Previous Adjuvant Chemotherapy Research Articles

Translated article] Toxicity of the FOLFOX-6 regimen, with or without 5-fluorouracil bolus, in metastatic colorectal cancer.

Standard treatment of metastatic colorectal cancer includes oxaliplatin and 5-fluorouracil in continuous infusion. Although FOLFOX-6 is the reference combination, it is aggressive and has high toxicity. Variants such as the TTD regimen, which does not include folinic acid or 5-fluorouracil bolus, are used. This study evaluates the toxicity of FOLFOX-6 and TTD in first line treatment for metastatic colorectal cancer and its effectiveness. Retrospective observational study with patients who started treatment with FOLFOX-6 and TTD, for 3 years. Demographic and clinical data were collected (age, sex, chronic pathologies, molecular profile, laterality, Eastern Cooperative Oncology Group classification, and stage), as well as treatment variables (previous adjuvant chemotherapy, intentionality, number of cycles, duration, and pharmacogenetic aspects) and toxicity. Objective response rate and progression-free survival were calculated. The study included 71 patients, 35 treated with FOLFOX-6, and 36 with TTD. Both groups showed similar overall toxicity profiles. FOLFOX-6 had a higher incidence of neutropenia (46% vs 8%; P < .01) and mucositis (51% vs 22%; P < .013). In addition, there were more treatment delays (40% vs 11%; P < .05) and 5-fluorouracil dose reductions (22% vs 14%; P < .05) in the FOLFOX-6 group. Deaths due to toxicity were only recorded in the FOLFOX-6 group. Effectiveness was similar in both groups. The TTD regimen could be a beneficial first-line option for metastatic colorectal cancer, with lower toxicity and effectiveness comparable to FOLFOX-6. It is a safe alternative for elderly or frail patients, suitable for reduced-dose 5-fluorouracil regimen with oxaliplatin.

Irinotecan- vs. Oxaliplatin-Based Doublets in KRASG12C-Mutated Metastatic Colorectal Cancer-A Multicentre Propensity-Score-Matched Retrospective Analysis.

KRASG12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown. A multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/- bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis to first-line start, number of metastatic sites, presence of mucinous component, gender, and age. Subgroup analyses were also performed to investigate subgroup treatment-effect interactions. KRASG12D-mutated patients were analysed as control. One hundred and four patients treated with irinotecan-(N = 47) or oxaliplatin-based (N = 57) chemotherapy were included. In the unmatched population, objective response rate (ORR) and median (m) progression-free and overall survival (mPFS and mOS) were comparable between the treatment arms. However, a late (>12 months) PFS advantage was observed with irinotecan (HR 0.62, p = 0.02). In the PSMA-derived cohort, a significant improvement with irinotecan vs. oxaliplatin was observed for both PFS and OS: 12- and 24-month PFS rates of 55% vs. 31% and 40% vs. 0% (HR 0.40, p = 0.01) and mOS 37.9 vs. 21.7 months (HR 0.45, p = 0.045), respectively. According to the subgroup analysis, interaction effects between the presence of lung metastases and treatment groups were found in terms of PFS (p for interaction = 0.08) and OS (p for interaction = 0.03), with a higher benefit from irinotecan in patients without lung metastases. No difference between treatment groups was observed in the KRASG12D-mutated cohort (N = 153). First-line irinotecan-based regimens provided better survival results in KRASG12C-mutated mCRC patients and should be preferred over oxaliplatin. These findings should also be considered when investigating chemotherapy plus targeted agent combinations.

Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC

BackgroundAmong patients with resected, epidermal growth factor receptor (EGFR)–mutated, stage IB to IIIA non–small-cell lung cancer (NSCLC), adjuvant osimertinib therapy, with or without previous adjuvant chemotherapy, resulted in significantly longer disease-free survival than placebo in the ADAURA trial. We report the results of the planned final analysis of overall survival.MethodsIn this phase 3, double-blind trial, we randomly assigned eligible patients in a 1:1 ratio to receive osimertinib (80 mg once daily) or placebo until disease recurrence was observed, the trial regimen was completed (3 years), or a discontinuation criterion was met. The primary end point was investigator-assessed disease-free survival among patients with stage II to IIIA disease. Secondary end points included disease-free survival among patients with stage IB to IIIA disease, overall survival, and safety.ResultsOf 682 patients who underwent randomization, 339 received osimertinib and 343 received placebo. Among patients with stage II to IIIA disease, the 5-year overall survival was 85% in the osimertinib group and 73% in the placebo group (overall hazard ratio for death, 0.49; 95.03% confidence interval [CI], 0.33 to 0.73; P<0.001). In the overall population (patients with stage IB to IIIA disease), the 5-year overall survival was 88% in the osimertinib group and 78% in the placebo group (overall hazard ratio for death, 0.49; 95.03% CI, 0.34 to 0.70; P<0.001). One new serious adverse event, pneumonia related to coronavirus disease 2019, was reported after the previously published data-cutoff date (the event was not considered by the investigator to be related to the trial regimen, and the patient fully recovered). Adjuvant osimertinib had a safety profile consistent with that in the primary analysis.ConclusionsAdjuvant osimertinib provided a significant overall survival benefit among patients with completely resected, EGFR-mutated, stage IB to IIIA NSCLC. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.)

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer

BackgroundStandard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear.MethodsIn this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair–deficient (dMMR) or mismatch repair–proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort.ResultsIn the 12-month analysis, Kaplan–Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy.ConclusionsIn patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.)

Second-line bevacizumab plus FOLFOX in patients with metastatic colorectal cancer previously treated with adjuvant oxaliplatin-based chemotherapy.

157 Background: There is a rarity of evidence for retreatment with oxaliplatin for metastatic colorectal cancer (mCRC), especially in combination with bevacizumab. This is a retrospective study of second line bevacizumab (Bev) plus FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) in patients with metastatic colorectal cancer previously treated with adjuvant oxaliplatin-containing chemotherapy. Methods: Patients with age older than 18 and histologically confirmed metastatic colorectal cancer treated with second line bevacizumab plus FOLFOX in a single institute between 2015 and 2020 were enrolled. History of previous adjuvant chemotherapy regimens in patients with metachronous metastatic colorectal cancer was analyzed. Progression-free survival (PFS) and overall survival (OS) of the second line treatment were calculated using Kaplan-Meier method and compared between patients pretreated with adjuvant oxaliplatin (ReOx) and oxaliplatin-naive patients (control) with the log rank test. Results: A total of 72 patients were included. 23 patients (ReOx) were pretreated with adjuvant oxaliplatin and 49 patients (control) were oxaliplatin-naive before the second line treatment. There was a tendency of younger age in the ReOx group, but not statistically significant. Liver metastasis was significantly more frequent in the control group. The median PFS and OS in the ReOx group and the control group were 4.3 months (95% confidence interval [CI], 3.67–21.50) versus 5.5 months (95% CI, 4.23–8.20, hazard ratio [HR] = 0.84), and 10.5 months (95% CI, 5.40–30.37) versus 9.4 months (95% CI, 6.00–14.9, HR = 1.01) respectively. There was no significant difference of PFS ( p= 0.523) and OS ( p= 0.9745) between two groups. Conclusions: This study suggests a potential survival benefit of bevacizumab plus FOLFOX for mCRC patients previously treated with adjuvant oxaliplatin-containing treatment comparable to oxaliplatin-naive patients. [Table: see text]

Efficacy and Safety of Immune Checkpoint Inhibitors in Triple-negative Breast Cancer: A Study Based on 41 Cohorts Incorporating 6558 Participants.

The project was designed to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs) in triple-negative breast cancer (TNBC). Electronic databases were screened to identify relevant trials. The primary endpoints were prognostic parameters and adverse events (AEs) through pooled rate, odds ratio, and hazard ratio (HR) with 95% CI. Totally, 6558 TNBC patients from 41 cohorts were included. The pooled pathologic complete response rate (odds ratio=2.03, 95% CI: 1.35-3.06, P =0.0007) and event-free survival (HR=0.84, 95% CI: 0.73-0.96, P =0.0100) of ICIs plus chemotherapy was higher than that of chemotherapy-alone in early-stage TNBC. For metastatic TNBC, compared with chemotherapy-alone, the addition of ICIs prolonged the progression-free survival (PFS) (HR=0.92, 95% CI: 0.88-0.96, P <0.0001); the improvement also existed in the following 3 subgroups: programmed cell death-ligand 1 positive, race of White and Asian, and patients without previous neoadjuvant or adjuvant chemotherapy; however, the benefit of the combined regimen was not observed in overall survival (OS) (HR=0.95; 95% CI: 0.89-1.03, P =0.2127). In addition, the pooled rates of OS, PFS, and objective response rate of ICIs plus chemotherapy were better than those of ICIs plus targeted therapy or ICIs-alone. In the safety analysis, compared with chemotherapy-alone, ICIs plus chemotherapy increased immune-related AEs and several serious AE. The regimen of ICIs plus chemotherapy is promising in both early-stage and metastatic TNBC, while the increased serious AE should not be neglected. Furthermore, the pooled rates of OS, PFS, and objective response rate of ICIs plus chemotherapy were better than those of ICIs plus targeted therapy or ICIs-alone.

Biomarker-oriented study of pembrolizumab in combination with chemotherapy in chemotherapy-naïve advanced pancreatic cancer: A phase 2 trial-in-progress.

TPS639 Background: Pancreatic cancer (PC) is well-known as a strongly immunosuppressive tumor. The tumor microenvironment of PC play a fundamental part in maintaining a non-immunogenic and immuno-suppressive environment through the production of inhibitory cytokines and complex interaction between tumor cells, regulatory T cells, and myeloid-derived suppressor cells (Li KY et al. 2020). However, through integrated genomics and immunophenotyping, the immune-rich type had a relatively good prognosis in advanced PC (Wartenberg M et al. 2018). Based on this, various attempts have been made to apply immune checkpoint inhibitor (ICI) to PC. Disappointingly, ICI monotherapy is ineffective in most advanced PCs, and a strategy of combining ICI with ICI, chemotherapy or targeted therapy has been recently tried. However, the mechanism of immune modulation induced by ICI in combination with chemotherapy in PC is still not well-known, so biomarker studies are needed to understand the role of immunotherapy in advanced PC. Also based on this, it is expected to develop an effective ICI treatment strategy in PC. This study is a non-randomized, parallel assignment phase 2 trial aimed to explore dynamic modulation of the immune system caused by co-administration of pembrolizumab and cytotoxic chemotherapy in patients with advanced PC. Methods: Eligible patients have recurred or metastatic pancreatic cancer. Patients who have received chemotherapy for advanced PC are excluded, except for previous adjuvant chemotherapy. Patients who have received ICI are excluded. There are 2 chemotherapy cohorts (FOLFIRINOX, n=41; Gemcitabine/Nab-paclitaxel, n=36). Patients enrolled in the FOLFIRINOX cohort will receive pembrolizumab 200mg intravenously once every 3 weeks, plus FOLFIRINOX chemotherapy every 2 weeks. In Gemcitabine/Nab-paclitaxel cohort, patients will receive gemcitabine 1000mg/m2 plus nab-paclitaxel 125mg/m2 day 1, 8, 15 of a 4-week cycle, plus pembrolizumab 200mg intravenously once every 3 weeks. The primary endpoint is objective response rate, with key secondary endpoints including progression-free survival, duration of response, disease control rate, overall survival, safety, and patient-reported outcome. For evaluating metabolic response, 18F-FDG PET-CT scan will be conducted before treatment and at the first response evaluation. Tumor tissue biopsies are performed three times in total: screening, the first response evaluation, and disease progression. Blood samples are being collected every cycles for translational biomarker studies. Clinical trial information: NCT04447092.

Postoperative Chemotherapy Use and Outcomes From ADAURA: Osimertinib as Adjuvant Therapy for Resected EGFR-Mutated NSCLC

IntroductionAdjuvant chemotherapy is recommended in patients with resected stages II to IIIA (and select IB) NSCLC; however, recurrence rates are high. In the phase 3 ADAURA study (NCT02511106), osimertinib was found to have a clinically meaningful improvement in disease-free survival (DFS) in patients with resected stages IB to IIIA EGFR-mutated (EGFRm) NSCLC. Here, we report prespecified and exploratory analyses of adjuvant chemotherapy use and outcomes from ADAURA. MethodsPatients with resected stages IB to IIIA EGFRm NSCLC were randomized 1:1 to receive osimertinib or placebo for 3 years. Adjuvant chemotherapy before randomization was not mandatory, per physician and patient choice. DFS in the overall population (IB–IIIA), with and without adjuvant chemotherapy, was a prespecified analysis. Exploratory analyses included the following: adjuvant chemotherapy use by patient age, disease stage, and geographic location; DFS by adjuvant chemotherapy use and disease stage. ResultsOverall, 410 of 682 patients (60%) received adjuvant chemotherapy (osimertinib, n = 203; placebo, n = 207) for a median duration of 4.0 cycles. Adjuvant chemotherapy use was more frequent in patients: aged less than 70 years (338 of 509; 66%) versus more than or equal to 70 years (72 of 173; 42%); with stages II to IIIA (352 of 466; 76%) versus stage IB (57 of 216; 26%); and enrolled in Asia (268 of 414; 65%) versus outside of Asia (142 of 268; 53%). A DFS benefit favoring osimertinib versus placebo was observed in patients with (DFS hazard ratio = 0.16, 95% confidence interval: 0.10–0.26) and without adjuvant chemotherapy (hazard ratio = 0.23, 95% confidence interval: 0.13–0.40), regardless of disease stage. ConclusionsThese findings support adjuvant osimertinib as an effective treatment for patients with stages IB to IIIA EGFRm NSCLC after resection, with or without previous adjuvant chemotherapy.

Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial.

Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma. In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2-4a or ypN+ tumours following neoadjuvant chemotherapy or pT3-4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients. Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2-29·8). Median disease-free survival was 19·4 months (95% CI 15·9-24·8) with atezolizumab and 16·6 months (11·2-24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74-1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group. To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time. F Hoffmann-La Roche/Genentech.

A case report of appendix mucinous adenocarcinoma that recurred after additional surgery and a brief literature review

BackgroundThe clinical incidence of appendiceal mucinous adenocarcinoma is low. Moreover, the case reports of postoperative relapse after surgery are rarely based on literature search results. Here, we report such a case spanning nearly 7 years and and review the relevant literature.Case presentationA 50-year-old female underwent additional surgery after appendectomy, and pathological examination confirmed mucinous adenocarcinoma. The patients underwent HIPEC (hyperthermic intraoperative chemotherapy) and adjuvant chemotherapy. Twenty-six months after the previous surgeries, another surgery, HIPEC, and adjuvant chemotherapy were performed again due to tumour recurrence. To date, the follow-up time is 43 months, and no recurrence or metastasis has been found.ConclusionsAppendix mucinous adenocarcinoma has a poor prognosis and the diagnosis depends on pathological and immunohistochemical examinations. Its clinical manifestations are non-specific, and CRS + HIPEC should be used for treatment, which is safe and effective.

MON-521 An Open-Label, Single-Arm, Multicenter, Phase 2 Trial of Lenvatinib (LEN) for the Treatment of Anaplastic Thyroid Cancer (ATC)

Background: ATC is aggressive, with a low 5-year patient (pt)-survival rate. Apart from recent advances in treating ATCs in pts with BRAF mutations, systemic treatments have limited efficacy and duration of response is short. In a small, phase 2 study conducted in Japan, 24% of pts with ATC achieved a partial response (PR) with LEN (Study 208 [Takahashi, Future Oncol. 2019]). This study (NCT02657369 [Study 213]) aimed to further evaluate the efficacy and safety of LEN in a broader population of pts with ATC. Methods: Study 213 was performed in collaboration with the International Thyroid Oncology Group and enrolled pts with ATC to receive LEN 24 mg/day. Key inclusion criteria were: histologic diagnosis of ATC, measurable disease per RECIST v1.1, ECOG score ≤1, and adequate organ function. Previous surgery, radiation, and neoadjuvant, adjuvant, or palliative chemotherapy for ATC were allowed. The primary end point (confirmed objective response rate [ORR]) was determined by investigator review per RECIST v1.1. Interim analysis was done after the first 20 evaluable pts completed ≥2 tumor assessments (baseline and 6-week scan) or discontinued treatment. Results: The study was halted for futility when the minimum threshold for ORR (15%) was not met at the interim analysis. The full analysis set (FAS) included 34 pts because the protocol allowed enrollment until the interim analysis was complete. The median pt age was 66.5 years old and most were female (n=21/34), white (n=27/34), and had been treated with 1 or 2 prior anticancer regimens (n=20/34). Unconfirmed PR was experienced in 1/20 pts (ORR 5%; 95% CI 0.1–24.9%) in the interim analysis set. In the FAS, 1/34 pts had a confirmed PR (cPR) (ORR 3%; 95% CI 0.1–15.8%). In the interim and FAS, median progression-free survival (2.6 and 2.6 months, respectively) and median OS (2.9 and 3.2 months, respectively) were similar. In addition to the 1 cPR, 7 pts had 22–63% shrinkage in tumor measurements but did not meet the response criteria (FAS). Grade 3/4 treatment-emergent (TE) adverse events (AEs) occurred in 82.4% of pts, and 61.8% of pts experienced grade 3/4 treatment-related AEs (FAS). Grade 5 TEAEs occurred in 14/34 pts and there were 27 deaths by the time of data cut-off. There were no treatment-related deaths, and no major treatment-related bleeding events occurred. Conclusion: In contrast to Study 208, Study 213 enrolled more pts with ATC (34 vs 17), more of whom had received prior chemotherapy (62% vs 41%). Additionally, in Study 208, all pts were Japanese and tumor assessments were conducted more frequently (4- vs 6-weekly). These differences may have contributed to the observed variation in results between the 2 studies. AEs observed were consistent with the safety profile of LEN or with ATC. Further investigation of LEN in combination with a checkpoint inhibitor may be warranted.

Liver metastases in patients with curatively treated colorectal cancer

Background. The problem of the development of liver metastases in colorectal cancer patients previously treated with curative intent surgery remains little studied. Identification of significant factors affecting the occurrence of metachronous metastasis contributes to a more accurate prediction of recurrence in this group of patients. material and methods. In our study we analyzed the incidence of liver metastases and prognostic factors in 116 colorectal cancer patients previously treated with curative intent at Irkutsk Regional Cancer Center between 2006 and 2017. The patients received combined modality treatment including neoadjuvant radiotherapy or chemoradiotherapy for localized and locally advanced rectal cancer, radical surgery and adjuvant chemotherapy. After curative treatment, 96 patients had no evidence of distant liver metastases, and 20 patients developed distant metastases. results. The incidence of liver metastases was 17 %. In most patients, metastases occurred 16.5 months after completion of curative treatment, reaching peak incidence at 12–18 months. Prognostic factors of colorectal liver metastases in colorectal cancer patients previously treated with curative intent surgery were: the stage of the tumor, tumor growth in the parirectal/mesocolic fatty tissue, and no previous preoperative chemoradiotherapy and adjuvant chemotherapy. conclusion. For early detection of liver metastases, the carcinoembryonic antigen (CEA) measurements, contrast-enhanced abdominal multislice CT, and ultrasound-guided liver biopsy were recommended to perform every 3 months in the postoperative period.

Upfront FOLFOXIRI Plus Bevacizumab and Reintroduction after Progression versus mFOLFOX6 Plus Bevacizumab Followed by FOLFIRI Plus Bevacizumab in the Treatment of Patients with Metastatic Colorectal Cancer (TRIBE2): A Multicentre, Open-Label, Phase 3, Randomised Controlled Trial by GONO

Upfront FOLFOXIRI Plus Bevacizumab and Reintroduction after Progression versus mFOLFOX6 Plus Bevacizumab Followed by FOLFIRI Plus Bevacizumab in the Treatment of Patients with Metastatic Colorectal Cancer (TRIBE2): A Multicentre, Open-Label, Phase 3, Randomised Controlled Trial by GONO

Exemestane and Everolimus combination treatment of hormone receptor positive, HER2 negative metastatic breast cancer: A retrospective study of 9 cancer centers in the Campania Region (Southern Italy) focused on activity, efficacy and safety.

Exemestane (Exe) in combination with Everolimus (Eve) represents an important treatment option for patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC), which was previously treated with non-steroidal aromatase inhibitors (NSAI). Data from unselected populations may be useful for defining the optimal therapeutic algorithm within a clinical setting. Data from 264 HR+, HER2-MBC patients who received Exe-Eve treatment in combination, following the failure of NSAIs was retrospectively analyzed. Different lines of endocrine treatment (ET) were investigated to evaluate the efficacy and toxicity of the treatment within the ‘everyday clinical practice’ population. The disease control rate (DCR) was 73.1%, with no statistically significant difference among the different settings. At a median follow-up of 42 months, the median progression free survival (PFS) was 11.6, 9.7 and 7.5 months for patients treated with Exe-Eve as first, second or third line therapy, respectively. There was a statistically significant correlation with younger age, no previous adjuvant chemotherapy (CT), no previous adjuvant endocrine therapy (ET), HT duration ≥36 months, involvement of liver and/or lung, no prior CT for metastatic disease and PS=0 at the start of treatment. The median overall survival (OS) was 33.0 months; at a median follow-up of 67 months, the median OS was 43.1, 31.7 and 27.9 months in patients treated with Exe-Eve in first, second or third line therapy, respectively. On multivariate analysis, diabetes and previous CT for metastatic disease were revealed to correlate with a worse outcome. Conversely, the presence of mucositis was significantly associated with long-term survival. Overall, Exe-Eve was typically well tolerated and the majority toxicities were G1 or 2, while treatment discontinuation due to unacceptable toxicity was only required in 5.7% of patients. Despite the limitations due to the observational nature of this study, the findings suggest that treatment with Exe-Eve is an active and safe therapeutic option for endocrine-sensitive MBC patients in a real-world clinical setting, regardless of treatment lines.

Metachronous Peritoneal Metastases After Adjuvant Chemotherapy are Associated with Poor Outcome After Cytoreduction and HIPEC

IntroductionCytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) improve the survival of colorectal cancer (CRC) patients with peritoneal metastases. Patient selection is key since this treatment is associated with high morbidity. Patients with peritoneal recurrence within 1 year after previous adjuvant chemotherapy are thought to benefit less from HIPEC treatment; however, no published data are available to assist in clinical decision making. This study assessed whether peritoneal recurrence within 1 year after adjuvant chemotherapy was associated with survival after HIPEC treatment.MethodsPeritoneal recurrence within 1 year after adjuvant chemotherapy, as well as other potentially prognostic clinical and pathological variables, were tested in univariate and multivariate analysis for correlation with primary outcomes, i.e. overall survival (OS) and disease-free survival (DFS). Two prospectively collected databases from the VU University Medical Center Amsterdam and Catherina Hospital Eindhoven containing 345 CRC patients treated with the intent of HIPEC were utilized.ResultsHigh Peritoneal Cancer Index (PCI) scores were associated with worse DFS [hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00–1.08, p = 0.040] and OS (HR 1.11, 95% CI 1.07–1.15, p < 0.001) in multivariate analysis. Furthermore, patients with peritoneal recurrence within 1 year following adjuvant chemotherapy had worse DFS (HR 2.13, 95% CI 1.26–3.61, p = 0.005) and OS (HR 2.76, 95% CI 1.45–5.27, p = 0.002) than patients who did not receive adjuvant chemotherapy or patients with peritoneal recurrence after 1 year.ConclusionPeritoneal recurrence within 1 year after previous adjuvant chemotherapy, as well as high PCI scores, are associated with poor survival after cytoreduction and HIPEC. These factors should be considered in order to avoid high-morbidity treatment in patients who might not benefit from such treatment.

Abstract P3-11-07: Factors associated with first line chemotherapy use in patients with hormone receptor positive, HER2 negative metastatic breast cancer – data from the PRAEGNANT breast cancer registry

Abstract Background For breast cancer patients with metastases which are not life threatening national and international guidelines recommend the exhaustion of all antihormonal therapeutic options before recommending chemotherapy. In Germany up to now only everolimus was an additional option to overcome endocrine resistance. CDK4/6 inhibitors recently became available in Germany (Nov 2011). Aim of this analysis was the identification of predictors for a decision against an antihormonal treatment. Methods The PRAEGNANT metastatic breast cancer registry (NCT02338167) is a prospective registry for metastatic breast cancer patients. Besides biomarker research the description of real-world treatment data was one of the main study aims. This analysis was restricted to first line metastatic patients who were hormone receptor (HR) positive and HER2 negative. First, predictors were identified with a multiple logistic regression model. Then patients, who received chemo or not ,were compared with regard to overall survival using Cox regression analysis with the predictors for chemotherapy from above and additionally chemo status (yes/no) Results A total of 389 HR-positive and HER2-negative patients with detailed treatment information were included during the 1st line therapy into PRAEGNANT. Of those 173 (44.5%) received a chemotherapy, 190 an antihormone therapy (AHT) (48.8%), and 26 (6.7%) everolimus+AHT. In the multiple logistic regression model, older patients, lower graded tumors, bone only disease and previous adjuvant chemotherapy were associated with a lower rate of first line chemotherapies. BMI and number of concomitant diseases had no influence on the choice of first line metastatic therapy. In patients with visceral metastases 58.1% were treated with a 1st line chemo, while in patients with brain metastases or bone only metastases these numbers were 55.6% and 26.9%. Grading had an influence with patients having a G1, G2 and G3 tumor receiving 1st line chemo in 28.0%, 38.4% and 63.2% of the cases respectively. Patients who received chemo seemed to have a worse overall survival than patients who did not receive chemo (adjusted HR 1.58; 95% CI, 0.89 to 2.18). However, this result was not signifcant (p = 0.12). Overall survival was primarily influenced by ECOG and location of metastasis Conclusion The usage of chemotherapy can be predicted with age, metastasis pattern, grading and previous use of chemotherapy. However, we could not show that patients benefited from chemotherapy. On contrary, there was a tendency that patients treated with chemotherapy had poorer overall survival. Further studies with larger sample sizes are needed to confirm this claim. Citation Format: Huober J, Fasching PA, Taran F-A, Volz B, Overkamp F, Kolberg HC, Hadji P, Tesch H, Haeberle L, Ettl J, Hartkopf AD, Lux MP, Lueftner D, Wallwiener M, Mueller V, Beckmann MW, Belleville E, Wimberger P, Hielscher C, Geberth M, Fersis N, Abenhardt W, Kurbacher C, Wuerstlein R, Thomssen C, Untch M, Janni W, Wallwiener D, Brucker SY, Schneeweiss A, Fehm TN. Factors associated with first line chemotherapy use in patients with hormone receptor positive, HER2 negative metastatic breast cancer – data from the PRAEGNANT breast cancer registry [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-11-07.

Changes in body composition and muscle attenuation during taxane-based chemotherapy in patients with metastatic breast cancer.

Body composition parameters including low muscle mass, muscle attenuation (which reflects muscle quality) and adipose tissue measurements have emerged as prognostic factors in cancer patients. However, knowledge regarding the possibility of excessive muscle loss during specific systemic therapies is unknown. We describe the changes in body composition and muscle attenuation (MA) during taxane- and anthracycline-based regimens and its association with overall survival (OS) in metastatic breast cancer patients. The lumbar skeletal muscle index (LSMI) was used as marker of muscle mass. LSMI, MA, subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and intramuscular adipose tissue (IMAT) were measured before and after first-line treatment with paclitaxel (n=73) or 5-fluorouracil-doxorubicin-cyclophosphamide (FAC) (n=25) using CT-images. Determinants of the change of LSMI and MA were analyzed using multiple linear regression. OS was assessed using Cox proportional hazard models. MA significantly decreased during paclitaxel treatment (-0.9 HU, p=0.03). LSMI (p=0.40), SAT (p=0.75), VAT (p=0.84) and IMAT (p=0.10) remained stable. No significant alterations in body composition parameters during FAC-treatment were observed. Previous (neo-)adjuvant chemotherapy contributed to larger loss of MA during the current treatment. Body composition changes during chemotherapy were not associated with OS. MA decreased during treatment with paclitaxel, while muscle mass was stable. Body composition changes are not associated with survival in the absence of progressive disease.

Cost-effectiveness of surveillance and prevention strategies in BRCA1/2 mutation carriers.

Cost-effectiveness analysis is an important aspect of healthcare, including in Japan, where preventive measures for BRCA1/2 mutation carriers are not covered by health insurance. We developed Markov models in a simulated cohort of women aged 35-70years, and compared outcomes of surveillance with risk-reducing mastectomy (RRM) at age 35, risk-reducing salpingo-oophorectomy (RRSO) at age 45, and both (RRM&RRSO). We used breast and ovarian cancer incidences and adverse event rates from the previous studies, adjuvant chemotherapy, and hormonal therapy rates from the Hereditary Breast and Ovarian Cancer Registration 2015 in Japan, mortality rates from the National Cancer Center Hospital, Japan Society of Clinical Oncology, and Ministry of Health, Labour and Welfare, and direct costs from St. Luke's International Hospital and Keio University Hospital. We used previously published preference ratings of women without known high risk to adjust survival for quality of life. The discount rate was 2%. Compared with surveillance, RRSO and RRM&RRSO were dominant (both cost-saving and more effective), and RRM was cost-effective in BRCA1 mutation carriers, while RRM and RRM&RRSO were dominant and RRSO was cost-effective in BRCA2. Among the four strategies including surveillance, RRM&RRSO and RRM were the most cost-effective in BRCA1 and BRCA2 mutation carriers, respectively. With quality adjustment, RRM, RRSO, and RRM&RRSO were all cost-effective preventive strategies in BRCA1/2 mutation carriers, with RRM&RRSO being the most cost-effective in BRCA1 and RRM in BRCA2. This result supports the inclusion of insurance coverage for BRCA mutation carriers in Japan.

Retrospective-prospective blinded evaluation predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort.

1071 Background: Epirubicin remains a cornerstone in the treatment of primary and advanced breast cancer. This study evaluated the predictive effect of a multigene mRNA-based Drug Response Predictor (DRP) in the treatment of advanced breast cancer (ABC). We applied a mathematical method combining in vitro sensitivity with gene expression patterns in tumors. Previously the DRP has been broadly validated1, 2 including retrospective validation of epirubicin3. Methods: Among 838 consecutive patients from a DBCG cohort 137 patients were treated with epirubicin between May 1997 and November 2016 at one of the participating sites. Patients were examined every 9 to 12 weeks by CT scan and clinical evaluation. After patient informed consent, mRNA was isolated from formalin fixed paraffin embedded tumor tissue from diagnostic biopsies and analyzed using Affymetrix arrays. Blinded predictions of epirubicin efficacy were compared to clinical data collected retrospectively from patients’ medical records. Statistical analysis was done using Cox proportional hazards model adjusted for treatment line. Primary endpoint was progression free survival (PFS). Results: Median time to progression was 9.3 months (95% CI: 7.2-13.2). Of the 137 patients, four received epirubicin more than once. Scoring the DRP as a continuous covariate demonstrated that the DRP was significantly associated to PFS (p = 0.02). The estimated hazard ratio was 0.56 (90% CI: 0.35-0.89) comparing two patients with DRP score differing by 50 percentage points. The estimated median time to progression for a patient with a DRP value of 25% was 7 months versus 13 months for a patient with a DRP value of 75%. No interaction with previous adjuvant chemotherapy was observed (p = 0.98). Conclusions: The current study demonstrates a potential clinical value by being able to select patients that benefit from epirubicin against patients predicted not to benefit sparing the last patients unnecessary toxicity. Studies evaluating the predictor in an adjuvant setting will follow. 1 Knudsen et al PLoS ONE 9(2): e87415; 2 Buhl et al PLoS ONE 11(5): e0155123; 3 Wang et al JNCI 105(17): 1284-91

Cost-effectiveness of surveillance and prevention strategies in BRCA 1/2 mutation carriers.

e13051 Background: Cost-effectiveness analysis is important in healthcare, especially in Japan, where preventive measures for carriers of BRCA 1/2 mutations are not covered by health insurance. Methods: We developed Markov models in a simulated cohort of women aged 35–70, and compared outcomes of surveillance with risk-reducing mastectomy at age 35 (RRM), risk-reducing salpingo-oophorectomy at age 45 (RRSO), and both (RRM&amp;RRSO), with quality adjustment. We used breast and ovarian cancer incidence, and adverse event rates from previous studies, adjuvant chemotherapy and hormonal therapy rates from Hereditary Breast and Ovarian Cancer Registration 2015, mortality rates from the National Cancer Center Hospital, Japan Society of Clinical Oncology and Ministry of Health, Labour and Welfare, and direct costs in 2016 Japanese yen from St. Luke’s International Hospital and Keio University Hospital. We used preference ratings for both of mutation carriers and controls (without known high risk) from a published study to adjust survival for quality of life (QALYs). Discount rate was 2%. Results: Compared with surveillance, RRSO and RRM &amp; RRSO were dominant (cost-saving and more effective) and RRM was cost effective for BRCA 1 mutation carriers. RRM and RRM &amp; RRSO were dominant, and RRSO was cost effective for BRCA 2 mutation carriers. Among four strategies including surveillance, RRM &amp; RRSO was the most cost effective for BRCA 1 mutation carriers and RRM was the most cost effective for BRCA 2 mutation carriers based on preference ratings of controls. Conclusions: With quality adjustment, all the preventive strategies (RRM, RRSO and RRM&amp;RRSO) were cost effective for BRCA 1 and 2. Using QALYs from the control group, RRM &amp; RRSO for BRCA 1 and RRM for BRCA 2 were the most cost effective. We will use this result to promote insurance coverage for BRCA mutations carriers in Japan.