Impact of biomarkers and primary tumor location on the metastatic colorectal cancer first-line treatment landscape in five European countries

Cancer shared this article with you from Inoreader Message: We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy. × Future Medicine Logo Search My Cart Sign in Institutional Access Skip main navigation JOURNALS BOOKS ABOUT US CONTACT US FUTURE ONCOLOGYAHEAD OF PRINTSHORT COMMUNICATIONOpen Accesscc iconby iconnc iconnd icon Impact of biomarkers and primary tumor location on the metastatic colorectal cancer first-line treatment landscape in five European countries George Kafatos , Victoria Banks , Peter Burdon , David Neasham , Kimberly A Lowe , Caroline Anger, Fil Manuguid & Jörg Trojan Published Online:19 Jan 2021https://doi.org/10.2217/fon-2020-0976 Sections View Article Tools Share Abstract Background: Advances in therapies for patients with metastatic colorectal cancer (mCRC) and improved understanding of prognostic and predictive factors have impacted treatment decisions. Materials & methods: This study used a large oncology database to investigate patterns of monoclonal antibody (mAb) plus chemotherapy treatment in France, Germany, Italy, Spain and the UK in mCRC patients treated in first line in 2018. Results: Anti-EGFR mAbs were most often administered to patients with RAS wild-type mCRC and those with left-sided tumors, while anti-VEGF mAbs were preferred in RAS mutant and right-sided tumors. Adopted treatment strategies differed between countries, largely due to reimbursement. Conclusion: Biomarker status and primary tumor location steered treatment decisions in first line. Adopted treatment strategies differed between participating countries. Lay abstract Each patient's cancer is unique. For example, colon cancer on the left side is different from colon cancer on the right side. Colon cancer is different from cancer of the rectum. Cancers also have changes in their genes, which means some treatments should work, while others may not. Doctors can select among different medicines to find the drug that works best for each patient. We looked at patients with cancer of the colon or rectum that has spread to other organs. We tried to find out how doctors in Europe select drugs for their patients after performing tests called RAS or BRAF. We found that doctors make different choices in different countries. Keywords: BRAFEGFRmCRCprimary tumor locationRAStumor sidednessVEGF During the last decade, improvements in the treatment of metastatic colorectal cancer (mCRC) have increased median survival time for patients from 12 months to approximately 3 years [1,2]. Major drivers of this success were the development of an antiangiogenic agent, the VEGF inhibitor bevacizumab, of monoclonal antibodies (mAbs) that inhibit the EGFR namely panitumumab and cetuximab, and a better understanding of prognostic and predictive biomarkers and of the different molecular profiles of left- and right-sided tumors [3,4,5]. Further important factors were the improvements in the adoption of multi-disciplinary teams/tumor boards, new surgical techniques, or local ablative therapies [6]. Chemotherapy, anti-VEGF mAbs and anti-EGFR mAbs are now the mainstay of systemic mCRC therapy. In the first line following diagnosis of mCRC, treatment is planned according to patient fitness, resectability of the tumor and/or metastases, and the tumor's biomarker status [7]. The European Society for Medical Oncology (ESMO) recommends the use of biologicals (targeted agents) as first line of treatment for most patients unless contraindicated [7]. According to European Medicines Agency (EMA) label, the anti-VEGF mAb bevacizumab should be used in combination with fluoropyrimidine-based chemotherapy [8]. Anti-EGFR mAbs should be used in combination with FOLFOX or FOLFIRI or as monotherapy in patients who have failed oxaliplatin- or irinotecan-based therapy, are intolerant of irinotecan (cetuximab) or have failed fluoropyrimidine-based therapy (panitumumab). Both are limited to patients with RAS wild-type tumors [9,10]. There is strong evidence that BRAF mutation is predictive for a la ck of benefit from anti-EGFR mAbs, although some discussions remain [7,11]. Evidence from the BEACON trial suggests some benefit of adding anti-EGFR mAb-based therapy to BRAF/MEK inhibitors. Anti-EGFR mAbs are thought to block the anticipated escape mechanism resulting from BRAF/MEK inhibition [12]. Primary tumor location, a surrogate of the different molecular profiles of left- and right-sided tumors, although first described in 2001 [13], has gained increasing attention after a 2017 meta-analysis of its prognostic and predictive value in patients with RAS wild-type mCRC [14]. In this retrospective analysis, six randomized trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181) were pooled, comparing chemotherapy plus anti-EGFR mAb therapy with chemotherapy or chemotherapy plus bevacizumab. A worse prognosis for overall survival, progression-free survival and objective response rate (ORR) was found for patients with right-sided primary tumors. Tumor side was also found to be predictive of treatment efficacy, with the greatest effect in patients with left-sided tumors receiving anti-EGFR mAb in combination with chemotherapy. Similar results were found when analyzing the anti-EGFR mAbs separately in the panitumumab trials PRIME [4,15,16] and PEAK [4,16,17] and the cetuxim ab trials CRYSTAL and FIRE-3 [18]. The present study aimed to capture the treatment patterns in the first line of therapy of mCRC patients actively treated in 2018 in real-world clinical practice in five European countries by tumor sidedness and biomarker status. Materials & methods Database This was a retrospective analysis using a large oncology database (Oncology Dynamics™, IQVIA Ltd., London, UK). The database was designed as a cross-sectional physician survey that collects anonymized individual-level information on drug-treated cancer patients in Europe (and other non-European countries) regardless of cancer type, disease stage and/or treatment [19,20,21,22,23,24,25,26]. The database has been described in detail elsewhere [27]. In brief, the database includes data from oncology centers in 10 countries (France, Germany, Italy, Spain, UK, China, Japan, South Korea, Saudi Arabia and Mexico). It is designed as repeated quarterly cross-sectional cohorts and contains more than 167,000 cancer cases per year and over 35 cancer indications. The database captures patient information via a standardized electronic case report form entered by the treating physician from patients' health records. Stratified random sampling is used to select physicians to represent the distribution of specialties for each cancer indication and country. It is limited to patients treated with a cancer drug at the time of data collection and excludes patients solely treated with radiotherapy, surgery, supportive care or on active surveillance. Objectives The study objective was to describe the demographic and clinical characteristics, as well as treatment patterns, i.e. anti-EGFR mAbs, anti-VEGF mAbs and/or chemotherapy, for patients treated for mCRC in first line during 2018 by tumor sidedness and biomarker status. Eligibility criteria All mCRC patients from the participating countries recorded in the database who received active anti-cancer first-line treatment in the advanced/metastatic setting in 2018, fulfilled the International Classification of Diseases, Tenth Revision codes used to define the mCRC population, and had a diagnosis date between July 2013 and December 2018, were included. Patients with unknown RAS or BRAF status, or unknown primary tumor location were excluded. Clinical trial participants were excluded. Demographic & clinical characteristics Description of demographics included country, age, sex, treatment facility site type and subtype. Clinical characteristics included the quarter of diagnosis, the BMI, Eastern Cooperative Oncology Group performance status, stage at diagnosis, site of metastasis and location of primary tumor. Left-sided tumors were defined as those originating in the splenic flexure, descending colon, sigmoid colon or rectum. Right-sided tumors were defined as those originating in the appendix, cecum, ascending colon or hepatic flexure as well as the transversum – between the hepatic and splenic flexure; this is in line with previous analyses, such as the meta-analysis of six trials mentioned above [14]. Tumor sidedness was determined by the treating physician. Where tumor sidedness was recorded as unknown by the physician, the International Classification of Diseases, Tenth Revision code, from which anatomy of tumor location could be determined, was used where available. Statistical considerations Frequencies and proportions were provided for mCRC patients within the selected cohorts with their corresponding 95% Binomial Exact CIs. SAS Software was used (SAS Enterprise Guide 7.1.; SAS Institute Inc., NC, USA). Results Patient & tumor characteristics There were 4455 mCRC patients within the database who were actively drug treated in 2018. A full description of all 4455 patients can be found elsewhere [27]. Of these, 42.0% (n = 1871) were receiving their first advanced/metastatic line of therapy and thus eligible for the present analysis; their RAS and BRAF status as well as their primary tumor location were known. Of these 1871 patients, two were excluded from the analysis as they received therapy other than anti-EGFR mAbs plus chemotherapy, anti-VEGF mAbs plus chemotherapy or only chemotherapy (see CONSORT [Consolidated Standards of Reporting Trials] flow diagram in Figure 1); 635 patients were from Italy, 337 from Germany, 318 each from France and the UK and 261 from Spain. The oncology center characteristics for the 1869 analyzed patients are provided in the supplemental material (Supplementary Table 1). Of patients, 60.8% (n = 1136) were male, 68.6% (n = 1282) were older than 60 years of age. Overall, 52.6% (n = 983) had RAS wild-type tumors and 6.5% (n = 122) had BRAF mutant tumors; 62.7% (n = 1172) had left-sided and 37.3% (n = 697) had right-sided or transverse primary tumors (summarized as right-sided). Left-sided tumors were RAS wild type in 55.8% of patients (n = 654). Of right-sided tumors, slightly fewer than half, 47.2% (n = 329), were RAS wild type. BRAF wild type status was found in 95.7% (n = 1122) of left-sided and 89.7% (n = 625) of right-sided tumors (Table 1). Further patient and tumor characteristics are listed in Table 1. Figure 1. CONSORT flow diagram describing the primary tumor location and biomarker status of first line of therapy for metastatic colorectal cancer patients. CONSORT: Consolidated standards of reporting trials; CRC: colorectal cancer; mCRC: Metastatic colorectal cancer. Table 1. Patient demographics and disease characteristics. Parameters, n (%) Left-sided tumors (n = 1172) Right-sided tumors† (n = 697) Overall (n = 1869) Sex – Female 445 (38.0) 288 (41.3) 733 (39.2) – Male 727 (62.0) 409 (58.7) 1136 (60.8) Age group at current line of therapy – <16 – – – – 16–50 102 (8.7) 73 (10.5) 175 (9.4) – 51–60 286 (24.4) 126 (18.1) 412 (22.0) – 61–75 591 (50.4) 355 (50.9) 946 (50.6) – ≥76 193 (16.5) 143 (20.5) 336 (18.0) ECOG status at current line of therapy – 0 390 (33.3) 219 (31.4) 609 (32.6) – 1 649 (55.4) 408 (58.5) 1057 (56.6) – 2 120 (10.2) 60 (8.6) 180 (9.6) – 3 3 (0.3) 6 (0.9) 9 (0.5) – 4 1 (0.1) 1 (0.1) 2 (0.1) – Unknown 9 (0.8) 3 (0.4) 12 (0.6) Stage at diagnosis – Stage I 10 (0.9) 4 (0.6) 14 (0.7) – Stage II 61 (5.2) 29 (4.2) 90 (4.8) – Stage III 156 (13.3) 84 (12.1) 240 (12.8) – Stage IV 905 (77.2) 558 (80.1) 1463 (78.3) – Unknown 40 (3.4) 22 (3.2) 62 (3.3) Primary tumor location – Left-sided 1172 (100.0) – 1172 (62.7) – Right-sided – 593 (85.1) 593 (31.7) – Transverse – 104 (14.9) 104 (5.6) RAS status – Wild type 654 (55.8) 329 (47.2) 983 (52.6) – Mutant 518 (44.2) 368 (52.8) 886 (47.4) BRAF status – Wild type 1122 (95.7) 625 (89.7) 1747 (93.5) – Mutant 50 (4.3) 72 (10.3) 122 (6.5) Site of metastasis – Liver & lung combination 281 (24.0) 164 (23.5) 445 (23.8) – Liver only 343 (29.3) 193 (27.7) 536 (28.7) – Liver with other combination 303 (25.9) 171 (24.5) 474 (25.4) – Lung only 63 (5.4) 31 (4.4) 94 (5.0) – Lung with other combination 59 (5.0) 26 (3.7) 85 (4.5) – Other 123 (10.5) 112 (16.1) 235 (12.6) Pre-existing comorbidities – No 541 (46.2) 334 (47.9) 875 (46.8) – Yes 631 (53.8) 363 (52.1) 994 (53.2) Type of comorbidities – Auto-immune disease 15 (1.3) 4 (0.6) 19 (1.0) – Bone disease 12 (1.0) 10 (1.4) 22 (1.2) – Cardiovascular 215 (18.3) 119 (17.1) 334 (17.9) – Gastrointestinal 29 (2.5) 12 (1.7) 41 (2.2) – Infection 5 (0.4) 1 (0.1) 6 (0.3) – Metabolic 224 (19.1) 134 (19.2) 358 (19.2) – Neurological 36 (3.1) 21 (3.0) 57 (3.0) – Renal 41 (3.5) 34 (4.9) 75 (4.0) – Respiratory 155 (13.2) 97 (13.9) 252 (13.5) – Other 223 (19.0) 114 (16.4) 337 (18.0) – None 513 (43.8) 309 (44.3) 822 (44.0) – NA 28 (2.4) 25 (3.6) 53 (2.8) CRC-related surgery – No surgery 548 (46.8) 308 (44.2) 856 (45.8) – Surgery 624 (53.2) 389 (55.8) 1013 (54.2) †Right-sided tumors include tumors of the transverse colon. CRC: Colorectal cancer; ECOG: Eastern cooperative oncology group; NA: Not available. Treatment landscape Patients with RAS wild-type tumors were most commonly treated with anti-EGFR mAbs plus chemotherapy (62.6%; 95% CI: 59.5%, 65.6%). The remaining patients were treated equally with anti-VEGF mAbs plus chemotherapy (18.4%; 95% CI: 16.0%, 21.0%) or chemotherapy-only (19.0%; 95% CI: 16.6%, 21.6%). Patients with RAS mutant tumors were most commonly prescribed anti-VEGF mAbs plus chemotherapy (60.5%; 95% CI: 57.2%, 63.7%) followed by chemotherapy-only (38.1%; 95% CI: 34.9%, 41.4%). There were 12 patients (out of 886 RAS mutant patients) documented as receiving anti-EGFR mAbs plus chemotherapy (1.4%; 95% CI: 0.7%, 2.4%; Table 2). Table 2. Treatments received overall and by RAS mutation status and primary tumor location, n (%) (95% CI). Treatment RAS wild type RAS mutant Left-sided Right-sided Total Left-sided Right-sided Total Anti-EGFR mAbs 468 (71.6) [67.9, 75.0] 147 (44.7) [39.2, 50.2] 615 (62.6) [59.5, 65.6] 11 (2.1) [1, 3.8] 1 (0.3) [0.0, 1.5] 12 (1.4) [0.7, 2.4] Anti-VEGF mAbs 76 (11.6) [9.3, 14.3] 105 (31.9) [26.9, 37.3] 181 (18.4) [16.0, 21.0] 308 (59.5) [55.1, 63.7] 228 (62.0) [56.8, 66.9] 536 (60.5) [57.2, 63.7] Chemo only 110 (16.8) [14.0, 19.9] 77 (23.4) [18.9, 28.4] 187 (19.0) [16.6, 21.6] 199 (38.4) [34.2, 42.8] 139 (37.8) [32.8, 42.9] 338 (38.1) [34.9, 41.4] Total 654 (100.0) [99.4, 100.0] 329 (100.0) [98.9, 100.0] 983 (100.0) [99.6, 100.0] 518 (100.0) [99.3, 100.0] 368 (100.0) [99.0, 100.0] 886 (100.0) [99.6, 100.0] Chemo: Chemotherapy; mAbs: Monoclonal antibodies. Of the 983 RAS wild-type patients, 654 (66.5%) had left-sided tumors and 329 (33.4%) had right-sided tumors. For both groups of patients, the most common treatment was anti-EGFR mAbs plus chemotherapy (71.6%; 95% CI: 67.9%, 75.0% and 44.7%; 95% CI: 39.2%, 50.2%) for left- and right-sided tumors, respectively). Of the 886 RAS mutant patients, 518 (58.4%) had left-sided tumors and 368 (41.5%) had right-sided tumors. For both left- and right-sided RAS mutant tumors, the majority were treated with anti-VEGF mAbs plus chemotherapy (59.5%; 95% CI: 55.1%, 63.7%) for left-sided and 62.0%; 95% CI: 56.8%, 66.9% for right-sided) (Table 2). Of the RAS wild-type patients, 108 (11.0%) were BRAF mutant. For tumors of both RAS and BRAF wild type status, the most common treatment was anti-EGFR mAbs plus chemotherapy (69.3%; 95% CI: 66.1%, 72.4%). For tumors of RAS wild type and BRAF mutant status the most common treatment were anti-VEGF mAbs plus chemotherapy (44.4%; 95% CI: 34.9%, 54.3%). Of the RAS mutant patients, 872 (98.4%) were BRAF wild type and 14 (1.6%) were documented as BRAF mutant. For RAS mutant and BRAF wild-type tumors the most common treatment were anti-VEGF mAbs (61.1%; 95% CI: 57.8%, 64.4%). In the rare case of patients who were reported as having both RAS and BRAF mutant tumor status (n = 14) the great majority was treated with chemotherapy only (78.6%; 95% CI: 49.2%, 95.3%) (Table 3). Table 3. Treatments received overall and by RAS mutation status and BRAF mutation status, n (%) (95% CI). Treatment RAS wild type RAS mutant BRAF wild type BRAF mutant Total BRAF wild type BRAF mutant Total Anti-EGFR mAbs 589 (69.3) [66.1, 72.4] 26 (24.1) [16.4, 33.3] 615 (62.6) [59.5, 65.6] 12 (1.4) [0.7, 2.4] 0 (0.0) [0.0, 23.2] 12 (1.4) [0.7, 2.4] Anti-VEGF mAbs 133 (15.6) [13.3, 18.3] 48 (44.4) [34.9, 54.3] 181 (18.4) [16.0, 21.0] 533 (61.1) [57.8, 64.4] 3 (21.4) [4.7, 50.8] 536 (60.5) [57.2, 63.7] Chemo only 153 (17.5) [15.0, 20.2] 34 (31.5) [22.9, 41.1] 187 (19.0) [16.6, 21.6] 327 (37.5) [34.3, 40.8] 11 (78.6) [49.2, 95.3] 338 (38.1) [34.9, 41.4] Total 875 (100.0) [99.6, 100.0] 108 (100) [96.6, 100.0] 983 (100.0) [99.6, 100.0] 872 (100.0) [99.6, 100.0] 14 (100.0) [76.8, 100.0] 886 (100.0) [99.6, 100.0] Chemo: Chemotherapy; mAbs: Monoclonal antibodies. When looking at the treatment landscape by country, there were differences regarding the adopted treatment strategies. In RAS wild-type mCRC patients, anti-VEGF mAbs plus chemotherapy were not prescribed in the UK as opposed to the other countries, in which anti-VEGF mAb-based combinations ranged from 15.2% in Spain to 25.6% in Italy. Patients with RAS mutant tumors also received anti-VEGF mAbs plus chemotherapy less frequently in the UK (5.1%; 95% CI: 2.2%, 9.8%) compared with other countries which ranged from 66.9% in France to 78.9% in Italy (Supplementary Tables 2 & 3). Discussion This study aimed to capture the treatment patterns in mCRC patients in real-world clinical practice in five European countries. There were large differences in treatment patterns by biomarker status and primary tumor location. RAS wild-type patients were mainly treated with anti-EGFR mAbs plus chemotherapy (62.6%; 95% CI: 59.5%, 65.6%) whereas RAS mutant patients were most commonly treated with anti-VEGF mAbs plus chemotherapy (60.5%; 95% CI: 57.2%, 63.7%). For RAS wild-type patients, anti-EGFR mAbs plus chemotherapy were more frequently prescribed in patients with left-sided compared with right-sided tumors (71.6%; 95% CI: 67.9%, 75.0% vs 44.7%; 95% CI: 39.2%, 50.2%, respectively). In RAS and BRAF wild-type patients, the most common treatment was anti-EGFR mAb plus chemotherapy (69.3%, 95% CI: 66.1%, 72.4%). RAS wild-type/BRAF mutant patients preferably received anti-VEGF mAbs (44.4%; 95% CI: 34.9%, 54.3%). For RAS mutant/BRAF wild-type patients, anti-VEGF mAbs plus chemotherapy was most commonly prescribed (61.1%; 95% CI: 57.8%, 64.4%). Studies with a broad focus evaluating the patterns of mCRC treatment, especially in first line, are rare; the authors are not aware of any studies using a similarly broad research angle as theirs. The predecessor of the database that was used in the present study (Oncology Analyzer™), was previously used to evaluate treatment patterns in the USA, the EU (France, Germany, Italy, Spain), UK and Japan using data from 2007 [21], and in France, Germany, Italy and Spain using a 2009 data snapshot [28]. In 2007, treatment combinations including targeted therapy (bevacizumab) accounted for a limited proportion of administered regimens in the first-line mCRC setting, with the highest uptake in France with <20%, followed by Italy and Germany with <10% [21]. By 2009, the proportion of bevacizumab-containing regimens had increased to approximately 40% in France, Germany and Italy, and 30% in Spain; cetuximab-containing regimens accounted for 7–14% [28]. Approved indications have changed subs tantially since these studies were conducted, generally allowing for refined use of these agents. The anti-EGFR mAbs labels changed several times over the last years, including changes in mandatory wild type status of KRAS to RAS and of allowed chemotherapy backbone (Figure 2). Panitumumab was initially approved as monotherapy, then in combination with FOLFOX in first line and with FOLFIRI in second-line; the combination with FOLFIRI in first line followed in 2015 [29]. Additionally, ESMO guidelines were continuously updated to incorporate new clinical evidence [7] and entailed considerable shifts in treatment practices. Figure 2. Selected European union label changes relating to the patient population eligible for anti-EGFR monoclonal antibody therapy. †And intolerant to irinotecan. ‡FOLFOX4 subsequently revised to FOLFOX (first line) in 2012. §For patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan). Therapeutic indications have been abbreviated; please see product labels for full details [9,10]. CTx: Chemotherapy; CTxR: Chemotherapy refractory; FOLFOX: Folinic acid, fluorouracil and oxaliplatin; FOLFIRI: Folinic acid, fluorouracil and irinotecan; IRI: Irinotecan; mAb: Monoclonal antibody; WT: Wild type. The meta-analysis of six Phase III trials by Arnold et al. provided strong evidence about the prognostic and predictive value of primary tumor location, which are biologically different [5]. It was shown that the greatest effect was obtained in patients with left-sided tumors receiving anti-EGFR mAbs in combination with chemotherapy [14]. In the present study, 71.6% (95% CI: 67.9%, 75.0%) of patients with left-sided RAS wild-type tumors and 44.7% (95% CI: 39.2%, 50.2%) of patients with right-sided RAS wild-type tumors received anti-EGFR mAb-based therapy, using a chemotherapy backbone. In the UK, the great majority of RAS mutant patients were treated with chemotherapy only (93.6%; 95% CI: 88.6%, 96.9%) whereas in the other European countries most patients were treated with anti-VEGF mAbs plus chemotherapy (between 67.2 and 78.9% in Germany and Italy, respectively). In the UK, National Institute for Health and Care Excellence (NICE) does not recommend the anti-VEGF mAb bevacizumab in combination with FOLFOX or oxaliplatin plus capecitabine (CAPEOX) for the treatment of mCRC [32] and it was removed from the UK cancer drug fund in November 2016 [33]. Apart from the differences in reimbursement in the different countries, it needs to be highlighted that the scientific evidence supporting a benefit of bevacizumab in patients with RAS mutant tumors is yet unclear, as was shown by a recent systematic review and network meta-analysis of ten papers reporting six randomized-controlled trials [34]. This analysis found a statistically nonsignificant benefit in progression-free survival and no benefit in overall survival for patients with RAS mutant mCRC receiving bevacizumab plus chemotherapy versus those receiving chemotherapy alone [34]. Prospective randomized, controlled clinical trials enrolling solely RAS mutant patients have not been conducted with bevacizumab. Interestingly, 1.4% (95% CI: 0.7%, 2.4%) of patients with RAS mutant tumors were documented to have receive d anti-EGFR mAbs plus chemotherapy. Patients with RAS mutant or unknown status should not receive anti-EGFR mAbs and it thus seems likely that this number is an error in either documentation or treatment choice. The tumors of 14 patients were documented as having both, a RAS and a BRAF mutation. RAS and BRAF mutations are considered as mutually exclusive although some rare cases have been reported in the literature [35,36,37] and there is evidence that with next-generation sequencing (NGS) more such cases might be identified [38,39]. Clinical implications of such concomitant mutations are still undetermined. The topic of primary tumor location as a surrogate for biologically different tumor entities was accepted on a broader scale after the publication of the large meta-analysis of six clinical trials conducted by Arnold et al. [14]. From that time onwards, extensive research was conducted to investigate the prognostic potential of primary tumor location on outcomes, although much of this research was retrospective. Although the 2016 ESMO recommendations could not yet take into consideration the primary tumor location as they predated the meta-analysis, the ESMO pan-Asian guidelines have been updated to include treatment recommendations including consideration of left- versus right-sided primary tumor location [40]. The pan-Asian ESMO guidelines recommend that for patients with left-sided RAS wild-type disease, a cytotoxic doublet such as FOLFOX or FOLFIRI plus an anti-EGFR mAb should be the treatment of choice, whereas for those with right-sided RAS wild-type tumors, the cytotoxic tripl et FOLFOXIRI plus bevacizumab should be or a cytotoxic doublet plus an anti-EGFR mAb can be, the treatment of choice [40]. There are some limitations to the present analysis. This study focused on describing the treatment patterns by biomarker status and tumor sidedness. However, there was less focus on the impact on clinical characteristics, such as resectability of the metastases or patient fitness of the choice of treatment. The database does not capture data on hospitalizations or survival. Observed country differences might be partly explained by differences in local treatment guidelines, physician prescribing behaviors, or reimbursement policies, some of which have been outlined above but no systematic analysis of the impact of these factors on treatment choice was conducted. A discussion of the database itself can be found elsewhere [27] . Conclusion In clinical practice in the five participating European countries, RAS wild-type patients were mainly treated with anti-EGFR mAbs plus chemotherapy whereas RAS mutant patients were most commonly treated with anti-VEGF mAbs plus chemotherapy in all countries except for the UK, where they were more commonly treated with chemotherapy-only in the UK. In RAS wild-type patients, the presence of a BRAF mutation diversified the prescribed treatments compared with BRAF wild-type patients. Future perspective In the era of precision medicine, there are many biomarker-driven drugs that are under development, especially within the oncology therapeutic area. As these drugs are gradually being introduced, it is important to understand the impact of biomarker status in the physicians' treatment decision making. Summary points Advances in therapies for patients with metastatic colorectal cancer (mCRC) and improved understanding of prognostic and predictive factors such as biomarkers or the recognition of the clinical impact of the biological differences between left- and right-sided primary tumors have impacted mCRC treatment patterns. The present study used a large international oncology database to investigate the treatment landscape of anti-VEGF monoclonal antibodys (mAbs) and anti-EGFR mAbs, both in combination with chemotherapy or chemotherapy alone in the first line of therapy of mCRC patients actively treated in 2018 in real-world clinical practice in five European countries (France, Germany, Italy, Spain, UK) by tumor sidedness and biomarker status. Of the 1869 analyzed patients, RAS wild-type patients were mainly treated with anti-EGFR mAbs plus chemotherapy (62.6%; 95% CI: 59.5%, 65.6%) whereas RAS mutant patients were most commonly treated with anti-VEGF mAbs plus chemotherapy (60.5%; 95% CI: 57.2%, 63.7%). Of RAS wild-type patients with left-sided primary tumors, 71.6% (95% CI: 67.9%, 75.0%) received anti-EGFR mAbs plus chemotherapy, as did 44.7% (95% CI: 39.2%, 50.2%) of RAS wild-type patients with right-sided primary tumors. For RAS wild-type/BRAF mutant as well as RAS mutant/BRAF wild-type patients, the most common treatment was anti-VEGF mAbs plus chemotherapy with 44.4% (95% CI: 34.9%, 54.3%) and 61.1% (95% CI: 57.8%, 64.4%), respectively. There were differences between countries regarding the adopted treatment strategies with the UK generally prescribing less frequently anti-VEGF mAb plus chemotherapy compared with the other countries. Supplementary data To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/fon-2020-0976 Author contributions All authors were involved in, and contributed to, the drafting and critical review of this manuscript. Financial & competing interests disclosure This research project was funded by Amgen Ltd. G Kafatos, D Neasham and KA Lowe are compensated employees of Amgen, Inc. and stockholders of Amgen, Inc. P Burdon was an employee of Amgen (Europe) GmbH at the time the research was conducted and owns shares in Amgen Inc.; he is currently an employee of MSD International GmbH. V Banks was a contract worker for Amgen, Ltd. at the time the research was conducted. C Anger and F Manuguid are compensated employees of IQVIA Ltd. J Trojan received consulting fees from Amgen, Bayer Healthcare, Bristol Myers-Squibb, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, Onkowissen TV, Pierre Fabre, PCI Biotech, Roche and Servier. He is serving on the speaker's bureau of Amgen, Bioprojet, Bristol Myers-Squibb, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, Roche, Servier and streammedup! and he received research grants from Roche and Ipsen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors would like to thank and acknowledge M Hemetsberger of hemetsberger medical services, Vienna, Austria, for medical writing support, funded by Amgen. Ethical conduct of research The Oncology Dynamics database (IQVIA Ltd.) used in this study is fully anonymized and complies with relevant regulations for protecting patient privacy. Data sharing statement The data that support the findings of this study are available from IQVIA Ltd, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of IQVIA Ltd. Open access This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ Figures References Related Details Ahead of Print eToC Sign up Follow us on social media for the latest updates Supplemental Materials Metrics Downloaded 0 times History Received 23 September 2020 Accepted 11 December 2020 Published online 19 January 2021 Information © 2021 Amgen Ltd. Keywords BRAFEGFRmCRCprimary tumor locationRAStumor sidednessVEGF Supplementary data To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/fon-2020-0976 Author contributions All authors were involved in, and contributed to, the drafting and critical review of this manuscript. Financial & competing interests disclosure This research project was funded by Amgen Ltd. G Kafatos, D Neasham and KA Lowe are compensated employees of Amgen, Inc. and stockholders of Amgen, Inc. P Burdon was an employee of Amgen (Europe) GmbH at the time the research was conducted and owns shares in Amgen Inc.; he is currently an employee of MSD International GmbH. V Banks was a contract worker for Amgen, Ltd. at the time the research was conducted. C Anger and F Manuguid are compensated employees of IQVIA Ltd. J Trojan received consulting fees from Amgen, Bayer Healthcare, Bristol Myers-Squibb, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, Onkowissen TV, Pierre Fabre, PCI Biotech, Roche and Servier. He is serving on the speaker's bureau of Amgen, Bioprojet, Bristol Myers-Squibb, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, Roche, Servier and streammedup! and he received research grants from Roche and Ipsen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors would like to thank and acknowledge M Hemetsberger of hemetsberger medical services, Vienna, Austria, for medical writing support, funded by Amgen. Ethical conduct of research The Oncology Dynamics database (IQVIA Ltd.) used in this study is fully anonymized and complies with relevant regulations for protecting patient privacy. Data sharing statement The data that support the findings of this study are available from IQVIA Ltd, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of IQVIA Ltd. Open access This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ back Future Medicine Logo Future Medicine Ltd, Unitec House, 2 Albert Place, London, N3 1QB, UK +44 (0)20 8371 6090 Information For Authors For Reviewers For Librarians For Advertisers Publishing Solutions Digital Enhancements Help & About Us News Help About Us Contact Us Links & Resources Catalogue Submit an Article Reprints and Permissions Terms and conditions Privacy policy Accessibility © 2021 Future Science Group Impact of biomarkers and primary tumor location on the metastatic colorectal cancer first-line treatment landscape in five European countries Via Future Medicine: Future Oncology: Table of Contents Future Oncology, Ahead of Print. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Biomarker testing and mutation prevalence in metastatic colorectal cancer patients in five European countries using a large oncology database

Cancer shared this article with you from Inoreader Message: Background: The literature on biomarker testing for metastatic colorectal cancer (mCRC) in Europe is scarce. This study aimed to estimate the percentage of mCRC patients from five European countries tested for biomarkers over time. Materials & methods: An oncology database was retrospectively analyzed; evaluated biomarkers were RAS, BRAF and microsatellite instability (MSI). The patients were drug treated during 2018 and tested for relevant biomarkers in 2013–2018. Results:RAS testing was conducted in >90% of mCRC patients from 2014 onwards. BRAF testing increased from 31% of mCRC patients in 2013 to 67% in 2018. MSI testing increased from 10 to 41%. There was no notable trend over time for RAS and BRAF mutation or MSI-high prevalence. Conclusion: Biomarker testing among patients diagnosed with mCRC was increased over time. This study demonstrates the quick uptake of biomarker testing in clinical pra ctice. These findings are significant as biomarker-based drugs are becoming more common. Lay abstract Each patient's cancer is unique. To find the best medicine for each patient, doctors perform tests to look at the cancer's genes. It is unknown how often and how well these tests are done. We tried to find this out for patients with cancer of the bowel or rectum that has spread to other organs. We found that an important genetic test called RAS is done in most patients. Other tests, called BRAF and microsatellite instability, are also conducted increasingly frequently. This is important because the results of such tests allow doctors to decide which drug(s) should be the most effective depending on the patient's cancer genes. Keywords: biomarkerBRAFEGFRmCRCMSIprevalenceRAS Globally, colorectal cancer (CRC) is the third most frequently diagnosed malignancy in men and the second in women, with an incidence of 1.8 million and almost 861,000 deaths in 2018 alone according to the WHO's GLOBOCAN database [1]. Of those, 20–25% already have metastatic CRC (mCRC) at initial diagnosis [2,3], which dramatically reduces survival. The 5-year survival rate is 90% for localized CRC versus 71% for CRC with regional spread and 14% for patients with distant metastases [4]. Clinical trials and observational studies of anti-EGFR monoclonal antibodies (mAbs) in mCRC indicated differences in response between patients with or without mutations in the RAS family of genes compared with the overall study population [5–18]. For RAS wild-type patients, a recent Cochrane systematic review quantified anti-EGFR mAb-induced risk reduction compared with standard treatments to be 40% for disease progression, 23% for mortality and the rate of early tumor shrinkage to have increased from 21 to 48% [19]. Therefore, RAS mutation status was established as an important marker for patient selection for anti-EGFR mAb-containing therapy by leading guideline bodies, such as the European Society of Medical Oncology (ESMO) [20]. The EMA restricted the indication for both, panitumumab and subsequently cetuximab, to RAS wild-type tumors in 2013 [21,22]. The validity of BRAF testing was established from the 2014 ESMO guidelines onwards [20,23,24]; however, it is not a prerequisite of anti-EGFR mAb use according to the respective EMA labels. Inclusion of BRAF testing was originally done for prognostic reasons [25,26]. Since the introduction of RAS testing in Europe, several observational studies were conducted to estimate the prevalence of RAS mutation in mCRC patients in the real-world setting. These studies showed RAS mutation prevalence estimates in the real world (44–46%) compared with the estimates from randomized controlled trials (RCTs) (43–56%) [27–30]. BRAF mutations are less common, affecting only 8–12% of mCRC patients [26,31–34]. BRAF mutations appear to be predominantly found in patients with right-sided primary tumors (68%, vs 35% in left-sided [34]), and are almost never found in combination with RAS mutations. BRAF-mutant status overlaps with the presence of microsatellite instability (MSI) in about a third of tumors [34]. Although several studies have been carried out to estimate biomarker prevalence, there has been limited published work on the percentage of diagnostic testing among mCRC patients in Europe [35]. The current study is based on an oncology database that includes patients from ten countries and over 35 cancer indications. It is designed as repeated quarterly cross-sectional cohorts capturing patient information through electronic case report forms (eCRFs). The study aim was to estimate the percentage of mCRC patients tested for biomarkers in Europe, and the mutation prevalence over time. Materials & methods Database The oncology database used for the present research (Oncology Dynamics™, IQVIA Ltd, London, UK) is a secondary database utilizing primary data collected in patient files. It includes data from ten countries (France, Germany, Italy, Spain, the UK, China, Japan, South Korea, Saudi Arabia and Mexico). It is designed as repeated quarterly cross-sectional cohorts and contains more than 167,000 cancer cases per year and over 35 cancer indications. This design ensures there is a large sample size even for rarer cancers such as acute lymphoblastic leukemia or glioblastoma. The patient numbers per cancer indication and country as collected in the year 2018 are given in Supplementary Table 1. The database captures patient information via a standardized eCRF entered by the treating physician from patients' health records. It is limited to patients treated with a cancer drug at the time of data collection, and excludes patients solely treated with radiotherapy, surgery, supportive care or on active surveillance. Stratified random sampling is used to select physicians to represent the distribution of specialties for each cancer indication and country. In most countries included in the database, cancer care is administered in hospitals; the only exception is Germany where both hospitals and office-based physicians administer anticancer therapy. The sample design aims to target no more than three physicians from the same hospital (and only one per ward) to avoid a cluster effect or duplication of patients and ensure a large number and variety of sites. At the patient level, a systematic sampling approach is used. Indeed, at each quarterly data collection point, participating physicians at each center are instructed to select systematically for inclusion the most recent patients (i.e., office encounters during the last 7–14 days) up to a predefined quota. Key data attributes include patient demographic and clinical characteristics at time of diagnosis, as well as treatment information at 'current' (at the time of data extraction) and 'previous' line of therapy (as defined by the treating physician). The most recent diagnostic test information is reported if carried out at any time since diagnosis. Detailed variables are shown in Supplementary Table 2. The online supplemental material provides further methodological details of the database. Quality control takes place at various stages, during data collection, coding, processing and creation of the final dataset for each quarterly data generation cycle. During data entry, the validation check system includes rules to avoid reporting of incorrect values (i.e., negative values between date of diagnosis and start of the current treatment) or are validated against previous answers to detect inadmissible responses (e.g., absence of metastatic sites in patients with stage IV cancer). Dosage of each drug reported by the physician is checked against a drug dose reference file and the reporting physician is prompted if out of range to ensure that it conforms to acceptable dose levels. Data coding uses standardized procedures to prevent errors in coding of free-text entries. Implausible data entries are checked directly with the participating physicians. Objectives The primary objectives of the study were to estimate the percentage of mCRC patients tested for RAS and BRAF (all types) mutations over time and to estimate the percentage of RAS and BRAF-mutant tests for mCRC patients over time. The secondary objectives included MSI testing and RAS, and BRAF testing specifically in mCRC patients receiving anti-EGFR mAbs. Eligibility criteria This study included mCRC patients from France, Germany, Italy, Spain and the UK, diagnosed with CRC, who received active anticancer treatment in the advanced/metastatic setting in 2018 and had a diagnosis date between July 2013 and December 2018. The International Classification of Diseases – Tenth Revision codes were used to identify the CRC population in combination with the staging information, which was used to define the metastatic status. Clinical trial participants and patients not on active anticancer therapy are not captured within the database as interest is on patients treated under routine clinical practice excluding experimental treatments. Primary tumor location was assigned by the treating physician. When recorded as unknown by the physician, the International Classification of Diseases – Tenth Revision code, from which anatomy of tumor location could be determined, was used where available. The definition of primary tumor location was in line with previous analyses [36], where left-sided tumors were defined as those originating in the splenic flexure, descending colon, sigmoid colon or rectum. Right-sided tumors were defined as those originating in the appendix, cecum, ascending colon or hepatic flexure as well as the transversum – between the hepatic and splenic flexure. Statistical considerations The analysis was descriptive providing frequencies and percentages with their corresponding 95% CI. SAS© Software was used (Enterprise Guide Version [7.1] on Linux [LIN X64], SAS Institute, Inc., NC, USA). Results Overall, 4455 mCRC patients were included in the study, 982 of whom received anti-EGFR mAb therapy. The patients captured were mostly treated in public facilities (n = 3310; 74.3%), mainly in France, Italy, Spain and the UK. In Italy (n = 1012; 76.3%) and France (n = 481; 63.3%) the majority of patients were reported as from nonuniversity hospitals, while in Spain (n = 427; 64.2%) and the UK (n = 536; 66.3%) the majority was from university hospitals; in Germany most patients were from office-based practitioners (n = 574; 64.1%). The current line of mCRC therapy was mainly prescribed by oncologists (n = 3121; 70.1%) or onco-hematologists (n = 837; 18.8%). Characteristics by site and participating physicians are shown in Table 1A. Table 1. Demographic and clinical characteristics of metastatic colorectal cancer patients by country. (A) Description of patients' cases by site and participating physicians France Germany Italy Spain United Kingdom Total All mCRC patients 760 895 1326 665 809 4455 Type of treating hospital – Office-based practitioner – 574 (64.1) – – – 574 (12.9) – Private 29 (3.8) 51 (5.7) 49 (3.7) 161 (24.2) 13 (1.6) 303 (6.8) – Private – not for profit 179 (23.6) 52 (5.8) 27 (2.0) 10 (1.5) – 268 (6.0) – Public 552 (72.6) 218 (24.4) 1250 (94.3) 494 (74.3) 796 (98.4) 3310 (74.3) Treating hospital status – Nonuniversity 481 (63.3) 216 (24.1) 1012 (76.3) 238 (35.8) 273 (33.7) 2220 (49.8) – University 279 (36.7) 105 (11.7) 314 (23.7) 427 (64.2) 536 (66.3) 1661 (37.3) – Office-based practitioner – 574 (64.1) – 574 (37.3) Physician specialty – Gastroenterologist 238 (31.3) 51 (5.7) 289 (6.5) – Hepatologist – – 4 (0.3) 4 (0.1) – Onco-hematologist – 837 (93.5) 837 (18.8) – Oncologist 505 (66.4) – 1302 (98.2) 665 (100) 649 (80.2) 3121 (70.1) – Radiotherapist 12 (1.6) 6 (0.7) 160 (19.8) (178 (4.0) – Others 5 (0.7) 1 (0.1) 20 (1.5) 26 (0.6) (B) Patient demographics France Germany Italy Spain United Kingdom Total All mCRC patients 760 895 1326 665 809 4455 Gender, n (%) – Females 299 (39.3) 337 (37.7) 544 (41.0) 251 (37.7) 317 (39.2) 1748 (39.2) – Males 461 (60.7) 558 (62.3) 782 (59.0) 414 (62.3) 492 (60.8) 2707 (60.8) Age group at current therapy, n (%) – <30 2 (0.3) 2 (0.2) 2 (0.2) 1 (0.2) 3 (0.4) 10 (0.2) – 31–40 12 (1.6) 3 (0.3) 19 (1.4) 4 (0.6) 34 (4.2) 72 (1.6) – 41–50 37 (4.9) 60 (6.7) 97 (7.3) 26 (3.9) 74 (9.1) 294 (6.6) – 51–60 120 (15.8) 154 (17.2) 257 (19.4) 144 (21.7) 192 (23.7) 867 (19.5) – 61–70 320 (42.1) 362 (40.4) 442 (33.3) 228 (34.3) 269 (33.3) 1621 (36.4) – 71–80 217 (28.6) 236 (26.4) 372 (28.1) 187 (28.1) 195 (24.1) 1207 (27.1) – >80 52 (6.8) 78 (8.7) 137 (10.3) 75 (11.3) 42 (5.2) 384 (8.6) Age at current therapy†, years – Mean (SD) 66.7 (10.0) 66.5 (10.1) 66.5 (11.1) 67.2 (10.3) 63.3 (11.7) 66.0 (10.8) – Median (IQR) 68 (63, 73) 68 (63, 73) 68 (58, 73) 68 (58, 73) 63 (53, 73) 68 (58, 73) (C) Clinical characteristics France Germany Italy Spain United Kingdom Total All mCRC patients 760 895 1326 665 809 4455 Stage at diagnosis‡, n (%) – Stage I 4 (0.5) 18 (2.0) 5 (0.4) 5 (0.8) 6 (0.7) 38 (0.9) – Stage II 26 (3.4) 36 (4.0) 65 (4.9) 25 (3.8) 38 (4.7) 190 (4.3) – Stage III 103 (13.6) 121 (13.5) 244 (18.4) 57 (8.6) 107 (13.2) 632 (14.2) – Stage IV 627 (82.5) 720 (80.4) 889 (67.0) 578 (86.9) 658 (81.3) 3472 (77.9) – Unknown – – 123 (9.3) – – 123 (2.8) Tumor location, n (%) – Right side§ 266 (35.0) 280 (31.3) 521 (39.3) 250 (37.6) 282 (34.9) 1599 (35.9) – Left side¶ 476 (62.6) 603 (67.4) 797 (60.1) 412 (62.0) 500 (61.8) 2788 (62.6) – Unknown 18 (2.4) 12 (1.3) 8 (0.6) 3 (0.5) 27 (3.3) 68 (1.5) Current metastatic sites, n (%) – 1 site 310 (40.8) 332 (37.1) 676 (51.0) 265 (39.8) 291 (36.0) 1874 (42.1) – 2 sites 274 (36.1) 271 (30.3) 448 (33.8) 258 (38.8) 336 (41.5) 1587 (35.6) – 3 sites 130 (17.1) 227 (25.4) 148 (11.2) 112 (16.8) 156 (19.3) 773 (17.4) – 4 sites 41 (5.4) 52 (5.8) 39 (2.9) 24 (3.6) 22 (2.7) 178 (4.0) – 5+ sites 5 (0.7) 13 (1.5) 15 (1.1) 6 (0.9) 4 (0.5) 43 (1.0) Site of metastases, n (%) – Liver and lung combination 179 (23.6) 244 (27.3) 292 (22.0) 179 (26.9) 232 (28.7) 1126 (25.3) – Liver only 240 (31.6) 218 (24.4) 447 (33.7) 185 (27.8) 192 (23.7) 1282 (28.8) – Liver with other combination 222 (29.2) 266 (29.7) 292 (22.0) 144 (21.7) 182 (22.5) 1106 (24.8) – Lung only 25 (3.3) 23 (2.6) 60 (4.5) 46 (6.9) 47 (5.8) 201 (4.5) – Lung with other combination 17 (2.2) 25 (2.8) 39 (2.9) 45 (6.8) 48 (5.9) 174 (3.9) – Other (no liver or lung) 77 (10.1) 119 (13.3) 196 (14.8) 66 (9.9) 108 (13.3) 566 (12.7) Current line of anticancer therapy in advanced/metastatic stage, n (%) – Neoadjuvant 23 (3.0) 14 (1.6) 25 (1.9) 11 (1.7) 27 (3.3) 100 (2.2) –Adjuvant 29 (3.8) 13 (1.5) 21 (1.6) 6 (0.9) 17 (2.1) 86 (1.9) – 1st line 488 (64.2) 650 (72.6) 1026 (77.4) 460 (69.2) 563 (69.6) 3187 (71.5) – 2nd line 138 (18.2) 139 (15.5) 167 (12.6) 132 (19.8) 152 (18.8) 728 (16.3) – 3rd line 58 (7.6) 44 (4.9) 69 (5.2) 44 (6.6) 41 (5.1) 256 (5.7) – 4th or subsequent line 24 (3.2) 35 (3.9) 18 (1.4) 12 (1.8) 9 (1.1) 98 (2.2) BMI at current therapy – Mean (SD) 24.1 (3.4) 25.1 (3.9) 24.7 (3.6) 24.6 (3.1) 25.8 (4.5) 24.9 (3.8) – Median (IQR) 23.8 (22, 26.2) 24.6 (22.5, 27.4) 24.5 (22.3, 26.9) 24.3 (22.7, 26.3) 25.1 (22.7, 28) 24.5 (22.4, 26.9) – Min, max 13.7, 40.8 15.6, 45.4 13.3, 42.7 15.8, 39.1 15.6, 50 13.3, 50 ECOG status at current therapy, n (%) – 0 129 (17.0) 151 (16.9) 531 (40.0) 166 (25.0) 187 (23.1) 1164 (26.1) – 1 442 (58.2) 553 (61.8) 646 (48.7) 416 (62.6) 542 (67.0) 2599 (58.3) – 2 169 (22.2) 185 (20.7) 113 (8.5) 76 (11.4) 77 (9.5) 620 (13.9) – 3 19 (2.5) 4 (0.4) 10 (0.8) 5 (0.8) 2 (0.2) 40 (0.9) – 4 1 (0.1) 2 (0.2) 1 (0.1) 2 (0.3) 1 (0.1) 7 (0.2) – Unknown – – 25 (1.9) – – 25 (0.6) Percentages are based on the number of participating patients overall and by country. †Exact age is not recorded within the database due to data governance rule relating to anonymization. Instead the following groups are provided: <16, 16–20, 21–25, 26–30, 31–35, 36–40, 41–45, 46–50, 51–55, 56–60, 61–65, 66–70, 71–75, 76–80 and >80 years old. To provide estimates of the mean and median of 'age', the age groups were substituted by the mid-range value, e.g., '<16' is substituted by '8', '16–20' by '18', etc. ‡Using TNM staging. §Primary tumors originating in the appendix, cecum, ascending colon, hepatic flexure or transversum (between hepatic and splenic flexure). ¶Primary tumors originating in the splenic flexure, descending colon, sigmoid colon or rectum. 0: Asymptomatic; 1: Symptomatic and fully ambulatory; 2: Symptomatic and in bed <50% of the day; 3: Symptomatic and in bed >50% of the day; 4: Bedridden; ECOG: Eastern Cooperative Oncology Group; IQR: Interquartile range; mCRC: Metastatic colorectal cancer; SD: Standard deviation. Most patients were male (n = 2707; 60.8%) and of advanced age, with 36.4% being 61–70 years (n = 1621) and 27.1% being 71–80 years old (n = 1207); median age was 68 years (Q1: 58 and Q3: 73; Table 1B). Gender and age distribution were consistent across countries. The vast majority of this cohort of mCRC patients were diagnosed with stage IV cancer (n = 3472; 77.9%) and were in their first line of treatment of advanced/metastatic stage cancer (n = 3187; 71.5%), with 16.3% being in second-line treatment (n = 728). The primary tumor was located on the left side in 62.6% of patients (n = 2788), on the right side in 35.9% (n = 1599) and location was unknown in 1.5% (n = 68). The site of metastasis was liver only in 28.8% of patients (n = 1282), a combination of either liver and lung in 25.3% (n = 1126) or liver and another site in 24.8% (n = 1106); 57.9% of patients (n = 2581) had two or more sites of metastasis. ECOG status was 0 or 1 in 84.5% (n = 3763) and ≥2 in 15.0% (n = 667; T able 1C). Biomarker & MSI testing As the eligibility criteria included patients on active anticancer drug treatment during 2018, the number of mCRC patients for whom testing percentage was calculated decreased going back in time (e.g., 2181 patients were tested for RAS in 2018 and only 34 in 2013, Figure 1). Figure 1. Percentage of metastatic colorectal cancer patients tested for RAS & BRAF mutations over time. (A) mCRC patients tested for RAS mutations, overall and in those receiving anti-EGFR mAb treatment. (B) mCRC patients tested for BRAF mutations, overall and in those receiving anti-EGFR mAb treatment. mAb: Monoclonal antibody; mCRC: Metastatic colorectal cancer. RAS testing was conducted in over 90% of mCRC patients from 2014 onwards (Figure 1A). BRAF testing rate increased from 31.0% in 2013 to approximately 50% between 2014 and 2016 and above 60% in 2017 and 2018 (Figure 1B). The percentage of mCRC patients tested for MSI increased over time from 10.0% in 2013 to 41.4% in 2018. The MSI assessment was performed more frequently for patients <50 years of age (56.5%; 95% CI: 48.5–64.3 in 2018) compared with those ≥50 years (40.0%; 95% CI: 7.7–42.3 in 2018; Table 2). Table 2. Percentage of patients tested for microsatellite instability and confirmed microsatellite instability-high status over time, n/N (%) (95% CI). 2013 2014 2015 2016 2017 2018 mCRC patients tested for MSI 5/50 (10.0) (3.3, 21.8) 40/173 (23.1) (17.1, 30.1) 73/318 (23.0) (18.4, 28.0) 159/551 (28.9) (25.1, 32.8) 502/1430 (35.1) (32.6, 37.6) 800/1933 (41.4) (39.2, 43.6) <50 years of age† 0/1 (0.0) (0.0, 97.5) 1/6 (16.7) (0.4, 64.1) 7/20 (35.0) (15.4, 59.2) 15/46 (32.6) (19.5, 48.0) 57/142 (40.1) (32.0, 48.7) 91/161 (56.5) (48.5, 64.3) ≥50 years of age† 5/49 (10.2) (3.4, 22.2) 39/167 (23.4) (17.2, 30.5) 66/298 (22.1) (17.6, 27.3) 144/505 (28.5) (24.6, 32.7) 445/1288 (34.5) (32.0, 37.2) 709/1772 (40.0) (37.7, 42.3) mCRC patients with confirmed MSI-H status 1/5 (20.0) (0.5, 71.6) 4/40 (10.0) (2.8, 23.7) 12/73 (16.4) (8.8, 27.0) 20/157 (12.7) (8.0, 19.0) 73/472 (15.5) (12.3, 19.0) 87/721 (12.1) (9.8, 14.7) †Age at current therapy. mCRC: Metastatic colorectal cancer; MSI: Microsatellite instability; MSI-H: MSI-high. The frequency of RAS testing was consistently high in all five countries. For BRAF, France had the highest testing rate (73.6%, 95% CI: 70.3–76.7) followed by Italy (65.9%, 95% CI: 63.3–68.5). MSI testing rates were generally lower, but again most frequently carried out in France (51.8%, 95% CI: 48.2–55.4) and Spain (49.3%, 95% CI: 45.5–53.2). The online supplement shows the testing frequencies for RAS, BRAF and MSI by country (Supplementary Table 5). Mutation & MSI-high prevalence In 2018, the percentage of mCRC patients with confirmed RAS mutant tumors was 53.6% (95% CI: 51.3–55.8) with no notable trend over time (Table 3). Prevalence of confirmed BRAF mutation status was 7.0% (95% CI: 5.6–8.5; Table 3). Table 3. Percentage of metastatic colorectal cancer patients with mutant biomarker status over time, n/N (%) (95% CI). 2013 2014 2015 2016 2017 2018 RAS biomarker overall 10/28 (35.7) (18.6, 55.9) 49/102 (48.0) (38.0, 58.2) 93/204 (45.6) (38.6, 52.7) 229/414 (55.3) (50.4, 60.2) 716/1351 (53.0) (50.3, 55.7) 1,007/1880 (53.6) (51.3, 55.8) BRAF biomarker overall 0/13 (0.0) (0.0, 24.7) 0/68 (0.0) (0.0, 5.3) 4/131 (3.1) (0.8, 7.6) 21/275 (7.6) (4.8, 11.4) 67/928 (7.2) (5.6, 9.1) 90/1294 (7.0) (5.6, 8.5) RAS biomarker anti-EGFR mAb patients 0/5 (0.0) (0.0, 52.2) 1/23 (4.3) (0.1, 21.9) 1/43 (2.3) (0.1, 12.3) 3/77 (3.9) (0.8, 11.0) 7/317 (2.2) (0.9, 4.5) 18/512 (3.5) (2.1, 5.5) BRAF biomarker anti-EGFR mAb patients 0/3 (0.0) (0.0, 70.8) 0/17 (0.0) (0.0, 19.5) 1/34 (2.9) (0.1, 15.3) 4/59 (6.8) (1.9, 16.5) 9/247 (3.6) (1.7, 6.8) 23/425 (5.4) (3.5, 8.0) mAb: Monoclonal antibody. Of mCRC patients in general the rate of MSI-high (MSI-H) tumors ranged between 10 and 16% over time (Table 3). There was no notable difference in the rate of MSI-H tumors by stage at time of diagnosis (Supplementary Table 6). Testing & prevalence in patients receiving anti-EGFR mAbs Of patients receiving anti-EGFR mAbs in 2018, almost all (99.8%; 95% CI: 98.9–100.0) were tested for RAS (Figure 1A). Of those, 3.5% (95% CI: 2.1–5.5) had confirmed RAS-mutant tumor status (Table 4). The percentage of patients receiving anti-EGFR mAbs that were tested for BRAF increased from below 60% in 2014 to 87% in 2018 (Figure 1B). The BRAF mutation prevalence in these patients was 5.4% in 2018 (95% CI: 3.5–8.0; Table 4). Discussion This study aimed to describe a population of patients actively treated for mCRC in 2018 and to estimate the percentage of these patients tested for biomarkers and the mutation prevalence over time (between 2013 and 2018). It was found that over 90% of mCRC patients receiving anticancer treatment had been tested for RAS, with consistent RAS testing rates over time. Testing for BRAF was less prevalent but increasing to approximately two-thirds of patients over time. The prevalence of RAS and BRAF mutations, respectively, were stable over time. Almost all patients receiving anti-EGFR mAb therapy were tested for RAS. In 2018, BRAF was tested in approximately 90% of patients receiving anti-EGFR mAbs, suggesting that BRAF testing is an easy add-on test when RAS testing is conducted as a default for anti-EGFR mAbs and/or that treating physicians believe in the value of BRAF in the anti-EGFR mAb treatment decision. MSI testing was done in more than half of patients <50 years of age and appro ximately 40% in the older age group in 2018. MSI-H status was confirmed in 12.1% overall. There is very limited information from observational studies describing characteristics of mCRC patients as the present study with several treatment lines and active treatments covered. However, the patient and disease characteristics found in the current study appear to be consistent with the literature. Of the total mCRC patients, 60.8% were male and the median age was 68 years. The stages at diagnosis were 0.9% stage I, 4.3% stage II, 14.2% stage III and 77.9% stage IV; 2.8% stage unknown. A study investigating the characteristics of mCRC patients participating in clinical trials found a median age of 62 years with 60% male patients. The clinical characteristics of these patients would not be expected to be representative of real-world clinical practice [37]. A Canadian chart review study following retrospectively mCRC patients from their first line of therapy in the metastatic setting onwards, found a median age at initiation of first-line therapy of 61.5 years with a distributio n of stages at diagnosis of 2% stage I, 9% stage II, 13% stage III and 78% stage IV [38]. Using the Oncology Analyzer™ database (predecessor of the Oncology Dynamics™ database prior to 2017), Bruce et al. [39] documented a shift in RAS testing patterns from KRAS only to full RAS testing after the respective anti-EGFR mAb label changes in late 2013 (14% full RAS testing prior to label change, 44% in Q3/2014, ~1 year after the label change). Similarly, Trojan et al. [40] demonstrated a very quick uptake of full RAS testing after the anti-EGFR mAb label change in a medical record review during two subsequent observation periods in 2012/2013 (97.7% of patients, KRAS only; prior label change) and 2014/2015 (83.2% of patients, full RAS; 16.8%, KRAS only; after label change). The present study included patients who received anti-EGFR mAb treatment in 2018 and reached back at their testing history for up to 5 years to see if they were tested for these important biomarkers at all and when. As recommended by the ESMO guidelines [20], our findings suggest that clinicians request expanded RAS analysis for almost all patients already at diagnosis with increasing numbers of patients additionally tested for BRAF mutations. BRAF testing was recommended by the ESMO as of the 2016 guidelines, which may have influenced the testing patterns. For BRAF, France had the highest testing rate, which may be due to the availability of a completely free nation-wide molecular testing platform in oncology in the French healthcare system since 2006 (https://www.e-cancer.fr). Finally, we noted a small decrease in RAS testing in 2017 and 2018. An explanation could be that primary tumor location started to be taken into account in some centers by excluding patients with right-sided primary tumors from anti-EGFR treatments [41]. Among patients receiving anti-EGFR mAb therapies, almost all were tested for RAS even in 2013 when the label changed to include RAS testing prior to treatment initiation. The quick uptake of biomarker testing in clinical practice is important as more drugs based on biomarkers are now being approved. Of those tested for RAS 3.5% (95% CI: 2.1–5.5) were confirmed with RAS-mutant status. This finding is consistent with past studies by van Krieken et al. [28] and Trojan et al. [40] which found that 2.3 and 5.0% of patients, respectively, had received panitumumab without having a confirmed wild-type KRAS status. BRAF mutation prevalence was 5.4% in 2018 (95% CI: 3.5–8.0). As this is not much lower than the 7.0% (95% CI: 5.6–8.5) mutation prevalence estimated among all mCRC patients, it can be interpreted that BRAF may not be a major factor in the treatment decision making. A number of observational studies have been carried out providing RAS/BRAF mutation prevalence estimates in the real world. In a survey among European pathology laboratories, Boleij et al. [29] found an overall crude RAS mutation prevalence of 46.0% (95% CI: 44.3–47.7) and 48.5% (95% CI: 46.4–50.6) for laboratories testing for all RAS hotspot codons. A meta-analysis of real-world data conducted by Kafatos et al. [27] found a pooled RAS mutation prevalence of 43.6% (95% CI: 38.8–48.5). For RCTs a pooled RAS mutation prevalence of 55.9% (95% CI: 53.9–57.9) was observed [30] although one study found 43% [28,42]. In the present study the RAS mutation prevalence was estimated as 53.6% (95% CI: 51.3–55.8) in 2018. The biomarker information was captured separately for KRAS and NRAS and assumptions were made for combining this information into RAS. If this had an effect on the RAS mutation prevalence estimates, this would apply throughout and therefore, not affecting any trends ove r time. Kafatos et al. [27] estimated BRAF mutation prevalence across different data sources. The overall pooled BRAF mutation prevalence was estimated as 5.8%, ranging between sources from 2.7 to 14.3%. In the GENIE cancer genomics database a confirmed BRAF mutation prevalence of 8.4% was documented [43]. In the present study, a BRAF mutation prevalence of 7% (95% CI: 5.6–8.5) was found. The performance of laboratory testing and the sensitivity of available biomarker test kits have improved over time, raising questions on whether this has affected the RAS/BRAF mutation prevalence estimates [44]. However, we found no notable trends over time. Patients with MSI-H CRC generally have a better prognosis than patients with microsatellite stable CRC [45]. MSI testing uptake, however, was slower but reached above 35% in 2017 and >40% in 2018. In these patients, the prevalence of confirmed MSI-H status decreased from 20 to 12.1% over time. It is possible that prior to 2016 more reflex testing was done and only if there was already a suspicion of MSI-H profile. In a systematic review, MSI-H prevalence was estimated at 17% with a wide range of 3–47% [46]. This is in accordance with the present study, where the prevalence of MSI-H was estimated between approximately 10 and 16% overall and may in part have been conducted to test selected patients with a family history of CRC for hereditary CRC, for example, Lynch syndrome. In order to interpret the study results and their significance for clinical practice, the following considerations need to be taken: the database used for the present study includes information from multiple countries, cancer indications, demographic and clinical characteristics, treatments (type and dosing) and biomarkers. In terms of outcomes, the eCRF captures duration of therapy, time-to-next-treatment, side effects (based on a fixed multiple-choice list) and tumor response. Hospitalizations and deaths/survival are not included. The information is collected quarterly with very small time lag following the end of each quarter (∼6 weeks). The database captures information at different time points of the patient history and specifically at diagnosis, previous and current line of therapy. Hence, it does not cover the full patient treatment history since cancer diagnosis. The advantage with using an eCRF completed by physicians is that variables such as line of therapy or precise su bclassifications of cancer types, for example, small cell versus non-small-cell lung cancer are often complex to define from claims or electronic health record data sources. Due to the design of the present database, such variables are provided by the participating physicians. The disadvantage is that there may be inconsistencies in the way patient information is being reported between physicians. The selection of the physician panel within the database is crucial as it is assumed that their drug-treated patients will, in turn, reflect the real-world cancer-treated population. Participation in quarterly data collection is limited to settings where physicians are able or willing to answer web questionnaires. Reasons for nonresponse may be work burden, with limited ability to participate in multiple, concurrent studies [47]. This especially applies to countries where physicians are required to seek approval form the hospital management prior to participation, for instance in Germany. Studies, however, show that physicians are interested in endorsing quality improvement and to contribute to clinical knowledge in areas of personal interest to them [48]. Moreover, there is a potential preference to sample physicians from larger sites as participation was restricted to physicians with a target number of treating patients. In terms of the patient sample, only drug-treated patients are captured within the database. This means that the data cannot be directly used to estimate prevalence and incidence (unless external information is used to extrapolate to population level). It is also important to consider that patients visiting the oncologists more frequently may be overrepresented in the database, but the possibility to report the same patient across multiple quarters is minimized by the definition of a patient cap and by limiting the data collection to a 14-days period in the quarter. The systematic sampling approach (physicians selecting the most recent treated patients) is chosen to minimize the potential for physicians to self-select patient cases. Conclusion Biomarker mutation prevalence was stable over time despite documented changes in laboratory practices. During the study period, an increase in biomarker testing rates was observed among patients diagnosed with mCRC. Clinicians appeared to be requesting expanded RAS tests for almost all mCRC patients with increasing numbers of patients additionally tested for BRAF mutations. All anti-EGFR patients had been tested for RAS even in 2013 when the anti-EGFR mAb labels were changed to include RAS testing prior to treatment initiation. This study demonstrates the quick uptake of biomarker testing in clinical practice. These findings are significant as biomarker-based drugs are becoming more common. Future perspective In the era of precision medicine, there are many biomarker-driven drugs that are under development, especially within the oncology therapeutic area. As these drugs will be gradually getting introduced, it is important to know that new biomarker testing practices can be quickly adopted by the pathology centers. Summary points There is little published work on the testing landscape of biomarkers for metastatic colorectal cancer (mCRC) patients in Europe. This study therefore aimed to estimate the percentage of mCRC patients tested for biomarkers and the mutation prevalence over time. This was a retrospective analysis using a large oncology database that includes data from ten countries and over 23 cancer indications. The database captures patient information via a standardized electronic case report form entered by the treating physician from patients' health records. This study included mCRC patients from five European countries, receiving an active anticancer therapy during 2018 and diagnosed at any time between July 2013 and December 2018. The mCRC population (n = 4455) had the following characteristics: 60.8% of patients were male, median age was 68 years. The stages at diagnosis were mostly stage III (14.2%), and stage IV (77.9%). RAS testing was conducted in over 90% of mCRC patients from 2014 onwards. BRAF testing increased from 31% of mCRC patients in 2013 to 67% in 2018. Microsatellite instability testing for mCRC patients increased over time from 10% in 2013 to 41% in 2018. The prevalence of RAS and BRAF mutations in 2018 were 53.6% (95% CI: 51.3–55.8) and 7.0% (95% CI: 5.6–8.5), respectively, with no notable trend over time. Of mCRC patients in general, the rate of microsatellite instability-high tumors ranged between 10 and 16% over time. Biomarker mutation prevalence was stable over time despite documented changes in laboratory practices. During the study period, an increase in biomarker testing rates was observed among patients diagnosed with mCRC. Clinicians appeared to be requesting expanded RAS tests for almost all mCRC patients with increasing numbers of patients additionally tested for BRAF mutations. All anti-EGFR patients had been tested for RAS even in 2013 when the anti-EGFR mAb labels were changed to include RAS testing prior to treatment initiation. This study demonstrates the quick uptake of biomarker testing in clinical practice. These findings are significant as biomarker-based drugs are becoming more common. Supplementary data To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/fon-2020-0975 Author contributions All authors were involved in, and contributed to, the drafting and critical review of this manuscript. Financial & competing interests disclosure This research project was funded by Amgen Ltd. G Kafatos, KA Lowe and D Neasham are compensated employees of Amgen, Inc., and stockholders of Amgen, Inc. P Burdon was an employee of Amgen (Europe) GmbH at the time the research was conducted and owns shares in Amgen, Inc.; he is currently an employee of MSD International GmbH. V Banks was a compensated contract worker for Amgen, Inc., during the time of this research. C Anger and F Manuguid are employees of IQVIA Ltd. P Cheung is an independent contractor providing programming services to Amgen Ltd. J Taieb received honoraria for advisory or speaker roles for Amgen, Astra Zeneca, Celgene, HallioDx, Lily, Merck, MSD, Pierre Fabre, Roche, Sanofi, Servier and Sirtex. JH van Krieken declares no conflicts of interest.The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. M Hemetsberger of hemetsberger medical services, Vienna, Austria, provided medical writing support, funded by Amgen Ltd. Ethical conduct of research The Oncology Dynamics™ database (IQVIA Ltd) used in this study is fully anonymized and complies with relevant regulations for protecting patient privacy. Data sharing statement The data that support the findings of this study are available from IQVIA but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of IQVIA. Open access This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ Biomarker testing and mutation prevalence in metastatic colorectal cancer patients in five European countries using a large oncology database Via Future Medicine: Future Oncology: Table of Contents Future Oncology, Ahead of Print. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Appropriateness of trifluridine/tipiracil in the clinical practice of third-line therapy in metastatic colorectal cancer

Cancer shared this article with you from Inoreader Message: Aim: To help to remove misperception of an appropriate position of trifluridine/tipiracil (FTD/TPI) in the treatment of metastatic colorectal cancer. Materials & methods: The RAND Corporation/UCLA Appropriateness Method was used by a panel of Italian experts to develop recommendations concerning daily practice with FTD/TPI. Forty-three clinical scenarios were discussed in two rounds and the resulting statements were rated as appropriate, uncertain or inappropriate, according to the median score. Results: Several topics were dealt with, covering the profile of eligible patients, therapeutic options beyond the second line, the practice of treatment with FTD/TPI, evaluation and efficacy and toxicity, as well as costs and compliance. Conclusion: FTD/TPI is an important therapeutic resource in refractory metastatic colorectal cancer that combines manageability and safety. Appropriateness of trifluridine/tipiracil in the clinical practice of third-line therapy in metastatic colorectal cancer Via Future Medicine: Future Oncology: Table of Contents Future Oncology, Ahead of Print. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Nomograms to predict lung metastasis probability and lung metastasis subgroup survival in malignant bone tumors

Cancer shared this article with you from Inoreader Message: The aim of this study was to construct and validate nomograms for predicting lung metastasis and lung metastasis subgroup overall survival in malignant primary osseous neoplasms. Least absolute shrinkage and selection operator, logistic and Cox analyses were used to identify risk factors for lung metastasis in malignant primary osseous neoplasms and prognostic factors for overall survival in the lung metastasis subgroup. Further, nomograms were established and validated. A total of 3184 patients were collected. Variables including age, histology type, American Joint Committee on Cancer T and N stage, other site metastasis, tumor extension and surgery were extracted for the nomograms. The authors found that nomograms could provide an effective approach for clinicians to identify patients with a high risk of lung metastasis in malignant primary osseous neoplasms and perform a personalized overall surviva l evaluation for the lung metastasis subgroup. Keywords: lung metastasisnomogramosseous neoplasmsSEER databasesurvival analysis Nomograms to predict lung metastasis probability and lung metastasis subgroup survival in malignant bone tumors Via Future Medicine: Future Oncology: Table of Contents Future Oncology, Ahead of Print. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The relationship between eGFR and capecitabine efficacy/toxicity in metastatic breast cancer

Cancer shared this article with you from Inoreader The relationship between eGFR and capecitabine efficacy/toxicity in metastatic breast cancer Via Latest Results for Medical Oncology Abstract The objective of this study was to evaluate the efficacy and toxicity of capecitabine in metastatic breast cancer (mBC) according to the estimated glomerular filtration rate (eGFR). A total of 135 patients included in the final analysis were stratified into 3 categories according to baseline eGFR, i.e., eGFR <60 mL/min/1.73 m2 (Group 1), eGFR 60–90 mL/min/1.73 m2 (Group 2) and eGFR >90 mL/min/1.73 m2 (Group 3). If a patient developed a level of toxicity that would lead to capecitabine dose reduction, this was recognized as dose-limiting toxicity (DLT). The dose was reduced due to toxicity in 95 cycles. A total of 95 DLTs were seen in 76 (56.2%) of the 135 patients. When 76 patients with DLT were evaluated according to eGFR, DLT was observed in 93.3% of those in Group 1, 72.5% of those in Group 2 and 41.3% of those in Group 3 (p < 0.001). The median time to progression (T TP) of all patients was 7.4 months. No significant difference in TTP was observed in patients stratified into 3 groups according to eGFR. When the patients were divided into two groups as DLT and without DLT, the median TTP was 8.68 months (95% CI, 7.53–9.81 months) in those with toxicity and 6.23 months (95% CI, 4.04–8.43 months) in those without toxicity (log-rank p = 0.004). We found a significant relationship between low eGFR and increased risk of DLT. Having a DLT was associated with a longer TTP. It indicates the need for more data/larger study investigating these discrepancies. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.