First-line chemotherapy with raltitrexed in metastatic colorectal cancer: an Association des Gastro-entérologues Oncologues (AGEO) multicentre study

BackgroundIn case of contraindication or intolerance to fluoropyrimidines, raltitrexed is a validated alternative in metastatic colorectal cancer (mCRC), associated or not with oxaliplatin. Little is known about the outcomes of raltitrexed combined with irinotecan or targeted therapies.MethodsThis retrospective multicentre study enroled mCRC patients treated with first-line raltitrexed-based chemotherapy. Treatment-related toxicities were recorded. Progression-free survival (PFS) and overall survival (OS) were calculated from treatment start.Results75 patients were treated with raltitrexed alone, TOMOX, or TOMIRI with or without bevacizumab. Grade 3–4 adverse events were seen in 31% of patients, without significant difference between the different treatment schedules. amongst the 36 patients with a history of fluoropyrimidine-induced cardiac toxicity, none developed cardiovascular events on raltitrexed.Median PFS and OS were 10.6 (95% CI 8.2 – 13.1) and 27.4 months (95% CI 24.1–38.1), respectively. Considering the chemotherapy regimen, TOMOX was significantly associated with better PFS and OS compared to TOMIRI and raltitrexed alone.ConclusionsIn patients with mCRC not eligible for fluoropyrimidines, first-line raltitrexed-based chemotherapy had an acceptable safety profile. PFS and OS were consistent with usual survival data in mCRC, and significantly better in patients treated with TOMOX, independently of associated targeted therapies.     

MiR-31-3p do not predict anti-EGFR efficacy in first-line therapy of RAS wild-type metastatic right-sided colon cancer

BackgroundLow miR-31-3p expression was identified as predictive of anti-EGFR efficacy in RAS-wt mCRC. Primary tumor side was also proposed as a predictive factor of anti-EGFR benefit. This retrospective multicentric study evaluated the predictive role of miR-31-3p in right-sided RAS-wt mCRC patients treated with first-line CT+anti-EGFR or CT+bevacizumab (Beva).MethodsSeventy-two right-sided RAS-wt mCRC patients treated in first-line with CT+anti-EGFR (n = 43) or Beva (n = 29) were included. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were analyzed and stratified according to tumor miR-31-3p expression level and targeted therapy (TT).ResultsBRAF V600E mutation was more frequent in high vs low miR-31-3p expressers (60.6% vs 15.4%, P < 0.001). PFS was significantly longer with CT+Beva than with CT+anti-EGFR (13 vs 7 months; P = 0.024). Among low miR-31-3p expressers, PFS, OS and RR were not significantly different between the two groups, while in high miR-31-3p expressers, only PFS was longer in the CT+Beva group (11 vs 6 months; P = 0.03). In patients treated with CT+anti-EGFR, low miR-31-3p expressers had a significantly longer OS (20 vs 13 months; P = 0.02) than high miR-31-3p expressers. ORR was not significantly different between the two groups of treatment, in both low and high miR-31-3p expressers. MiR-31-3p expression status was statistically correlated between primary tumors and corresponding metastases.ConclusionIn this study, miR-31-3p couldn't identify a subgroup of patients with right-sided RAS-wt mCRC who might benefit from anti-EGFR and suggest that Beva is the TT of choice in first-line treatment of these patients.     

Baseline,Trend, and Normalization of Carcinoembryonic Antigen as Prognostic Factors in Epidermal Growth Factor Receptor-Mutant Nonsmall Cell Lung Cancer Patients Treated With First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Among epidermal growth factor receptor (EGFR) mutation status unknown nonsmall cell lung cancer (NSCLC) patients, those with higher carcinoembryonic antigen (CEA) level are more likely to response to EGFR-tyrosine kinase inhibitors (TKIs) because they tend to have mutant epidermal growth factor receptor (EGFR). However, patients with higher CEA also have more tumor burden. With the above paradoxical evidence, it is prudent to understand the prognostic significance of baseline CEA in patients with EGFR-mutant NSCLC treated with first-line EGFR-TKIs. The clinical significance of the trend in CEA after treatment and the impact of CEA normalization during EGFR-TKI therapy are also unknown and potentially important.A total of 241 patients who received first-line EGFR-TKIs were included. As to baseline CEA, patients were divided into normal, low, and high baseline CEA by cut point determined by receiver operating characteristic curves. As to CEA responses, patients were divided into 3 groups accordingly to their amount of CEA change after taking TKIs. In group A, 1-month follow-up CEA level decreased more than 35% with nadir CEA normalization; in group B, 1-month follow-up CEA level decreased more than 35% without nadir CEA normalization; and in group C, 1-month follow-up CEA level decreased less than 35% or increased.Patients with higher baseline CEA levels had shorter progression-free survival (PFS) and overall survival (OS) (CEA > 32 vs 5–32 vs <5 ng/mL, PFS = 8.8 vs 11.3 vs 14.4 months, respectively, P < 0.001; OS = 17.8 vs 22.0 vs 27.9 months, respectively, P = 0.01). For trend and CEA normalization in groups A, B, and C, PFS was 14.3, 10.6, and 7.1 months, respectively (P < 0.001); OS was 29.7, 20.0, and 16.2 months, respectively (P < 0.001).Baseline, trend, and normalization of CEA levels are potential prognostic markers for patients with EGFR-mutant advanced NSCLC treated with first line EGFR-TKIs.     

Impact of sarcopenia on prediction of progression-free survival and overall survival of patients with pancreatic ductal adenocarcinoma receiving first-line gemcitabine and nab-paclitaxel chemotherapy

Background and aimsSarcopenia is an important prognostic factor for cancer patients. Here, we assessed the effects of sarcopenia on progression-free survival (PFS) and overall survival (OS) of patients with pancreatic ductal adenocarcinoma (PDAC) who underwent treatment with first-line gemcitabine and nab-paclitaxel (GEM and nab-PTX).MethodsThe study enrolled patients with unresectable PDAC who underwent chemotherapy between April 2016 and May 2020. The skeletal muscle index (SMI) at the third lumbar spine level (L3) was calculated from computed tomography (CT) images. Propensity score analysis was used to compare PFS and OS in the sarcopenia and non-sarcopenia groups. Univariate and multivariate analyses were performed to determine variables significantly associated with prognosis.ResultsOf the 176 patients who received first-line GEM and nab-PTX, 84 were selected and divided into two groups of 42 (the sarcopenia and the non-sarcopenia groups) by propensity score matching. The median PFS of the sarcopenia and the non-sarcopenia groups was 5.0 and 8.0 months, respectively (p = 0.004). The median OS was 10.3 and 18.1 months, respectively (p = 0.001). Multivariate analyses revealed that sarcopenia was an independent prognostic factor for PFS and OS (p = 0.004, p = 0.001, respectively). The rates of major grade 3 or 4 AEs were significantly higher in the sarcopenia group (p = 0.008).ConclusionsSarcopenia is an independent indicator of a poor prognosis in patients with PDAC treated with first-line GEM and nab-PTX.     

Neuron - specific enolase predicts the prognosis in advanced small cell lung cancer patients treated with first-line PD-1/PD-L1 inhibitors

There has been no effective biomarker for small cell lung cancer (SCLC) patients with first-line immune checkpoint inhibitors (ICIs) treatment. The predictive value of neuron-specific enolase (NSE) in this cohort remains unclear.The medical records of 254 consecutive SCLC patients receiving programmed cell death receptor-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors were compiled from January 2015 to October 2020 in Chinese PLA General Hospital. Survival analysis was performed to explore the prognostic role of NSE at baseline and 3 weeks post treatment.One hundred two advanced SCLC patients treated with first-line PD-1/PD-L1 inhibitors were enrolled in this study. Normal baseline NSE levels were correlated with significantly prolonged progression-free survival (PFS, median: 8.7 vs 4.7 months, P = .006) and overall survival (OS, median: 23.8 vs 15.2 months, P = .014) compared with elevated baseline NSE levels, so as for normal NSE levels at 3 weeks with prolonged PFS (median PFS: 8.4 vs 4.5 months, P = .0002) and OS (median OS: 23.3 vs 7.4 months, P < .0001). Intriguingly, elevated NSE levels at 3 weeks were associated with shorter PFS (median PFS: 4.5 vs 5.8 months, P = .04) and OS (median OS: 5.5 vs 14.7 months, P < .0001) compared with normal NSE levels in the elevated baseline NSE subgroup. Most subgroup analyses stratified by clinical characteristics confirmed the prognostic value of baseline NSE level.Elevated NSE levels at baseline and 3 weeks were associated with worse prognosis in advanced SCLC patients receiving first-line ICIs treatment. NSE level might be applied as a useful prognostic tool for SCLC patients with immunotherapy.     

Curative efficacy might be an early predictor of prognosis in patients with small cell lung cancer treated with 2 cycles of platinum-based first-line chemotherapy

BackgroundPlatinum-based chemotherapy remains the essential therapy for small cell lung cancer (SCLC). Here, we conducted a statistical analysis to explore whether the curative efficacy of 2-cycle platinum-based chemotherapy can predict the survival of patients with SCLC.MethodsFifty-six SCLC patients who had each received 2 cycles of platinum-based chemotherapy were enrolled. The curative efficacy of the chemotherapy was evaluated, mainly by chest computed tomography, and the treatment response was categorized according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients were continuously followed up for progression-free survival (PFS) and overall survival. The 55 patients were separated into 2 groups by the curative efficacy of the 2-cycle first-line platinum-based chemotherapy. All statistical analyses were performed with SPSS software (version 17.0; SPSS, Inc.; Chicago, IL, USA)ResultsPatients who responded to 2-cycle chemotherapy (partial response, PR) had significantly better survival than others who did not (stable disease, SD or progressive disease, PD). The median progression-free survival (mPFS) in the PR group was 6.330 months, which was significantly longer than the 2.870 months seen in SD+PD group (95% CI: 4.631–8.029 vs. 0.000–5.790, P=0.022). The median overall survival (mOS) was 10.870 months in the PR group, which was remarkably longer than the 8.970 months observed in the SD+PD group (95% CI: 9.546–12.194 vs. 6.517–11.423, P=0.028). Curative efficacy had no correlation with clinical features.ConclusionsThe curative efficacy of 2-cycle first-line platinum-based chemotherapy was significantly correlated with PFS and OS, and showed prognostic value in SCLC patients. Patients who were sensitive to chemotherapy had superior survival to those who were chemotherapy insensitive.     

Avelumab versus standard second line treatment chemotherapy in metastatic colorectal cancer patients with microsatellite instability: The SAMCO-PRODIGE 54 randomised phase II trial

Immune checkpoint inhibitors have failed in treating metastatic colorectal cancer (mCRC) patients except those with dMMR/MSI tumors. However, until very recently we had only non-comparative promising data in this population with anti-programmed cell death 1/ programmed cell death ligand 1 (PD1/PD-L1) antibodies alone or combined with anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies.This comparative phase II trial (NCT 03186326), conducted in more than 100 centers in France, will include dMMR/MSI mCRC patients with progression after a first-line treatment with chemotherapy ± targeted therapies, to evaluate efficacy and safety of the anti-PDL1 Avelumab versus a standard second-line treatment. Main inclusion criteria were patients aged 18 to 75 years, ECOG performance status ≤2, dMMR/MSI mCRC and failure of a standard first-line regimen. Patient will be randomised to receive Avelumab 10 mg/kg versus standard second-line doublet chemotherapy plus a targeted agent according to tumor RAS status. Patients will be followed for 4 years. A gain of 5 months in median PFS is expected in favour of the Avelumab arm (12 vs 7 months; HR=0.58). Secondary endpoints include objective response rate, overall survival, quality of life and toxicity. In addition, circulating tumour DNA and microbiota will be explored to test their potential prognostic and predictive values. The study was opened in March 2018.     

Contrast-enhanced harmonic endoscopic ultrasonography for predicting the efficacy of first-line gemcitabine and nab-paclitaxel chemotherapy in pancreatic cancer

Background and aimsThe purpose of this study was to assess prognosis with different intratumoral vascularity on contrast-enhanced endoscopic harmonic ultrasonography (CH-EUS) in pancreatic cancer patients receiving chemotherapy.MethodsPatients with unresectable pancreatic cancer who underwent CH-EUS before first-line gemcitabine and nab-paclitaxel (GEM and nab-PTX) therapy were classified into four groups according to vascularity on the early and late phases of contrast enhancement: “Group A″, poor on both phases; “Group B″, rich and poor on the early and late phases, respectively; “Group C″, poor and rich on the early and late phases; “Group D″, rich on both phases. Subgroups were compared in terms of progression-free survival (PFS) and overall survival (OS). We also assessed whether the results with CH-EUS correlate with those of contrast-enhanced computed tomography (CE-CT).ResultsOn CH-EUS, 57, 64, 0, and 24 patients were classified into Groups A, B, C, and D, respectively. The median PFS of patients in groups A, B, and D was 3.9, 7.6, and 10.8 months, respectively, and the median OS were 9.5, 13.1, and 18.6 months, respectively. Both PFS and OS were longest in Group D (p < 0.001 and p < 0.001, respectively). The results of CE-CT were consistent with those of CH-EUS, and there was a correlation between CE-CT and CH-EUS.ConclusionsEvaluation of intratumoral vascularity by CH-EUS may be useful for predicting the efficacy of chemotherapy in patients with pancreatic cancer. A better response to GEM and nab-PTX can be expected in patients showing rich vascularity at both the early and late phases.     

First-line therapies in metastatic colorectal cancer: integrating clinical benefit with the costs of drugs

Purpose

In light of the relevant expenses of pharmacological interventions, it might be interesting to make a balance between the cost of the new drugs administered and the added value represented by the improvement in progression free survival (PFS) in first-line for metastatic colorectal cancer CRC (mCRC).

Methods

Phase III randomized controlled trials (RCTs) that compared at least two first-line chemotherapy regimens for mCRC patients were evaluated. Differences in PFS between the different arms were compared with the pharmacological costs (at the pharmacy of our hospital). The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) was applied to the above RCTs.

Results

Overall 28 phase III RCTs, including 19,958 patients, were analyzed. The FOLFOX resulted the least expensive (56 € per month of PFS gained) while the addition of irinotecan to FOLFOX (FOLFOXIRI) increased only marginally the costs (90 € per month of PFS gained). Treatments including the monoclonal antibodies showed a cost per month of PFS gained of 2823 € (FOLFIRI with cetuximab in KRAS wild-type patients and liver-only metastases), of € 15,822 (FOLFOX with panitumumab in KRAS wild type), and of 13,383 € (FOLFOX with bevacizumab). According to the ESMO-MCBS, the treatments including an EGFR-inhibitor (cetuximab or panitumumab) were associated with a score of 4, while the inclusion of bevacizumab reached a score of 3.

Conclusions

Our data demonstrate a huge difference in cost per month of PFS gained in modern first-line treatments in mCRC.

     

Normal carcinoembryonic antigen indicates benefit from perioperative chemotherapy to gastric carcinoma patients

AIM: To evaluate pretreatment serum carcinoembryonic antigen (CEA) as a predictor of survival for patients with locally advanced gastric cancer receiving perioperative chemotherapy.METHODS: We retrospectively studied a cohort of 228 gastric cancer patients who underwent D2 gastrectomy combined with chemotherapy at the Sun Yat-sen University Cancer Center between January 2005 and December 2009. Among them, 168 patients received 6-12 cycles of oxaliplatin-based adjuvant (post-operative) chemotherapy, while 60 received perioperative chemotherapy (2 cycles of FOLFOX6 or XELOX before surgery and 4-10 cycles after surgery). Serum CEA was measured using an enzyme immunoassay. The follow-up lasted until December 2010.RESULTS: In the group that had elevated serum CEA, the difference in survival time between patients receiving perioperative chemotherapy and those receiving adjuvant chemotherapy had no statistical significance (P > 0.05). However, in the group that had normal serum CEA, patients receiving perioperative chemotherapy had a longer survival time. In multivariate analysis, T staging and lymph node metastatic rate were independent prognostic factors for the patients. Perioperative chemotherapy improved the overall survival of patients who had a normal pretreatment CEA level (P = 0.070).CONCLUSION: Normal pretreatment serum CEA is a predictor of survival for patients receiving perioperative chemotherapy.     

Prognostic impact of carcinoembryonic antigen (CEA) on patients with metastatic pancreatic cancer: A retrospective cohort study

BackgroundCarcinoembryonic antigen (CEA) is one of the most widely used tumor markers, and its level is increased in 30–60% of patients with pancreatic cancer (PC). However, little is known about the implications of CEA as a prognostic marker in metastatic PC. The purpose of this study was to examine the usefulness of CEA levels as a prognostic marker in patients with metastatic PC.MethodsWe conducted a retrospective cohort study using data from a computerized database. A total of 433 patients with metastatic disease were analyzed.ResultsMedian overall survival (OS) was significantly shorter for patients with high CEA (>5 ng/ml) than with normal CEA (≤5 ng/ml) (6.8 vs. 10.3 months, respectively; p < 0.001). After adjustment, CEA level was an independent predictive factor for OS (hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.45–2.26). In the high CEA group, OS in patients treated with combination chemotherapy was similar to that with single-agent chemotherapy (median, 7.1 vs. 6.8 months; HR for OS, 0.99; 95% CI, 0.71–1.40).ConclusionsThe present results show that CEA level is an independent prognostic factor in patients with metastatic PC. A combination chemotherapy regimen may offer modest survival benefit in patients with high CEA.     

Factors that predict progression-free survival in Chinese lung adenocarcinoma patients treated with epidermal growth factor receptor tyrosine kinase inhibitors

Background

Although first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have shown efficacy in patients with advanced lung cancers, survival predictors with these drugs have not been extensively investigated. This study was performed to explore factors that may predict progression-free survival (PFS) in Chinese lung adenocarcinoma patients treated with EGFR-TKIs.

Methods

We retrospectively collected clinicopathologic data on 208 patients who received either gefitinib, erlotinib or icotinib, including the patients’ EGFR mutation status and levels of six serum tumor markers [carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cancer antigen 125 (CA125), squamous cell carcinoma antigen (SCC), cytokeratin-19 fragments (CYFRA21-1) and lactate dehydrogenase (LDH)]. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with PFS.

Results

At the study cutoff date, 189 (90.9%) of the patients met the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria for progressive disease (PD), while 19 (9.1%) had stable disease (SD). The median PFS of the 208 patients was 12.4 months (95% CI, 11.0–13.8 months). In the multivariate analysis using a Cox proportional hazard model, a non-smoking history [hazard ratio (HR) =2.460; 95% CI, 1.484–4.079; P<0.001], first-line treatment (HR =1.500; 95% CI, 1.062–2.119; P=0.021), and a high pretreatment serum level of CEA (HR =1.424; 95% CI 1.026–1.977; P=0.035) were found to be significant predictors of a longer PFS.

Conclusions

In Chinese lung adenocarcinoma patients treated with EGFR-TKIs, a non-smoking history, first-line EGFR-TKIs treatment and a high serum level of CEA were independent predictors of a longer PFS along with an EGFR-activating mutation.     

Prospective evaluation of 18F‐fluorodeoxyglucose positron emission tomography in patients receiving hepatic arterial and systemic chemotherapy for unresectable colorectal liver metastases

BackgroundThe prognostic and predictive abilities of 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) coupled with conventional computed tomography (CT) have not been studied in patients with unresectable colorectal liver metastases (uCRLM) treated with combined hepatic arterial infusion (HAI) and systemic chemotherapy.ObjectivesThe ability of PET‐CT metabolic response parameters to predict conversion to resectability and oncologic outcome in this setting was evaluated.MethodsThirty‐eight patients undergoing serial PET‐CT as part of a Phase II trial of HAI and systemic chemotherapy for uCRLM were included. Metabolic response was determined as the percentage change in standard uptake value (SUV) and total lesion glycolysis (TLG). Conversion to resection, overall survival (OS), progression‐free survival (PFS) and recurrence‐free survival were evaluated using standard statistics.ResultsVolumetric response sufficient to facilitate resection was seen in 53% of patients after a median of 5 months of therapy. Median follow‐up was 38 months (range: 32–52 months). Median OS was not reached [95% confidence interval (CI) 32 months–unknown] and 3‐year OS was 54% (range: 33–71%). Median PFS was 13 months (95% CI 6–21 months) and 3 year PFS was 10% (range: 3–20%). Neither baseline values nor the percentage change in any of the metabolic parameters evaluated correlated with conversion to resection, survival variables or hepatic recurrence on Cox regression analysis.ConclusionsPre‐ and post‐treatment PET‐related metabolic parameters do not predict conversion to resection or oncologic outcome in patients with uCRLM treated with HAI and systemic chemotherapy. Metabolic parameters should not be used to monitor response or to determine prognosis in these patients.     

Circulating tumor cells in metastatic colorectal cancer: do we need an alternative cutoff?

Purpose

To assess the prognostic and predictive value of circulating tumor cells (CTCs) in metastatic colorectal cancer (mCRC) irrespective of detection level.

Materials and methods

We evaluated the prognostic and predictive significance of CTC count at baseline and under treatment in 119 mCRC subjects and compared the standard cutoff (≥3 CTCs/7.5 mL to ≥1 CTCs/7.5 mL).

Results

An overall comparison was made between patients with 0, 1–2 and ≥3 CTC (median PFS 8, 4 and 5 months, respectively). Two poor prognostic groups were found, including patients with ≥1 CTCs before and during treatment and patients with 0 CTC at baseline who converted to ≥1 CTCs (p = 0.014).

Conclusions

The presence of at least 1 CTC at baseline count is predictive for poor prognosis in mCRC patients. Patients with 1–2 CTC should be switched from the favorable prognostic group—conventionally defined by the presence of <3 CTC—to the unfavorable, deserving a more careful monitoring.     

3种常用联合化疗方案一线治疗晚期胃癌的疗效和安全性比较

目的比较3种常用联合化疗方案一线治疗晚期胃癌的临床疗效和安全性。方法回顾性研究2010年1月至2013年6月期间一线接受联合化疗的晚期胃癌患者46例。其中奥沙利铂联合氟尿嘧啶（mFOLFOX6）方案治疗14例;伊立替康联合氟尿嘧啶（FOLFIRI）方案治疗12例;多西他赛、奥沙利铂或顺铂联合氟尿嘧啶（DOF/DCF）方案治疗20例。化疗2月后评价疗效,化疗期间监测药物不良反应,对无进展生存时间（PFS）和总生存期（OS）进行随访。结果 3种联合化疗的总体客观缓解率为23.9%,总体疾病控制率为82.6%。mFOLFOX6、FOLFIRI、DOF/DCF治疗的患者中位OS分别为20月、11.5月和26月（P=0.043）。分层分析显示对于复发后一线治疗的患者,3种化疗方案没有统计学差异,而对于初治的患者,一线使用FOLFIRI或mFOL-FOX6或DOF/DCF的PFS分别为2.5月、5.5月和7月,中位OS分别为4.5月、19月和14月（P=0.020）。全部Ⅲ~Ⅳ度药物不良反应发生率在mFOLFOX6组（21.4%）较低,但无统计学差异。结论 3种化疗方案用于晚期胃癌均有效且可耐受,但对于初治患者mFOLFOX6或DOF/DCF较FOLFIRI具有更多的生存获益。     

Maintenance treatment with fluoropyrimidine plus bevacizumab versus fluoropyrimidine alone after induction chemotherapy for metastatic colorectal cancer: The BEVAMAINT - PRODIGE 71 - (FFCD 1710) phase III study

BackgroundMaintenance treatments with fluoropyrimidine alone or combined with bevacizumab after induction chemotherapy are two standard options in first-line metastatic colorectal cancer (mCRC). However, no trial has compared these two maintenance regimens.MethodsBEVAMAINT is a multicenter, open-label, randomized phase III trial comparing fluoropyrimidine alone or plus bevacizumab as maintenance treatment after induction polychemotherapy in mCRC. The primary endpoint is the time-to-treatment failure (TTF), calculated from date of randomization to first radiological progression, death, start of a new chemotherapy regimen (different from induction or maintenance chemotherapy) or end of maintenance treatment without introduction of further chemotherapy. We expect a 2-month TTF improvement from 6 months in the monotherapy arm to 8 months in the combination arm (hazard ratio [HR], 0.75). Based on a two-sided α risk of 5% and a power of 80%, using Schoenfeld method, 379 events are required (planned enrolment, 400 patients). Patients with mCRC, whose disease is measurable according to RECIST 1.1 criteria and controlled (objective response or stable disease) – but remains unresectable – after 4 to 6 months of induction polychemotherapy (doublet or triplet chemotherapy with or without anti-EGFR or bevacizumab), and who have recovered from limiting adverse events of induction polychemotherapy are eligible for randomization. Randomization is stratified according to center, response to induction chemotherapy (objective response vs stable disease), ECOG performance status (0-1 vs 2), maintenance fluoropyrimidine (5-fluorouracil vs capecitabine) and primary tumor status (resected vs not). Capecitabine or bolus and infusional 5-fluorouracil plus folinic acid (simplified LV5FU2 regimen) are both accepted for maintenance chemotherapy, at investigator's discretion. Clinical evaluation, tumor imaging, carcinoembryonic antigen and circulating tumor DNA dosages are planned at enrolment and every 9 weeks. The maintenance treatment will be discontinued in the event of unbearable toxicity, progression or patient refusal. After maintenance discontinuation, reintroduction of induction polychemotherapy is recommended; otherwise a second-line treatment is started. The enrolment has begun in January 2020.     

雷替曲塞联合伊立替康治疗晚期结直肠癌的临床观察

目的分析雷替曲塞联合伊立替康治疗晚期结直肠癌的疗效及安全性。 方法纳入中国医学科学院肿瘤医院内科2015年1月至2018年12月收治的34例既往一线或二线使用含氟尿嘧啶类化疗方案失败的晚期结直肠癌患者,接受雷替曲塞联合伊立替康方案治疗,主要观察终点为客观有效率（ORR）,次要观察终点包括疾病无进展生存时间（PFS）、总生存时间（OS）、疾病控制率（DCR）和安全性。 结果34例患者病理确诊均为结直肠腺癌。近期疗效中观察到部分缓解（PR）为6例,疾病稳定（SD）为25例,疾病进展（PD）为3例,客观有效率（ORR）为17.6%（6/34）,疾病控制率（DCR）为91.2%（31/34）。其中,二线患者ORR为21.7%（5/23）,DCR为91.3%（21/23）;三线患者ORR为9.1%（1/11）,DCR为90.9%（10/11）。34位患者全部追踪至疾病进展,疾病无进展中位生存时间（mPFS）为180天（95% CI：157.2~202.8）,截止2020年2月27日末次随访未观察到中位总生存时间（mOS）,平均OS（389.0±51.1）天。其中,接受二线治疗患者的mPFS为193天,平均OS（412.0±61.5）天。接受三线治疗患者的mPFS为150天,mOS为311天。治疗后肿瘤标志物CEA与CA19-9水平均有降低,其中CA19-9治疗前后平均水平为（169.8±48.0）U/mL和（143.8±57.7）U/mL（t=0.700,P=0.655）。CEA治疗前平均水平为（255.0±40.6）ng/mL,治疗后为（104.2±32.4）ng/mL,下降趋势经比较差异具有统计学意义（t=1.759,P=0.001）。安全性方面,常见不良反应包括恶心呕吐、腹泻、白细胞及中性粒细胞减少、血红蛋白降低和转氨酶升高等,多为Ⅰ~Ⅱ级,Ⅲ级不良反应有中性粒细胞减少（2/34）、白细胞减少（1/34）和转氨酶升高（1/34）,无Ⅳ级不良反应及化疗相关死亡事件发生。 结论雷替曲塞联合伊立替康治疗晚期结直肠癌疗效确切,安全性良好。其中二线治疗ORR与国内外既往研究相似,但不良反应更低,值得临床进一步推广应用。     

Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies

Background

Bevacizumab is frequently combined with 5-fluorouracil-based chemotherapy for patients with metastatic colorectal cancer (mCRC). The relative benefit of bevacizumab in older patients has not been widely studied and is of interest.

Patients and methods

This retrospective analysis used data from three first-line randomized controlled studies and one second-line randomized controlled study of bevacizumab plus chemotherapy in medically fit (Eastern Cooperative Oncology Group performance status 0 or 1) patients with mCRC. Overall survival (OS) and on-treatment progression-free survival (PFS) were assessed in patients aged <65, ≥65, and ≥70 years. Results were compared using unstratified hazard ratios (HRs). Grade 3–5 adverse events were also assessed.

Results

Bevacizumab statistically significantly improved PFS [HR 0.58; 95% confidence interval (CI) 0.49–0.68] and OS (HR 0.85; 95% CI 0.74–0.97) in patients aged ≥65 years; patients aged ≥70 years had similar improvements. Benefits were consistent across the studies, irrespective of setting, bevacizumab dose, or chemotherapy regimen. Increases in thromboembolic events were observed in patients aged ≥65 and ≥70 years in the bevacizumab group compared with the control group, mainly as a result of increases in arterial thromboembolic events. No other substantial age-related increases in grade 3–5 adverse events were observed.

Conclusions

In medically fit older patients, bevacizumab provides similar PFS and OS benefits as in younger patients.     

Immune checkpoint inhibitors for patients with isolated peritoneal carcinomatosis from dMMR/MSI-H colorectal cancer,a BIG-RENAPE collaboration

BackgroundImmunotherapy with immune checkpoint inhibitors has significantly improved the survival of patients with MSI/dMMR mCRC. These tumors are associated with a specific metastatic spread, i.e. frequent peritoneal carcinomatosis (PC) that may be treated surgically when there is no other metastatic location. We aimed at evaluating the prognosis of patients treated with immune checkpoint inhibitors for MSI/dMMR mCRC with isolated PC.Material and MethodsAll consecutive patients with isolated PC from MSI/dMMR mCRC, initially considered as unresectable by multidisciplinary team meeting, treated with immune checkpoint inhibitors were included in this French multicenter cohort study.ResultsAmong 45 patients included, we observed 11 complete responses and 10 partial responses for an overall response rate iRECIST of 46%. After a median follow-up of 24.4 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. Seven of the eight patients who underwent cytoreductive surgery after treatment with anti-PD1 ± anti-CTLA-4 were in complete pathologic response.ConclusionThese results demonstrate long-term benefit of immune checkpoint inhibitors for patients with isolated PC from MSI/dMMR mCRC. Such treatment appears as the best therapeutic option for patients with isolated PC from MSI/dMMR mCRC. With a majority of pathological complete responses for patients who underwent surgery for residual lesions, the value of such therapeutic strategy remains unknown.