptable with only 8 of 36 patients (22%) experiencing grade 3 or 4 neutropenia. Grade 3 non-haematological adverse reactions included peripheral sensory neuropathy in three, asthenia in one, diarrhea in two, and clinically insignificant increase in serum transaminases in two patients, respectively. Conclusions:Our data suggest that the combination of oxaliplatin and raltitrexed has substantial antitumour activity in patients with progressive fluoropyrimidine–leucovorin ± irinotecan pretreated colorectal cancer. Because of its favorable toxicity profile and convenient three-weekly outpatient administration schedule, further evaluation of this regimen seems warranted.     

Second-line systemic therapy for the treatment of metastatic renal cell cancer

The discovery of molecular mechanisms driving the progression of renal cell carcinoma (RCC) has led to the development of drugs that target RCC at the molecular level. Inhibition of VEGF-targeting pathways is successful as a front-line treatment in patients with metastatic RCC. In addition, bevacizumab/IFN-α, sunitinib and pazopanib are recommended for first-line use in good- or intermediate-risk patients, whereas temsirolimus is approved for poor-risk patients. Second-line options are valuable as these patients eventually progress. The present review addresses which drug is best in this second-line setting. Options for sequential therapy include tyrosine kinase inhibitor (TKI)–mTOR inhibitor or TKI–TKI sequences. We also address the question of whether sequential therapy with TKIs or the combination of VEGF followed by mTOR inhibition is the best choice for specific patients, and which sequence of TKIs is most beneficial.     

Irinotecan as a Second-line Monotherapy for Small Cell Lung Cancer

Objectives: The present study was designed to investigate the efficacy of irinotecan monotherapy as a secondlinetreatment for small cell lung cancers (SCLCs). Methods: Irinotecan monotherapy was administered to 46SCLC patients who were previously undergone cisplatin based chemotherapy protocols. Response to treatment,time to progression (TTP), overall survival rates and adverse events associated with irinotecan monotherapy(300mg/m2; total 153 cycles; mean 3.78 ± 1.98) were determined, retrospectively. Results: Limited stage diseasewas diagnosed in 19.6% of patients (n=9) while 80.4% (n=37) were diagnosed with extensive stage cancerpreceeding the irinotecan monotherapy. None of the patients had complete response to irinotecan. Partialresponse and stable disease were achieved among 17.5% of patients. Mean time to tumor progression (TTP) wasdetermined to be 11.3±5.94 weeks while overall survival was 13.3±6.83 months. Considering adverse events, grade3 and 4 toxicity was encountered in 8.9% and 4.5% of patients, respectively. Irinotecan monotherapy in brainmetastasized tumors was found to be associated with significantly higher survival times compared with tumorslacking brain metastasis (15.0±5.95 vs 10.7±4.82 months; p<0.05). Conclusions: Irinotecan as a monotherapy inthe second-line treatment of SCLC seems to have an acceptable level of toxicity and significant palliative effects.The prominent survival step-up effect particularly in brain metastasis patients appears worthy of note.     

Five-day infusion fluorouracil plus vinorelbine in women with breast cancer previously treated with anthracyclines and paclitaxel

The continuous infusion of fluorouracil presents a superior pharmacological profile than its bolus administration, while vinorelbine is a new drug associated with good clinical activity in pretreated metastatic breast cancer. We investigated the combination of this two antitumor drugs with the aim to determine a tolerant and active second-line therapy in metastatic pretreated patients. Patients and methods.Fifty six patients pretreated with chemotherapy received a median of six cycles [2–11] of fluorouracil, 700mg/m² for 5 day-continuous i.v. infusion and vinorelbine, 20mg/m² on days 1 and 6, every three weeks. The inclusion and evaluation criteria required measurable disease by conventional clinical and/or instrumental means. Findings.Iatrogenic toxicity in 340 administered cycles was mild: stomatitis==11% (Grade 3==5%), constipation and abdominal pain==12, G2 neutropenia==4, G1 thrombocytopenia==0.5. In nine cases moderate infections occurred and six women experienced catheter related complications. Complete and partial remissions were observed in 12% and 36% of evaluable patients, respectively. In particular major tumor regression was documented in 28% of anthracyclines or taxol unresponsive cases. Conclusions.This drug combination is active in metastatic pretreated breast cancer patients and devoid of serious iatrogenic toxicity. Although it deserves future optimization, for instance with the inclusion of oral fluoropirimidines, it represents a good choice for second-line or non cross-resistant regimens.     

Irinotecan as a Second-line Chemotherapy for Small Cell Lung Cancer: a Systemic Analysis

Purpose: This analysis was conducted to evaluate the efficacy and safety of irinotecan based regimens assecond-line chemotherapy in treating patients with small cell lung cancer. Methods: Clinical studies evaluatingthe efficacy and safety of irinotecan based regimens as second-line chemotherapy for patients with small celllung cancer were identified using a predefined search strategy. Pooled response rates (RRs) of treatment werecalculated. Results: In irinotecan based regimens as second-line chemotherapy, 4 clinical studies which including155 patients with small cell lung cancer were considered eligible for inclusion. In all chemotherapy consistedof irinotecan with or without nedaplatin. Pooled analysis suggested that, in all patients, the pooled RR was27.1% (42/155) in irinotecan based regimens. Nausea, vomiting, diarrhea and myelosuppression were the mainside effects. No grade III or IV renal or liver toxicity was observed. No treatment related death occurred withthe irinotecan based treatments. Conclusion: This systemic analysis suggests that irinotecan based regimens assecond-line chemotherapy are associated with mild response rate and acceptable toxicity for patients with smallcell lung cancer.     

A phase I study of gemcitabine and epirubicin for the treatment of platinum-resistant or refractory advanced ovarian cancer

Background:Gemcitabine is active in patients with otherwiseresistant or refractory ovarian cancer. As the drug is well tolerated, studiesusing gemcitabine combined with other antineoplastic agents are needed. Theaim of the study was to determine the maximum tolerated dose (MTD) ofepirubicin combined with gemcitabine, with and without support of G-CSF. Patients and methods:Patients with platinum-resistant orrefractory ovarian cancer were eligible. Gemcitabine (G) (starting dose 800mg/m² day 1 and 8; 200 mg/m² escalation per level) andepirubicin (E) (starting dose 60 mg/m² day 1; 15 mg/m²escalation per level) were given every 21 days for four to six cycles. G-CSF(filgrastim 5 µg/kg/die) was given in case of grade 4 neutropenia(levels without support) or from day 9 up to leukocyte count>10,000/mm³ after nadir (levels with support). Cohorts of threepatients were enrolled at each level, and another three patients were planned,if one dose-limiting toxicity (DLT) was registered. MTD was determined firstwithout and then with G-CSF. Results:Four levels were studied (G 800 + E 60; G 1000 + E 60;G 1000 + E 75; G 1000 + E 75 + G-CSF) with four, four, three and threepatients enrolled, respectively. DLT (grade 4 febrile neutropenia) wasobserved in two patients at level 3. Thus, G1000 + E 60 mg/m² wasthe MTD without G-CSF. The addition of prophylactic G-CSF did not allow afurther increase of the dose and grade 4 thrombocytopenia was the DLT at level4. Non-hematological toxicity was mild. Grade 2 mucositis was reported in fourpatients. Among the 13 patients with measurable or evaluable disease, 3partial responses were observed for an overall response rate of 23.1%. Conclusions:The combination of gemcitabine 1000 mg/m²(day 1, 8) and epirubicin at 60 mg/m² (day 1) is a feasibletherapy. Grade 4 neutropenia is frequent and G-CSF support is often required.With prophylactic support of G-CSF, the DLT is thrombocytopenia.     

Second-line chemotherapy for non-small cell lung cancer

Several agents have been evaluated for the second-line treatment of patients with non-small cell lung cancer. The TAX 317 trial found that patients treated with docetaxel (Taxotere^®) 75 mg/m² had significantly longer survival than those treated with best supportive care alone. In addition, symptom control was better for patients who received chemotherapy. The TAX 320 trial found that treatment with docetaxel 75or 100 mg/m²resulted in significantly higher response rates than treatment with vinorelbine (Navelbine^®) or ifosfamide (Mitoxana^®), and the 1-year survival rate was also significantly better for patients treated with docetaxel 75 mg/m². A large randomized trial compared pemetrexed (LY-231514 or Alimta^®) 500 mg/m² with docetaxel 75 mg/m². Response and survival rates were similar in the two treatment arms, however, the toxicity profile of pemetrexed was superior to that of docetaxel with significantly less Grade 3/4 neutropenia and febrile neutropenia. Fewer patients in the pemetrexed arm required hospitalization. Topotecan (Hycamtin^®) 2.3 mg/m²/day orally for 5 days has been compared with docetaxel 75 mg/m²in a large 800-patient study. The results of this trial are awaited. Gemcitabine (Gemzar^®) and irinotecan (Campto^®) have been evaluated both as single agents and in combination with each other and study results do not suggest that either of these drugs is superior to docetaxel or pemetrexed. The vinca alkaloid vinorelbine has proved to be inferior to docetaxel in a randomized trial. The epidermal growth factor receptor inhibitors gefitinib (ZD1839, Iressa^®) and erlotinib (CP-358774, OSI 774, Tarceva^®) have been evaluated in Phase II trials in the second- and third-line setting. Both drugs have demonstrated interesting response rates ranging from 10 to almost 20%. The results of placebo-controlled randomized trials of this family of drugs are awaited. In summary, several studies have now found a definite role for the second-line treatment of patients with non-small cell lung cancer.     

双铂联合氟尿嘧啶二线治疗复发转移食管癌研究

[目的]观察双铂方案二线治疗复发转移食管癌的近期疗效及不良反应。[方法]30例一线化疗后复发转移食管癌患者,进行二线治疗,化疗方案：顺铂25mg/m^2d1,奈达铂25mg/m^2d2,3,氟尿嘧啶0.35g/m^2civ d1～7,3周重复。[结果 ]部分缓解（PR）11例,疾病稳定（SD）8例,疾病进展（PD）11例,有效率（RR）为36.7%,疾病控制率（DCR）为63.3%,中位达进展时间（TTP）为4.3个月（95%CI：1.1～10.5）,中位生存时间（MST）为8.9个月（95%CI：2.1～15.3）。主要不良反应为血液学毒性,Ⅲ～Ⅳ级白细胞减少的发生率分别为13.3%,Ⅲ级口腔炎的发生率为6.7%。[结论]双铂联合氟尿嘧啶二线治疗复发转移食管癌的近期疗效较好,不良反应可耐受。     

长春瑞滨联合奈达铂二线治疗复发转移鼻咽癌的疗效评价

目的观察长春瑞滨联合奈达铂二线治疗复发和(或)转移晚期鼻咽癌的疗效及不良反应。方法 92例复发和(或)转移晚期鼻咽癌,既往均予一线化疗或同步放、化疗。长春瑞滨25~30mg/m2,第1、8天,静脉滴注,30 min内完成,奈达铂100 mg/m2,第1、8天,静脉滴注。长春瑞滨滴注前后将25%硫酸镁4 ml、2%利多卡因4 ml,加入0.9%生理盐水250 ml,静脉滴注。化疗3周为一周期,重复4~6周期。结果 CR 2.2%(2/92),PR 52.2%(48/92),NC 21.8%(20/92),PD 23.9%(22/92),RR54.3%(50/92)。1年生存率52.2%(48/92),2年生存率15.2%(14/92),中位生存期14(4.2~33.0)个月。无进展生存期(progress free survival,PFS)为5.3个月。结论长春瑞滨联合奈达铂治疗复发和(或)转移晚期鼻咽癌具有协同作用,毒副作用可耐受,能延长患者的生存时间。     

Combination chemotherapy in the treatment of advanced breast cancer

Seventy-two women with metastatic breast cancer were treated with multiple-agent chemotherapy. Fifty women were treated with 5 drugs in combination: 5-FU, methotrexate, vincristine, cytoxan, and prednisone; 22 were treated with the combination of 3 drugs: 5-FU, cytoxan, and prednisone. In 14 patients receiving 5 drugs and in 22 receiving 3 drugs, the multiple chemotherapy was the primary palliative treatment of extensive visceral metastases unsuitable for adrenalectomy. Results were similar with 6 responders in 14 (0.43) receiving 5 drugs, and 10 responders in 22 (0.45) receiving 3 drugs. The remaining 36 patients who were given 5-drug therapy all had previous adrenalectomy, and there were 16 responders (0.44). Toxicities from 3-drug treatment were substantially less severe than those from the 5-drug combination therapy. Whereas treatment-related death occurred in 6 of 50 patients receiving the 5-drug combination, no such incidence occurred in those receiving 3-drug combination therapy.     

Second-line chemotherapy for patients with advanced gastric cancer: who may benefit?

No established second-line chemotherapy is available for patients with advanced gastric cancer failing to respond or progressing to first-line chemotherapy. However, 20-40% of these patients commonly receive second-line chemotherapy. We evaluated the influence of clinico-pathologic factors on the survival of 175 advanced gastric cancer patients, who received second-line chemotherapy at three oncology departments. Univariate and multivariate analyses found five factors which were independently associated with poor overall survival: performance status 2 (hazard ratio (HR), 1.79; 95% CI, 1.16-2.77; P=0.008), haemoglobin 50 ng ml(-1) (HR, 1.86; 95% CI, 1.21-2.88; P=0.004), the presence of greater than or equal to three metastatic sites of disease (HR, 1.72; 95% CI, 1.16-2.53; P=0.006), and time-to-progression under first-line chemotherapy 相似文献   

胆管癌的化疗现状

胆管癌是一种较少见的恶性肿瘤,其预后差,死亡率高。对于某些经选择的患者,外科切除是唯一的治愈方法。目前,尚缺乏有指导意义的术后辅助化疗的研究。初步数据显示部分经新辅助放化疗的患者,可通过肝移植延长生存期。对于已经处于局部晚期或远处转移的患者的治疗,有一些小型、非随机的Ⅱ期试验,部分试验的入组患者不仅有胆管癌,还包括胆囊癌、胰腺癌和肝细胞肝癌。对于晚期胆管癌,试验常选择吉西他滨、顺铂或氟尿嘧啶进行治疗,但不论单药还是联合用药,其效果均很微弱,并且疗效不持久,故尚无标准治疗。     

肺癌二线治疗新进展

该文以循征医学观点,分析肺癌二线治疗的临床试验结果,提示二线化疗对一般情况良好的病人有效:并对新的生物靶向治疗作了展望.     

Phase II study of weekly irinotecan (CPT-11) as second-line treatment of patients with advanced colorectal cancer

This phase II trial studied the antitumor effect and toxicity of weekly irinotecan (CPT-11, 125 mg/m² 60 min iv infusion, weekly for 4 wk plus 2 wk rest) as second-line chemotherapy in patients with advanced colorectal cancer (CRC) resistant or refractory to prior 5-fluorouracil (5-FU) therapy. Sixty-nine patients with adenocarcinoma (57% in the colon and 43% in the rectum) were enrolled. The median number of treatment cycles received per patient was 4 (range, 1–6). Overall response rate was 18% (95% CI, 9–26), with 4 complete responses (6%) and 8 partial responses (12%), and a median duration of response of 8.1 mo (95% CI, 4.2–12.1). Stable disease was observed in 19 patients (28%). The median time to disease progression was 5.2 mo (95% CI, 4.3–6.1), and the median overall survival was 13.3 mo (95% CI, 9.8–16.8 months). The toxicity profile was favorable: grade 3/4 delayed diarrhea was observed in 10 patients (14.5%) in one cycle each, and grade 3/4 neutropenia in 6 patients (8.7%) and 6 cycles (3.3%). No febrile neutropenia or infection was documented. Grade 3/4 nausea and vomiting were reported in 1 (1.4%) and 7 patients (10.1%), respectively. In conclusion, this phase II trial showed a response rate and a toxicity profile of weekly CPT-11 in line with the results of prior phase II studies.     

A phase II study of weekly docetaxel as salvage chemotherapy for advanced gastric cancer

Background:Docetaxel has shown some activity in advanced gastriccancer. Recent phase I studies found low hematologic toxicity and a favourabletoxicity profile when docetaxel was administered on a weekly schedule. In thisstudy, we explored the activity of weekly docetaxel in patients with advancedgastric cancer who failed first-line chemotherapy. Materials and methods:Patients with stable or progressing diseaseafter first-line chemotherapy received 36 mg/m² weekly docetaxel.One cycle consisted of six administrations followed by a two-weeks rest,patients were re-evaluated at week eight. The optimal two-stage design wasadopted for early stopping of the trial if responses were one or less in 21patients (<20% response rate with and errorprobabilities 0.05 and 0.010 respectively). Results:Twenty-one patients have been enrolled and they are fullyevaluable for response and toxicity. One patient achieved partial response,8 patients had stable disease and 12 patients progressed. Median overallsurvival from the onset of salvage chemotherapy was 3.5 months. Hematologictoxicity was observed in two patients who experienced grade III leukopenia.Beginning from the third week of treatment, most of the patients (90%)showed grade II asthenia which resulted the commonest side-effect. Conclusions:This schedule of weekly docetaxel did not showsignificant activity in pretreated patients with advanced gastric cancer.     

Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort

Background:

There is currently no standard second-line treatment for metastatic pancreatic adenocarcinoma (MPA), and progression-free survival is consistently <4 months in this setting. The aim of this study was to evaluate the efficacy and tolerability of Nab-paclitaxel plus gemcitabine (A+G) after Folfirinox failure in MPA.

Methods:

From February 2013 to July 2014, all consecutive patients treated with A+G for histologically proven MPA after Folfirinox failure were prospectively enrolled in 12 French centres. A+G was delivered as described in the MPACT trial, until disease progression, patient refusal or unacceptable toxicity.

Results:

Fifty-seven patients were treated with Nab-paclitaxel plus gemcitabine, for a median of 4 cycles (range 1–12). The disease control rate was 58%, with a 17.5% objective response rate. Median overall survival (OS) was 8.8 months (95% CI: 6.2–9.7) and median progression-free survival was 5.1 months (95% CI: 3.2–6.2). Since the start of first-line chemotherapy, median OS was 18 months (95% CI: 16–21). No toxic deaths occurred. Grade 3–4 toxicities were reported in 40% of patients, consisting of neutropenia (12.5%), neurotoxicity (12.5%), asthenia (9%) and thrombocytopenia (6.5%).

Conclusions:

A+G seems to be effective, with a manageable toxicity profile, after Folfirinox failure in patients with MPA.     

Nanoliposomal irinotecan plus fluorouracil and folinic acid: a new treatment option in metastatic pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with half of patients diagnosed in the metastatic setting. Until recently, patients after progression on front-line gemcitabine-based regimen had no standard second-line option, although flouropyrimidine-based regimens were frequently used in this setting. Encapsulation of chemotherapeutics in liposomal formulation is an effective way of prolonging drug deposition thereby enhancing cytotoxic efficacy. In a large phase III randomized trial on metastatic PDAC patients who progressed after gemcitabine-based chemotherapy, a novel nanoliposome-encapsulated irinotecan (PEP02, MM-398, nal-IRI, Onivyde, Merrimack, Boston, US) plus fluorouracil and folinic acid demonstrated a significant survival advantage compared to fluorouracil and folinic acid alone. This pivotal study led to the recent FDA approval of nanoliposomal irinotecan in patients with metastatic PDAC. In this article, we will review the literature regarding existing treatment options for metastatic PDAC, focusing specifically on nanoliposomal irinotecan in the clinical setting and its future implication.     

Prospects for colorectal cancer treatment: oral chemotherapy and targeted biotherapy

Since the 1990s, the emergence of new drugs has modified the prognosis of metastatic colorectal cancer. This malignant disease has largely benefited from the development of new drugs and new therapeutic concepts, such as oral chemotherapy or targeted biotherapy. Although a significant improvement in survival has been reached with these new therapeutic approaches, the optimal strategy remains to be defined, particularly the best sequence of drug administration. This review will focus upon new anticancer drugs, some of them with original mechanism of action, and steps towards the goal of better understanding and anticipating new treatments in colorectal carcinoma.     

Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma.

BACKGROUND: A phase III trial in patients with malignant pleural mesothelioma demonstrated a survival advantage for pemetrexed plus cisplatin compared with single-agent cisplatin. Because post-study chemotherapy (PSC) may have influenced the outcome of the trial, we examined its use and association with survival. PATIENTS AND METHODS: Eighty-four patients from the pemetrexed plus cisplatin arm and 105 patients from the single-agent cisplatin arm received PSC. Kaplan-Meier survival estimates were compared by treatment groups, and by PSC and non-PSC subgroups. RESULTS: The percentage of patients receiving PSC was imbalanced between the treatment arms. Fewer pemetrexed plus cisplatin treated patients received PSC (37.2% versus 47.3%). A multiple regression analysis performed in this trial showed that PSC had a statistically significant correlation with prolonged survival (P <0.01), adjusting for baseline prognostic factors and treatment intervention. The adjusted hazard ratio for PSC over non-PSC subgroups was 0.56 (confidence interval 0.44-0.72). CONCLUSIONS: PSC in malignant pleural mesothelioma was significantly associated with prolonged survival. It is not known whether the reduced risk of death was associated with PSC or whether patients who had prolonged survival tended to receive more PSC. The pemetrexed plus cisplatin treatment group had a statistically significant survival advantage even though fewer patients from that arm of the trial received PSC. The potentially beneficial role of PSC should be assessed in prospective trials.     

Antitumour activity of three second-line treatment combinations in patients with metastatic colorectal cancer after optimal 5-FU regimen failure: a randomised, multicentre phase II study.

BACKGROUND: We have investigated the efficacy, safety and quality of life profiles of three therapeutic combinations [irinotecan + leucovorin (LV)/5-fluorouracil (5-FU), oxaliplatin + LV/5-FU and irinotecan +oxaliplatin] in patients with metastatic colorectal cancer after failure of a 5-FU-based regimen, or whose disease had progressed within 6 months of the end of treatment. PATIENTS AND METHODS: One hundred and one patients were randomised to receive either: (i) irinotecan 180 mg/m(2) on day 1 followed by an LV 200 mg/m(2) infusion, before a 5-FU 400 mg/m(2) bolus followed by a 5-FU 600 mg/m(2) infusion (LV5FU2 regimen), on days 1 and 2 every 2 weeks; (ii) oxaliplatin 85 mg/m(2) on day 1 followed by the LV5FU2 regimen on days 1 and 2 every 2 weeks; or (iii) oxaliplatin 85 mg/m(2) followed by irinotecan 200 mg/m(2), both on day 1 every 3 weeks. The primary end point was overall response rate (ORR). RESULTS: The intention-to-treat ORRs were 11.4% [95% confidence interval (CI) 3.2-26.7), 21.2% (95% CI 9.0-38.9) and 15.2% (95% CI 5.1-31.9), respectively, in the three arms. Tumour growth control was >or=60% for all three combinations and overall survivals were 12.2 months (95% CI 9.2-16.0), 11.5 months (95% CI 9.0-14.1) and 11.0 months (95% CI 8.1-12.2), respectively. All patients were evaluable for safety. Main grade 3-4 toxicity was neutropenia (33 to 39% of patients). CONCLUSIONS: Thus, second-line treatment with irinotecan/LV5FU2, oxaliplatin/LV5FU2 or irinotecan/oxaliplatin, provides good tumour growth control and survival coupled with an acceptable safety profile.