Second-line systemic treatment for advanced cholangiocarcinoma

Background

Gemcitabine plus platinum (GEM-P) combination chemotherapy is standard treatment for first-line advanced cholangiocarcinoma (aCC). GEM-P first-line therapy reports a progression-free survival (PFS) of 8 months and overall survival (OS) of 11.7 months. Treatment in the second-line setting is less clear. Five-year survival for aCC remains dismal at 5-10%. The purpose of this study was to describe the outcomes with second-line systemic treatment at our institution.

Methods

This study was a single institution retrospective chart review of aCC patients who initiated second-line systemic treatment during 1/1/2009 to 12/31/2012. The primary objective was to evaluate PFS with second-line systemic treatment. Secondary objectives were OS and disease control rate. Second-line systemic regimens were classified into four treatment groups: GEM-P, gemcitabine + fluoropyrimidine (GEM-FU), other FU combination (FU-combo), and others.

Results

Fifty-six patients were included and the majority had intrahepatic aCC. A total of 80% received first-line gemcitabine-based therapy. Second-line therapy consisted of GEM-P (19.6%), GEM-FU (28.6%), FU-combo (37.5%), and others (14.3%). Median PFS was 2.7-month (95% CI, 2.3-3.8 months) with a median OS of 13.8 months (95% CI, 12-19.3 months) and a disease control rate of 50%. No significant difference in survival was identified between the four treatment groups.

Conclusions

This study revealed a 2.7-month PFS, 50% disease control rate, and potential survival benefit with second-line treatment. Options for second-line systemic therapy include GEM-FU, FU-combo, GEM-P if not given in the first-line setting. Targeted therapy with erlotinib or bevacizumab could be considered in addition to chemotherapy.     

Pemetrexed and Gemcitabine Versus Carboplatin and Gemcitabine in Non‐Small Cell Lung Cancer: A Randomized Noninferiority Phase II Study in One Center

Background.

The standard treatment for non-small cell lung cancer (NSCLC) stages IIIb and IV is a platinum compound combined with a third-generation cytotoxic agent. We decided to conduct a phase II study to assess whether the platinum compound could be replaced with pemetrexed with similar results and without an increase in side effects.

Methods.

Consecutive eligible patients were randomized to either the standard arm of gemcitabine plus carboplatin (GC) or the experimental arm of gemcitabine plus pemetrexed (GP).

Results.

Fifty evaluable patients were enrolled in the GC arm, and 44 received GP. There were 10 partial responses in the GC arm and 16 in the GP arm. With GC, mean survival was 9 months compared with 15 months with GP. The side effects were similar in both groups.

Conclusion.

Pemetrexed can replace platinum compounds in the first-line treatment of stage IIIb and IV NSCLC without increasing the side effects. A trend toward better survival was observed in the patients receiving pemetrexed instead of a platinum compound, and this should be studied further.     

Survival and Lifetime Costs Associated With First‐Line Bevacizumab Use in Older Patients With Metastatic Colorectal Cancer

Introduction.

The objective of this study was to investigate clinical effectiveness and incremental lifetime costs associated with first-line bevacizumab in older patients with metastatic colorectal cancer (mCRC).

Methods.

Patients diagnosed with mCRC in 2004–2007 were identified from the Surveillance, Epidemiology, and End Results-Medicare database and stratified by first-line treatment (no chemotherapy [CTx], CTx alone, CTx plus bevacizumab). The impact of first-line bevacizumab on survival was investigated using a propensity score adjusted multivariate Cox proportional hazards model. Mean lifetime costs for each cohort were calculated using Medicare claims for all services rendered between diagnosis and end of follow-up, adjusting for death and censoring.

Results.

A total of 4,414 patients (mean age: 77.3 years) were identified, of whom 15% received first-line bevacizumab. Among first-line-treated patients, bevacizumab receipt was associated with improved overall survival (hazard ratio: 0.85 [95% confidence interval: 0.75–0.97]; p = .013), and this benefit was limited to patients who received >1 month of bevacizumab therapy. Median and mean survival were greatest in patients treated with CTx plus bevacizumab relative to CTx alone (CTx plus bevacizumab median 19.4 months [mean 28.0 months] vs. CTx alone median 15.1 months [mean 22.9 months]; p < .001), as were mean lifetime costs (mean per patient cost $143,284 vs. $111,280). Compared with CTx alone, CTx plus bevacizumab was associated with a 5.1-month increase in mean survival and a $32,004 increase in mean lifetime treatment costs, with an incremental cost of $75,303 per life-year gained.

Conclusion.

Bevacizumab use is associated with longer survival than CTx alone in older patients treated in real-world clinical settings, at an incremental cost of $75,303 per life-year gained.     

Treatment Patterns and Clinical Outcomes in Patients With Metastatic Colorectal Cancer Initially Treated with FOLFOX–Bevacizumab or FOLFIRI–Bevacizumab: Results From ARIES,a Bevacizumab Observational Cohort Study

Background.

The Avastin® Registry: Investigation of Effectiveness and Safety (ARIES) study is a prospective, community-based observational cohort study that evaluated the effectiveness and safety of first-line treatment patterns, assessing the impact of chemotherapy choice and treatment duration.

Methods.

The ARIES study enrolled patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy with bevacizumab and followed them longitudinally. The protocol did not specify treatment regimens or assessments. Analyses included all patients who initiated bevacizumab in combination with either first-line oxaliplatin with infusional 5-fluorouracil and leucovorin (FOLFOX) or irinotecan with infusional 5-fluorouracil and leucovorin (FOLFIRI). Progression-free survival (PFS) and overall survival (OS) times were estimated using Kaplan–Meier methods. Hazard ratios (HRs) were estimated with multivariate Cox regression analysis, adjusting for potential confounding factors.

Results.

In total, 1,550 patients with first-line mCRC were enrolled (median follow-up, 21 months) and most received FOLFOX–bevacizumab (n = 968) or FOLFIRI–bevacizumab (n = 243) as first-line therapy. The baseline characteristics and median treatment duration were generally similar between subgroups. There were no significant differences in the median PFS (10.3 months vs. 10.2 months) or OS (23.7 months vs. 25.5 months) time between the FOLFOX–bevacizumab and FOLFIRI–bevacizumab subgroups, respectively, by unadjusted analyses. Multivariate analyses showed FOLFIRI–bevacizumab resulted in a similar PFS (HR, 1.03; 95% confidence interval [CI], 0.88–1.21) and OS (HR, 0.95; 95% CI, 0.78–1.16) outcome as with FOLFOX–bevacizumab. The incidence proportions of bevacizumab-associated adverse events were similar for FOLFOX- and FOLFIRI-based therapies.

Conclusions.

In first-line mCRC patients, the FOLFOX–bevacizumab and FOLFIRI–bevacizumab regimens were associated with similar treatment patterns and clinical outcomes.     

Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma

Background:

The aim of this open label phase II study ({"type":"clinical-trial","attrs":{"text":"NCT00407459","term_id":"NCT00407459"}}NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM).

Methods:

Eligible patients received pemetrexed 500 mg m⁻², carboplatin area under the plasma concentration–time curve (AUC) 5 mg ml⁻¹ per minute and bevacizumab 15 mg kg⁻¹, administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated.

Results:

Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7–46.0%). Forty-four (57.9%, 95% CI 46.0–69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3–4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred.

Conclusion:

The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM.     

Epidermal Growth Factor Receptor (EGFR)‐Tyrosine Kinase Inhibitor Treatment and Salvage Chemotherapy in EGFR‐Mutated Elderly Pulmonary Adenocarcinoma Patients

Background.

Lung cancer is frequently a disease of elderly patients. However, these patients are often treated less actively owing to a higher comorbidity rate and poor performance status. The efficacy of different treatments in elderly patients with epidermal growth factor receptor (EGFR)-mutated lung cancer is still unknown.

Materials and Methods.

We retrospectively reviewed the records of our pulmonary adenocarcinoma patients treated between 2010 and 2013. Data on patient age, type of tumor EGFR mutation, response to first-line EGFR-tyrosine kinase inhibitor (TKI) treatment, type of salvage chemotherapy, and efficacy of EGFR-TKI and salvage chemotherapy were collected.

Results.

In all, 473 of 1,230 stage IV adenocarcinoma patients had an EGFR mutation, and 330 of them received first-line TKI treatment. Of the 330 patients, 160 were ≥70 years old (elderly group) and 170 were <70 years old (younger group). The response rate and progression-free survival (PFS) with first-line TKI treatment were not significantly different. The elderly group had shorter median survival. A total of 107 patients received salvage chemotherapy after first-line EGFR-TKI treatment: 45 in the elderly group and 62 in the younger group. Their response rate and PFS were not significantly different; however, the younger group had longer median survival. Additional subgroup analysis showed that younger patients who received platinum-based chemotherapy or combination chemotherapy had better median survival than did the elderly patients. The PFS was longer among younger patients receiving a platinum-based regimen than that among the elderly patients.

Conclusion.

Elderly patients with disease progression after first-line EGFR-TKI treatment can receive chemotherapy and have a response rate similar to that of younger patients.

Implications for Practice:

The aim of the present study was to investigate the efficacy of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in elderly patients and the outcomes of subsequent salvage chemotherapy after disease progression. The most important finding was that elderly patients with disease progression after first-line EGFR-TKI treatment can receive salvage chemotherapy and have a response rate similar to that of younger patients who received salvage chemotherapy.     

First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study

Purpose.

The aim of this phase III trial was to compare the efficacy and safety of bevacizumab alone with those of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment following induction chemotherapy with XELOX plus bevacizumab in the first-line treatment of patients with metastatic colorectal cancer (mCRC).

Patients and Methods.

Patients were randomly assigned to receive six cycles of bevacizumab, capecitabine, and oxaliplatin every 3 weeks followed by XELOX plus bevacizumab or bevacizumab alone until progression. The primary endpoint was the progression-free survival (PFS) interval; secondary endpoints were the overall survival (OS) time, objective response rate (RR), time to response, duration of response, and safety.

Results.

The intent-to-treat population comprised 480 patients (XELOX plus bevacizumab, n = 239; bevacizumab, n = 241); there were no significant differences in baseline characteristics. The median follow-up was 29.0 months (range, 0–53.2 months). There were no statistically significant differences in the median PFS or OS times or in the RR between the two arms. The most common grade 3 or 4 toxicities in the XELOX plus bevacizumab versus bevacizumab arms were diarrhea, hand–foot syndrome, and neuropathy.

Conclusion.

Although the noninferiority of bevacizumab versus XELOX plus bevacizumab cannot be confirmed, we can reliably exclude a median PFS detriment >3 weeks. This study suggests that maintenance therapy with single-agent bevacizumab may be an appropriate option following induction XELOX plus bevacizumab in mCRC patients.     

Role of pemetrexed in advanced non-small-cell lung cancer: meta-analysis of randomized controlled trials, with histology subgroup analysis

Purpose

Platinum-based regimens represent the standard first-line treatment for non-small-cell lung cancer (nsclc). However, newer data have established a role for pemetrexed in the treatment of this disease. Such data suggest that histology represents a determining factor in the selection of treatment.

Methods

We undertook a systematic review of the literature for randomized controlled trials that compared the efficacy of pemetrexed with that of other treatments in advanced nsclc. Data and study quality were assessed according to published guidelines.

Results

We identified five trials that compared pemetrexed with other treatments or with placebo. Overall survival for patients treated with pemetrexed was superior to that with other treatments: hazard ratio (hr): 0.89; 95% confidence interval (ci): 0.80 to 0.99. The survival benefit was limited to patients with non-squamous histology: hr: 0.82; 95% ci: 0.73 to 0.91. Pemetrexed was inferior to other chemotherapy options in patients with squamous histology: hr: 1.19; 95% ci: 0.99 to 1.43.

Conclusions

Compared with other chemotherapy agents, pemetrexed is more effective for the treatment of nsclc in patients with non-squamous histology.     

Pre-treatment lactate dehydrogenase levels as predictor of efficacy of first-line bevacizumab-based therapy in metastatic colorectal cancer patients

Background:

Lactate dehydrogenase (LDH) represents a predictive factor in colorectal cancer patients treated with the angiogenesis inhibitor PTK/ZK. We explored the role of pre-treatment LDH serum levels in colorectal cancer patients receiving first-line bevacizumab.

Methods:

Metastatic colorectal cancer treated with first-line bevacizumab was eligible. A control group including all consecutive patients treated with chemotherapy alone was also considered. Pre-treatment LDH serum levels were collected for all cases.

Results:

Median progression-free survival (PFS) in the control group for patients with high and low LDH levels was 4.2 and 8 months, respectively (P=0.0003). Median overall survival (OS) was 19.6 and 34.9 months for patients with high and low LDH levels, respectively (P=0.0014). In the bevacizumab group, partial responses were seen in 14 (58%) high-LDH and 8 (14%) low-LDH patients (P=0.0243), respectively, median PFS was 7.3 and 8.5 months, respectively (P=0.2), and median OS was 22 and 26.6 months, respectively (P=0.7).

Conclusion:

High LDH levels correlated with worse prognosis. Bevacizumab seemed capable of improving clinical outcome in this specific group of patients who usually present with an adverse natural history. The improved response rate also suggests a role for LDH as a predictive marker.     

Single-institution experience with pemetrexed and bevacizumab as salvage therapy in advanced non-small-cell lung cancer

BACKGROUND: Second-line cytotoxic therapy for patients with advanced non-small-cell lung cancer (NSCLC) includes single-agent pemetrexed or docetaxel. The addition of bevacizumab to carboplatin/paclitaxel in the first-line setting was shown to improve survival and response. We assessed pemetrexed and bevacizumab compared with pemetrexed alone in the salvage setting. PATIENTS AND METHODS: Patients with advanced NSCLC, in whom at least first-line therapy failed and who received pemetrexed alone or pemetrexed/bevacizumab, were analyzed. RESULTS: From March 2005 through March 2006, we identified 25 patients treated with pemetrexed or pemetrexed/bevacizumab in the salvage setting. There were no significant differences in clinical features. All 25 were evaluable for overall survival, 21 for time to progression, and 19 for objective response evaluation. After a median follow-up of 9.3 months, there were no differences between the cohorts for median overall survival, time to progression, or objective disease control rate (partial response and stable disease). The 6-month survival rate was 56.3% for the pemetrexed group and 66.7% for the pemetrexed/bevacizumab group. There were no grade 3-5 hemorrhagic events. CONCLUSION: This retrospective single institution analysis showed that pemetrexed/bevacizumab was safely administered in the salvage setting of advanced NSCLC. Whether bevacizumab enhances the efficacy of pemetrexed remains to be determined and is the subject of an ongoing randomized clinical trial. Until those results are reported, off-label use of pemetrexed and bevacizumab is not recommended.     

Efficacy of Trastuzumab in Routine Clinical Practice and After Progression for Metastatic Breast Cancer Patients: The Observational Hermine Study

Background.

The Hermine study observed the use of trastuzumab for metastatic breast cancer (MBC) in routine practice, including patients who received trastuzumab treatment beyond progression (TBP).

Patients and Methods.

The study observed 623 patients for ≥2 years. Treatment was given according to oncologists'' normal clinical practices. Endpoints included duration of treatment, efficacy, and cardiac safety. The TBP subanalysis compared overall survival (OS) in 177 patients who received first-line trastuzumab and either continued trastuzumab for ≥30 days following progression or stopped at or before progression.

Results.

The median treatment duration was 13.3 months. In the first-, second-, and third-line or beyond treatment groups, the median time to progression (TTP) were 10.3 months, 9.0 months, and 6.3 months, and the median OS times were 30.3 months, 27.1 months, and 23.2 months, respectively. Heart failure was observed in 2.6% of patients, although no cardiac-associated deaths occurred. In the TBP subanalysis, the median OS duration from treatment initiation and time of disease progression were longer in patients who continued receiving trastuzumab TBP (>27.8 months and 21.3 months, respectively) than in those who stopped (16.8 months and 4.6 months, respectively). However, the groups were not completely comparable, because patients who continued trastuzumab TBP had better prognoses at treatment initiation. The median TTP was longer in patients who continued trastuzumab TBP (10.2 months) than in those who stopped (7.1 months).

Conclusion.

The Hermine findings confirm that the pivotal trials of first-line trastuzumab treatment in MBC patients are applicable in clinical practice. The subanalysis suggests that trastuzumab TBP offers a survival benefit to MBC patients treated with first-line trastuzumab.     

A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer

Background:

This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC).

Methods:

This single arm, multicentre phase II trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg⁻¹, pemetrexed 500 mg m⁻², and cisplatin 75 mg m⁻², every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients.

Results:

The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months.

Conclusion:

Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.     

The combination of intravenous bevacizumab and metronomic oral cyclophosphamide is an effective regimen for platinum-resistant recurrent ovarian cancer

Objective

To determine the efficacy, progression-free survival (PFS) and overall survival (OS) for the combination of intravenous bevacizumab and oral cyclophosphamide in heavily pretreated patients with recurrent ovarian carcinoma.

Methods

A retrospective review was performed for all patients with recurrent ovarian carcinoma treated with intravenous bevacizumab 10 mg/kg every 14 days and oral cyclophosphamide 50 mg daily between January 2006 and December 2010. Response to treatment was determined by Response Evaluation Criteria in Solid Tumors criteria and/or CA-125 levels.

Results

Sixty-six eligible patients were identified. Median age was 53 years. Fifty-five patients (83%) had undergone optimal cytoreduction. All patients were primarily or secondarily platinum resistant at the time of administration of bevacizumab and cyclophosphamide. The median number of prior chemotherapy treatments was 6.5 (range, 3 to 16). Eight patients (12.1%) had side effects which required discontinuation of bevacizumab and cyclophosphamide. There was one bowel perforation (1.5%). Overall response rate was 42.4%, including, complete response in 7 patients (10.6%), and partial response in 21 patients (31.8%), while 15 patients (22.7%) had stable disease and 23 patients (34.8%) had disease progression. Median PFS for responders was 5 months (range, 2 to 14 months). Median OS from initiation of bevacizumab and cyclophosphamide was 20 months (range, 2 to 56 months) for responders and 9 months (range, 2 to 51 months) for non-responders (p=0.004).

Conclusion

Bevacizumab and cyclophosphamide is an effective, well-tolerated chemotherapy regimen in heavily pretreated patients with recurrent ovarian carcinoma. This combination significantly improved PFS and OS in responders. Response rates were similar and favorable to the rates reported for similar patients receiving other commonly used second-line chemotherapeutic agents.     

Retrospective practice review of treatment of metastatic non-small-cell lung cancer with second-line erlotinib

Background

Epidermal growth factor receptor tyrosine kinase inhibitors (egfr-tkis) and chemotherapy have both demonstrated efficacy in recurrent metastatic non-small-cell lung cancer (nsclc) following failure of first-line platinum-based chemotherapy. Although the 3 available therapeutic agents—docetaxel, erlotinib, and pemetrexed—have significantly changed the treatment landscape for recurrent nsclc, the optimal selection of second- and third-line therapy has not been established. This practice review examines the outcomes in clinical practice of using second-line erlotinib followed by third-line chemotherapy in the treatment of recurrent metastatic nsclc.

Methods

We conducted a retrospective review of nsclc patient charts at three Canadian institutions. Patients with recurrent nsclc who had received second-line erlotinib therapy followed by third-line chemotherapy were selected by census. A chart review assessed key outcomes that included time to progression (ttp), response, and change in performance status. Outcomes for specific patient subgroups were also examined.

Results

We identified 35 patients for this retrospective practice review. First-line platinum-doublet therapy demonstrated a mean ttp of 6.6 months and a 46% overall response rate (15 partial responses and 1 complete response). Second-line treatment with erlotinib produced the highest mean ttp of all lines of therapy (9.2 months) and an overall response rate of 40% (all being partial responses). In the third-line setting, in which most patients received docetaxel, the mean ttp was 4.3 months and the overall response rate was 18% (all being partial responses). Subgroup analysis showed that all patient subgroups demonstrated benefit from second-line erlotinib treatment; improved benefit was observed in patients who developed rash, in female patients, in never smokers, in Asian patients, in patients with positive egfr status, and in patients with adenocarcinoma histology.

Conclusions

For patients with advanced nsclc who progressed following first-line platinum-based chemotherapy, the data demonstrate that second-line egfr-tki treatment is efficacious and well-tolerated and that it does not appear to diminish the benefit of third-line chemotherapy.     

First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC

Background:

Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design.

Methods:

Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria.

Results:

In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months.

Conclusions:

Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.     

AP化疗方案治疗EGFR-TKI一线化疗失败非小细胞肺癌患者的疗效及对预后的影响

目的探讨培美曲塞联合顺铂(AP)化疗方案二线治疗表皮生长因子受体-酪氨酸激酶抑制剂(EGFRTKI)一线治疗失败非小细胞肺癌(NSCLC)患者的疗效及对预后的影响。方法将90例经EGFR-TKI一线化疗失败的NSCLC患者根据随机数字表法分为AP组(培美曲塞联合顺铂)和GP组(吉西他滨联合顺铂),每组45例。比较两组患者化疗近期疗效、不良反应、生活质量及生存情况。结果AP组患者客观缓解率(ORR)与疾病控制率(DCR)均略高于GP组,但差异均无统计学意义(P>0.05)。AP组患者白细胞减少、中性粒细胞减少、血小板下降发生率均低于GP组,差异均有统计学意义(P<0.05)。化疗前,两组患者Karnofsky评分比较,差异均无统计学意义(P>0.05);化疗后,两组患者Karnofsky评分均升高,差异均有统计学意义(P<0.05)。两组生存情况比较,差异无统计学意义(P>0.05)。结论二线AP和GP化疗方案对EGFR-TKI一线治疗失败NSCLC患者近期疗效、生存时间和生活质量影响相似,但AP方案不良反应较少,更为安全。     

Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy

Background

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that responds poorly to chemotherapy. Although treatment with pemetrexed in combination with cisplatin serves as first-line chemotherapy for MPM, the optimal second-line and beyond therapy has not yet been fully examined.

Methods

Between March 2008 and October 2011, 17 consecutive Japanese patients pretreated with at least one regimen of platinum plus pemetrexed chemotherapy received gemcitabine and vinorelbine. Responses, survival time, and toxicity were retrospectively evaluated.

Results

Response [partial response (PR) + complete response (CR)] and disease control [stable disease (SD) + PR + CR] rates were 18 and 82 %, respectively. The median progression-free survival (PFS) after combination chemotherapy was 6.0 months, whereas the median overall survival (OS) was 11.2 months. Grade 3 or 4 neutropenia and anemia were observed in 41 and 29 % of patients, respectively, and one patient experienced febrile neutropenia. Grade 3 or 4 nonhematologic toxicities included constipation (6 %) and phlebitis (6 %).

Conclusion

Combination chemotherapy using gemcitabine with vinorelbine was shown to have moderate activity in Japanese MPM patients pretreated with platinum plus pemetrexed chemotherapy. A further multicenter phase II trial is warranted to confirm the efficacy and safety of this combination treatment.     

Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer

BackgroundThe randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61–0.93]. We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL).Patients and methodsPatients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety.ResultsOf the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59–1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68–1.05) or OS (HR = 0.96, 95% CI 0.76–1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected.ConclusionsIn this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life.ClinicalTrials.govNCT01250379.     

Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial

Background:

In the AXIS trial, axitinib prolonged progression-free survival (PFS) vs sorafenib in patients with advanced renal cell carcinoma (RCC) previously treated with sunitinib or cytokines.

Methods:

In post hoc analyses, patients were grouped by objective response to prior therapy (yes vs no), prior therapy duration (< vs ⩾median), and tumour burden (baseline sum of the longest diameter < vs ⩾median). PFS and overall survival (OS), and safety by type and duration of prior therapy were evaluated.

Results:

Response to prior therapy did not influence outcome with second-line axitinib or sorafenib. PFS was significantly longer in axitinib-treated patients who received longer prior cytokine treatment and sorafenib-treated patients with smaller tumour burden following sunitinib. Overall survival with the second-line therapy was longer in patients who received longer duration of prior therapy, although not significant in the sunitinib-to-axitinib sequence subgroup; OS was also longer in patients with smaller tumour burden, but not significant in the cytokine-to-axitinib sequence subgroup. Safety profiles differed modestly by type and duration of prior therapy.

Conclusions:

AXIS data suggest that longer duration of the first-line therapy generally yields better outcome with the second-line therapy and that lack of response to first-line therapy does not preclude positive clinical outcomes with a second-line vascular endothelial growth factor-targeted agent in patients with advanced RCC.     

Phase II study of pemetrexed plus intermittent erlotinib combination therapy for pretreated advanced non-squamous non-small cell lung cancer with documentation of epidermal growth factor receptor mutation status

Introduction

Erlotinib and pemetrexed have been approved for the second-line and maintenance treatment of non-small cell lung cancer (NSCLC). With the recommended doses determined by our previous phase I study, we conducted a phase II study to evaluate the efficacy and safety of combination of the two agents in pretreated non-squamous NSCLC patients.

Methods

This study was performed in patients with stage IIIB/IV or post-surgically recurrent non-squamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. Patients received 500 mg/m² of intravenous pemetrexed every 21 days and 150 mg of oral erlotinib on days 2–16 until disease progression, unacceptable toxicity, or withdrawal of consent. The expected response rate and threshold were defined as 33.5% and 10%, respectively. Assuming a one-sided alpha of 5%, a power of 80%, the possible deviation from assessment, 26 patients were necessary.

Results

A total of 27 patients, 16 males and 11 females were recruited. Patients had the median age of 70 years (range, 48–80 years) and included 21 stage IV diseases, 22 adenocarcinomas. Epidermal growth factor receptor (EGFR) mutations were examined in all patients. One patient had positive EGFR mutation, but the other 26 patients had wild-type EGFR. The median number of treatment courses was 3 (range, 1 to over 19). The best overall response rate and disease control rate were 11.1% and 63.0%, respectively. The median progression-free survival and overall survival were 2.8 months (95% confidence interval (CI); 1.9–7.5 months) and 15.8 months (95% CI; 9.3 months to not available), respectively. Dermal, hepatic, gastrointestinal and hematological disorders were the frequently observed adverse events. One patient experienced grade 3 drug-induced interstitial lung disease.

Conclusions

We could not demonstrate the add-on effect of intermittent erlotinib on pemetrexed in a second-line setting for patients with non-squamous NSCLC without EGFR mutations.