A population-based study on treatment and outcomes in patients with gastric adenocarcinoma diagnosed with distant interval metastases

BackgroundIn patients with gastric or gastroesophageal junction (GEJ) cancer treated with curative intent, distant interval metastases may be detected after start of neoadjuvant chemotherapy or during surgery. The aim of this study was to explore characteristics, allocated treatment and overall survival (OS) in gastric/GEJ cancer patients with interval metastases, and to compare OS with synchronous metastatic gastric/GEJ cancer patients who started palliative chemotherapy.MethodsPatients with interval metastases were selected from the Netherlands Cancer Registry by including patients with potentially curable gastric/GEJ adenocarcinoma (2010–2018) who started chemotherapy without concurrent radiotherapy. The OS since start of neoadjuvant treatment of patients with interval metastases was compared with a propensity score-matched cohort of patients with synchronous metastases who received palliative systemic treatment.Results164 patients with interval metastases diagnosed in 2010–2018 were included. Metastases were most frequently detected during surgery (83%) and most frequently located in the peritoneum (77%). Peritoneal interval metastases were observed in 63% and 80% of the patients who did and did not have a diagnostic laparoscopy prior to neoadjuvant treatment, respectively (P = 0.041). Median OS was 8.9 months (IQR 5.5–13.4), compared to 8.0 months (IQR 4.1–14.1) in matched synchronous metastatic patients calculated from start of neoadjuvant and palliative systemic treatment, respectively (P = 0.848).ConclusionThis population-based study shows that gastric/GEJ cancer patients who started neoadjuvant treatment and were diagnosed with interval metastases most frequently suffered from peritoneal metastases detected during (exploratory) surgery, even when a diagnostic laparoscopy was performed before start of treatment. OS was comparable to patients with synchronous metastatic gastric/GEJ cancer.     

Bevacizumab in combination with taxanes for the first-line treatment of metastatic breast cancer

BackgroundTaxanes are an established treatment of metastatic breast cancer (mBC). Biological therapies that can be effectively combined with taxanes may provide an alternative to taxane–chemotherapy doublets, which are not suitable for all patients.Patients and methodsBevacizumab is a humanised mAb against vascular endothelial growth factor (VEGF) which inhibits angiogenesis. This review summarises outcomes from trials evaluating bevacizumab in the first-line treatment of mBC.ResultsBevacizumab demonstrated considerable efficacy in combination with taxane therapy in the first-line treatment of human epidermal growth factor receptor-2 (HER2)-negative mBC in three phase III trials. Improved response rate and progression-free survival (PFS) were also observed in patients who had received taxanes in the adjuvant setting. Bevacizumab–taxane combinations are effective across a broad range of patient subgroups and have greater efficacy than single-agent taxanes in first-line mBC. Importantly, the tolerability of bevacizumab–taxane combinations compares favourably with that of taxanes in combination with other chemotherapy agents.ConclusionsBevacizumab–taxane combinations provide an alternative to chemotherapy doublet regimens in first-line mBC, with equivalent efficacy and potentially lower toxicity. Ongoing trials are investigating the efficacy and safety of bevacizumab in various stages of breast cancer and in breast cancer with a range of hormonal or receptor characteristics.     

Efficacy of a triplet and doublet-based chemotherapy as first-line therapy in patients with HER2-negative metastatic gastric cancer: a retrospective analysis from the clinical practice

The best choice of chemotherapy regimen for patients with metastatic gastric cancer is still debated. Although several studies support a superior efficacy of a triplet chemotherapy regimen over a doublet-based regimen, the magnitude of this benefit appears small and accompanied by an increased toxicity. Based on this background, we evaluated the outcome of patients with HER2-negative metastatic gastric cancer (mGC) who received in the clinical practice a triplet or doublet regimen as first-line therapy. A total of 165 patients (pts) with HER2-negative mGC treated outside of clinical trials at our department with FOLFOX-4 or ECX from 2012 and 2015 were included in our retrospective analysis: FOLFOX-4: 86 pts; ECX: 79 pts. Median progression-free survival (PFS) was 5.1 months for FOLFOX-4 and 5.6 months for ECX regimen, respectively. Median overall survival (OS) was 10.3 months for FOLFOX-4 and 10.9 months for ECX regimens. Toxicity: grade 3–4 vomiting (12.6%), neutropenia (31.6%), mucositis (11.3%) and fatigue (22.7%) occurred more frequently in ECX regimen, while grade 3–4 peripheral neuropathy was more common with FOLFOX-4 (19.7%). Both evaluated regimens are active and safe in the palliation of HER2-negative mGC in the first-line setting: Three-drug chemotherapy regimen appear more active but offer only a slight improvement in OS with an increased G3–G4 toxicity. Our data suggest that a doublet therapy should be preferred in the clinical practice, preferentially reserving a three-drug combination to pts with bulky disease and/or to pts with initially unresectable locally advanced disease.     

Impact of Baseline Clinical Biomarkers on Treatment Outcomes in Patients With Advanced NSCLC Receiving First-line Pembrolizumab-Based Therapy

BackgroundWhile the introduction of immune checkpoint inhibitors (ICI) such as pembrolizumab has significantly improved survival for patients with metastatic non-small cell lung cancer (NSCLC), there remains a need for improved predictive and prognostic biomarkers.Patients and MethodsWe conducted a retrospective, 3-center study using electronic medical record data for patients with stage IV NSCLC treated with first-line pembrolizumab, either as monotherapy or in combination with chemotherapy, between 2014 and 2019. We categorized variables as covariates or confounders. Covariates, which were the focus of analysis due to their emerging prognostic value, included pretreatment body mass index (BMI), neutrophil-to-lymphocyte ratio (NLR), albumin, and antibiotic exposure. Confounders, which highlighted characteristics for each patient and their cancer, included sex, age at start of immunotherapy, Programmed death-ligand 1 (PD-L1) expression, performance status (PS), tumor mutational burden and whether pembrolizumab was given as monotherapy or in combination with chemotherapy. The association between these variables with time to treatment failure (TTF) and overall survival (OS) was assessed using Kaplan-Meier method and Cox proportional hazards models.ResultsOne hundred thirty-six patients were included in our study. Antibiotics usage, serum albumin, and NLR have univariate relationships with TTF. Serum albumin, NLR, and BMI were associated with OS in univariate analyses. In our multivariate analysis, antibiotic usage had a strong negative association with TTF when adjusting for all 6 confounders.ConclusionPretreatment usage of antibiotics, as well as albumin, NLR, and BMI have potential to predict treatment outcomes in patients with advanced NSCLC receiving first-line immunotherapy.     

双药方案对比单药方案治疗老年晚期非小细胞肺癌的Meta分析

背景与目的双药方案治疗老年晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的疗效是否优于单药化疗尚存争议,本研究旨在对双药方案治疗老年晚期NSCLC患者的有效性和安全性进行系统评价。方法计算机检索PubMed、EMBASE、Cochrane Library、中国期刊全文数据库和中国生物医学文献等数据库,收集双药方案治疗老年晚期NSCLC的随机对照试验,用Stata11.0软件对数据进行meta分析。结果共纳入12项随机对照试验(2,306例病例),meta分析结果显示与单药化疗相比双药化疗明显提高了老年晚期NSCLC患者的有效率(OR=1.80,95%CI:1.50-2.17,P<0.000,1)和1年生存率(OR=1.45,95%CI:1.22-1.72,P<0.000,1);含铂双药(OR=1.55,95%CI:1.18-2.03,P=0.001)和非铂双药组(OR=1.38,95%CI:1.10-1.73,P=0.006)的1年生存率均明显高于单药组;含铂双药组更易发生3/4级贫血、中性粒细胞减少、血小板减少和神经毒性(P<0.05),非铂双药组毒副反应发生率与单药组相似。结论与单药组相比,双药组可明显提高化疗有效率和生存率,更适合作为老年晚期NSCLC一线化疗方案,但尚需开展针对老年患者的随机对照试验加以验证。     

Capecitabine monotherapy as salvage treatment after failure of chemotherapy containing oxaliplatin and irinotecan in patients with metastatic colorectal cancer

Aim: There has been limited data on capecitabine monotherapy in metastatic colorectal cancer (CRC) patients who were previously treated with both oxaliplatin/5‐fluorouracil(FU)/leucovorin (FOLFOX) and irinotecan/5‐FU/leucovorin (FOLFIRI). Methods: We analyzed 20 patients between August 2002 and March 2008 with metastatic CRC who had been treated with capecitabine monotherapy after the failure of FOLFOX and FOLFIRI. Results: Overall, one partial response was observed (overall response rate, 5%) and stable disease was observed in 11 patients (55.0%). The disease control rate was 60.0%. The median progression‐free survival (PFS) was 2.3 months (95% CI 1.9–2.7) and the median overall survival (OS) was 5.3 months (95% CI 4.6–6.0). Patients without ascites had longer PFS than those with ascites (P = 0.02). Patients with more than three metastatic sites had poorer OS than those with less than two (P = 0.01). Grade 3 or 4 non‐hematological toxicities included hand–foot syndrome in one patient. There were no grade 3 or 4 hematological toxicities or treatment‐related deaths. Conclusion: The capecitabine monotherapy had a moderate disease control rate and a tolerable toxicity profile as third‐line or fourth‐line treatment for metastatic CRC patients who were refractory to standard chemotherapy with no further treatment options.     

曲妥珠单抗治疗141例人表皮生长因子受体2阳性乳腺癌的回顾性分析

目的 总结曲妥珠单抗在人表皮生长因子受体2(Her-2)阳性乳腺癌患者新辅助、辅助和复发转移治疗中的临床应用经验,评价其与化疗联用的疗效.方法 对2004年1月至2008年12月门诊应用曲妥珠单抗治疗的141乳腺癌患者进行回顾性分析.随访时间为3～319个月.分析患者的无病生存时间(DFS),比较患者辅助、复发转移一线及二线使用曲妥珠单抗治疗的总生存时间(OS)、治疗失败时间(TTF)和临床有效率的差异.结果 与曲妥珠单抗治疗联用的新辅助化疗中,紫杉醇联合卡铂方案占66.7%;辅助治疗中,蒽环类和蒽环类序贯紫杉类方案占53.9%.复发转移的患者治疗后中位DFS为17个月.复发转移的患者经一线曲妥珠单抗联合化疗治疗后,临床总有效 率为84.5%,中位TTF为24个月;二线治疗有效率为44.4%,中位TTF为5个月.两者比较,差异有统计学意义(P=0.002).结论 紫杉醇和卡铂化疗联合曲妥珠单抗,值得在新辅助治疗中推广,紫杉类和蒽环类联合或序贯靶向治疗仍是辅助治疗的标准方案.转移性乳腺癌一线应用曲妥珠单抗联合化疗比二线治疗的临床有效率更高,在继续应用曲妥珠单抗的基础上改用化疗方案,可提高治疗有效率,减少治疗失败的概率.     

In real life,one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium

BackgroundThe objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer.Patients and methodsAll the 815 consecutive patients diagnosed with metastatic breast cancer in 2007–2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan–Meier method and compared using the log-rank test.ResultsFrom the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2–6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3–15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors.ConclusionsA high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors.     

Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis

BackgroundThe efficacy and safety of a combination of chemotherapeutic agent compared with single-agent chemotherapy in the second-line setting of advanced urothelial carcinoma (UC) are unclear. We aimed to study the survival impact of single-agent compared with doublet chemotherapy as second-line chemotherapy of advanced UC.Patients and methodsLiterature was searched for studies including single-agent or doublet chemotherapy in the second-line setting after platinum-based chemotherapy. Random-effects models were used to pool trial-level data according to treatment arm, including median progression-free survival (PFS), overall survival (OS), objective response rate (ORR) probability, and grade 3–4 toxicity. Univariable and multivariable analyses, including sensitivity analyses, were carried out, adjusting for the percent of patients with ECOG performance status ≥1 and hepatic metastases.ResultsForty-six arms of trials including 1910 patients were selected: 22 arms with single agent (n = 1202) and 24 arms with doublets (n = 708). The pooled ORR with single agents was 14.2% [95% confidence interval (CI) 11.1–17.9] versus 31.9% [95% CI 27.3–36.9] with doublet chemotherapy. Pooled median PFS was 2.69 and 4.05 months, respectively. The pooled median OS was 6.98 and 8.50 months, respectively. Multivariably, the odds ratio for ORR and the pooled median difference of PFS were statistically significant (P < 0.001 and P = 0.002) whereas the median difference in OS was not (P = 0.284). When including single-agent vinflunine or taxanes only, differences were significant only for ORR (P < 0.001) favoring doublet chemotherapy. No statistically significant differences in grade 3–4 toxicity were seen between the two groups.ConclusionsDespite significant improvements in ORR and PFS, doublet regimens did not extend OS compared with single agents for the second-line chemotherapy of UC. Prospective trials are necessary to elucidate the role of combination chemotherapy, with or without targeted agents, in the salvage setting. Currently, improvements in this field should be pursued considering single-agent chemotherapy as the foundation for new more active combinations.     

Real-world effectiveness of third- or later-line treatment in Japanese patients with HER2-positive,unresectable, recurrent or metastatic gastric cancer: a retrospective observational study

Background

Real-world evidence on the preference for and effectiveness of third- or later-line (3L +) monotherapy for HER2-positive gastric cancer is limited in Japan. This study evaluated the utility of nivolumab, irinotecan, and trifluridine/tipiracil (FTD/TPI) monotherapy as 3L + treatment in Japanese patients with HER2-positive gastric/gastroesophageal junction (G/GEJ) cancer who were previously treated with trastuzumab.

Methods

In this multicenter, retrospective, observational study (20 centers), data of eligible patients were extracted from medical records (September 22, 2017–March 31, 2020), with follow-up until June 30, 2020. Outcomes included overall survival (OS), real-world progression-free survival (rwPFS), time to treatment failure (TTF), objective response rate (ORR; complete response [CR] + partial response [PR]), and disease control rate (DCR).

Results

Of 127 enrolled patients, the overall analysis population comprised 117 patients (median [range] age, 71 [38–89] years). The most commonly prescribed 3L + monotherapy was nivolumab (n = 100), followed by irinotecan (n = 12) and FTD/TPI (n = 5). The median (95% confidence interval [CI]) OS, rwPFS, and TTF were 6.2 (4.5–8.0), 1.9 (1.5–2.3), and 1.8 (1.5–2.2) months, respectively, at median (range) 150 (25–1007) days of follow-up. The ORR (CR + PR) and DCR were 9.0% (1% + 8%) and 32.0%, respectively. Factors such as higher neutrophil–lymphocyte ratio (≥ 2.54), Glasgow prognostic score (≥ 1), Eastern Cooperative Oncology Group performance status (ECOG PS; ≥ 2), and hepatic metastasis significantly impacted OS.

Conclusions

The observed OS in this study for HER2-positive G/GEJ cancer was shorter than that reported previously, suggesting that the effectiveness of nivolumab, irinotecan, or FTD/TPI as 3L + therapy may be limited.

     

Capecitabine monotherapy: review of studies in first-line HER-2-negative metastatic breast cancer

The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First-line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long-term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first-line treatment of patients with human epidermal growth factor receptor 2-negative MBC.     

Geographic difference in safety and efficacy of systemic chemotherapy for advanced gastric or gastroesophageal carcinoma: a meta-analysis and meta-regression

Background

The standard of chemotherapy regimens for advanced or metastatic gastric cancer and the clinical outcome were heterogeneous in Asian versus non-Asian countries. This study aimed to explore predictors of safety and efficacy of chemotherapy for patients with advanced or metastatic gastric cancer.

Methods

Treatment group-based meta-analysis and meta-regression were performed to analyze results of randomized trials published since 2005 for advanced or metastatic gastric cancer patients who received systemic chemotherapy as first-line treatment. Data were extracted and synthesized according to the Cochrane guidelines.

Results

Twenty-five trials (8 Asian, 17 Western or international) with 56 treatment groups were analyzed. Asian trials reported a lower percentage of gastroesophageal junctional carcinoma, higher percentage of diffuse-type histology, and more frequent use of second-line chemotherapy. Meta-analysis revealed significant heterogeneity both in treatment safety (grade 3–4 neutropenia and diarrhea) and efficacy [6-month progression-free survival (PFS) and 1-year overall survival (OS)]. Meta-regression analyses indicate that Asian trials are associated with an 8.2% lower incidence of grade 3–4 neutropenia and 2.1% lower incidence of grade 3–4 diarrhea. A lower percentage of patients with gastroesophageal junction carcinoma and the use of combination regimens predicted better PFS. The use of second-line chemotherapy predicts better 1-year OS, which will increase by 10% for every 10% increase in patients who received second-line chemotherapy.

Conclusion

Geographic region (Asian vs. non-Asian) is an independent predictor of safety in systemic therapy for gastric cancer.     

American Society of Clinical Oncology 2010 colorectal update

The 2010 American Society of Clinical Oncology (ASCO) Gastrointestinal (Colorectal) Cancer Track included several notable presentations. The addition of cetuximab to FOLFOX in stage III colon cancer did not improve disease-free survival, but increased toxicity. In the metastatic setting, cetuximab demonstrated benefit only in a small subset of patients (KRAS wild-type and limited metastatic disease). Bevacizumab monotherapy may be equivalent to combination chemotherapy in the maintenance phase of treatment in advanced disease, and in another study bevacizumab did not appear to incur excess morbidity in patients with an intact primary tumor. Alternate strategies for the treatment of stage II/III rectal cancer included short-course radiotherapy with adjuvant chemotherapy and neoadjuvant FOLFOX–bevacizumab without radiation, both demonstrating promising results.     

Continuous versus intermittent chemotherapy strategies in metastatic colorectal cancer: a systematic review and meta-analysis

There are no clinically significant survival differences between continuous and intermittent strategies of delivering chemotherapy for first-line metastatic colorectal cancer. Intermittent strategies should be part of an informed discussion of treatment options with patients with untreated metastatic colorectal cancer.BackgroundAn important goal of intermittent strategies of delivering systemic treatment as first-line treatment of metastatic colorectal cancer (mCRC) is to maintain efficacy while improving patients' quality of life (QoL). Given the varying impact on efficacy demonstrated in individual randomized, controlled trials (RCTs), a systematic review and meta-analysis of RCTs of these intermittent strategies was carried out.DesignRelevant databases were systematically searched for the period 2000–2014. RCTs that compared a continuous versus intermittent strategy of delivering systemic treatment were identified by a systematic review. Overall survival (OS) hazard ratios (HRs) were extracted from the most recently reported trial results. The results of identified trials were clinically homogeneous so the data were pooled using Review Manager software (RevMan 5.1).ResultsEleven RCTs were identified (n = 4 854). For the eight (n = 4508) trials with available HRs, the treatment patients received after induction was: none (five trials,n = 3036), fluoropyrimidine (one trial,n = 620), and biologic (two trials,n = 852). There were no statistically significant survival differences observed between the continuous and intermittent chemotherapy strategies. There was no statistically significant difference observed between continuous and intermittent strategies [HR = 1.03, 95% confidence interval (CI) 0.96–1.10,P = 0.38)]. Subgroup analyses demonstrated results were generally robust across induction and maintenance regimens. One subgroup analysis of the three trials (CAIRO3, OPTIMOX2, COIN,n = 2403) with combination treatment induction and no maintenance until progression revealed a statistically, but nonclinically significant benefit for continuous treatment (HR = 1.10, 95% CI 1.00–1.20,P = 0.049). QoL life was either the same in both arms in two trials (n = 912) or improved in the intermittent strategy arm in one trial (n = 1630).ConclusionIntermittent strategies of delivering systemic treatment of mCRC do not result in a clinically significant reduction in OS compared with a continuous strategy of delivery, and should be part of an informed discussion of treatment options with patients with mCRC.     

Bevacizumab-containing chemotherapy for non-small cell lung cancer patients: a population-based observational study by the Ibaraki thoracic integrative (POSITIVE) research group

To evaluate the efficacy and safety of bevacizumab-containing chemotherapy for non-small cell lung cancer (NSCLC), we performed a population-based observational study. The efficacy and safety of bevacizumab-containing chemotherapy for NSCLC patients were evaluated at 14 sites (17 hospital departments) in a prefecture of Japan between December 2009 and August 2011. Complete data sets were obtained from 159 patients with NSCLC. The median age was 66?years, and 34.0?% of the patients were 70?years or older. The overall response rate to bevacizumab therapy was 41.6?%, and the disease control rate was 78.5?%. In 88 patients who received bevacizumab-containing chemotherapy as first-line therapy, the response and disease control rates were 55.0 and 78.9?%, respectively. The incidence of clinically significant (grade 3 or more) adverse events was generally low: proteinuria occurred in 2 (1.3?%) patients, hypertension in 2 (1.3?%), hemoptysis in 1 (0.6?%), and interstitial pneumonia in 1 (0.6?%). The time to treatment failure (TTF) in the 159 patients was 169?days, and the median overall survival (OS) was 580?days. In patients who received bevacizumab-containing chemotherapy as first-line therapy, the TTF and OS were 152 and 520?days, respectively. The difference in TTF between patients who received bevacizumab-containing chemotherapy as first-line therapy and those who received it as second-line or later-line therapy was not significant (p?=?0.4971). With regard to first-line therapy, the difference in TTF between patients treated with carboplatin?+?pemetrexed?+?bevacizumab and those treated with carboplatin?+?paclitaxel?+?bevacizumab was not significant (p?=?0.9435). We deduced that bevacizumab-containing chemotherapy is effective against NSCLC and also tolerable in clinical practice.     

CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC

IntroductionFirst-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC.MethodsThis open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety.ResultsA total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6–19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6–18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67–1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5–8.5) and 3.2 months (95% CI: 2.7–5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52–0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04–2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS.ConclusionsThe addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.     

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study

BackgroundA targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy.Patients and methodsPatients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety.ResultsThree hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75–1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81–1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups.ConclusionBevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment.Clinical trial identifierUMIN000002557.     

Gemcitabine and cisplatin combined with regional hyperthermia as second-line treatment in patients with gemcitabine-refractory advanced pancreatic cancer

Purpose: There is no standard second-line therapy for patients with advanced pancreatic cancer (APC) after gemcitabine (G) failure. Cisplatin (Cis)-based chemotherapy has shown activity in APC. It is proven that cytotoxicity of G and Cis is enhanced by heat exposure at 40° to 42°C. Therefore G plus Cis with regional hyperthermia (RHT) might be beneficial for patients with G-refractory APC.

Patients and methods: We retrospectively analysed 23 patients with advanced (n?=?2) or metastatic (n?=?21) pancreatic cancer with relapse after G mono first-line chemotherapy (n?=?23). Patients had received G (day 1, 1000?mg/m²) and Cis (day 2 and 4, 25?mg/m²) in combination with RHT (day 2 and 4, 1?h) biweekly for 4 months. We analysed feasibility, toxicity, time to second progression (TTP2), overall survival (OS) and clinical response.

Results: Between October 1999 and August 2008 23 patients were treated. Haematological toxicity was low with no grade 4 event. Hyperthermia-associated toxicity consisted of discomfort because of bolus pressure (3%), power-related pain (7%) or position-related pain (17%). Median TTP1 was 5.9 months (95% confidence interval (CI): 2.6–9.2), median TTP2 was 4.3 months (95%CI: 1.2–7.4) and OS 12.9 months (95%CI: 9.9–15.9). The disease control rate in 16 patients with available CT scans was 50%.

Conclusion: We show first clinical data of G plus Cis with RHT being clinically active in G-pretreated APC with low toxicity. A prospective controlled phase II second-line clinical trial (EudraCT: 2005-003855-11) and a randomised phase III adjuvant clinical trial offering this treatment (HEAT; EudraCT: 2008-004802-14) are currently open for recruitment.     

Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy

BackgroundIn the placebo-controlled phase III SATURN study, maintenance erlotinib after first-line chemotherapy demonstrated significantly prolonged progression-free survival (PFS) and overall survival (OS) in the overall study population of patients with advanced non-small-cell lung cancer (NSCLC).MethodsAfter four cycles of platinum-based doublet chemotherapy, patients without progressive disease (PD) were randomised to erlotinib (150 mg/day) or placebo until PD or unacceptable toxicity. In this pre-planned analysis, data are assessed according to response to first-line chemotherapy (complete/partial response [CR/PR] or stable disease [SD]).ResultsFollowing first-line chemotherapy, 889 non-PD patients were included in the intention-to-treat population (55% SD; 44% CR/PR; <1% unknown response). Erlotinib maintenance therapy significantly prolonged PFS in both the SD (hazard ratio [HR] = 0.68; P < 0.0001) and CR/PR (HR = 0.74; P = 0.0059) groups, while OS was significantly prolonged in the SD group only (HR = 0.72; P = 0.0019). The erlotinib-related OS benefit in the SD group remained significant across subgroups, irrespective of tumour histology and/or EGFR mutation status. The incidence of adverse events was similar in the SD group and the overall population, and erlotinib treatment did not negatively impact quality of life.ConclusionsPatients with advanced NSCLC and SD following first-line platinum-based doublet chemotherapy derive a significant OS benefit from maintenance erlotinib therapy.     

A phase II study of docetaxel and vinorelbine plus filgrastim for HER-2 negative, stage IV breast cancer: SWOG S0102

Docetaxel and vinorelbine have demonstrated Single-agent activity in breast cancer. Preclinical studies suggest potential synergy between these antitubulin chemotherapy agents. This study evaluates these drugs in combination in metastatic breast cancer. Taxane-naive patients with HER-2 negative, stage IV breast cancer without prior chemotherapy for metastatic disease, were eligible. Docetaxel (60 mg/m²) was given intravenously on Day 1, vinorelbine (27.5 mg/m²) intravenously on Days 8 and 15, and filgrastim on Days 2–21 of a 21-day cycle. The primary study outcome was one-year overall survival (OS), with secondary outcomes of progression-free survival (PFS), response rate (RR), and toxicity. Of 95 patients registered, 92 were eligible and received treatment. One-year OS was 74 % (95 % CI 64–82 %) with a median OS of 22.3 months (95 % CI 18.8–31.4 months). One-year PFS was 34 % (95 % CI 24–43 %) with median of 7.2 months (95 % CI 6.4–10.3). OS at 2 and 3 years were 49 % (95 % CI 38–59 %) and 30 % (95 % CI 21–40 %), respectively. OS was poorer for women with estrogen-receptor negative disease (n = 32) compared to estrogen-receptor positive (n = 60) (log-rank p = 0.031), but PFS was not significantly different (p = 0.11). RR was 59 % among the 74 patients with measurable disease. Grade 3 and 4 adverse events were 48 and 16 %, respectively. Grade 4 neutropenia was 12 % and grade 3/4 febrile neutropenia was 3 %. Common grade 3/4 nonhematologic toxicities were fatigue (14 %), pneumonitis (10 %), and dyspnea (9 %). The combination of docetaxel and vinorelbine is an active first-line chemotherapy in HER-2 nonoverexpressing, metastatic breast cancer. This combination is associated with significant hematologic and nonhematologic toxicity. The safety profile and expense of the filgrastim limit recommendations for routine use.