Cancer burden in adolescents and young adults in Europe.

BACKGROUND: Cancer epidemiology is unique in adolescents and young adults (AYAs; aged 15-39 years). The European Society for Medical Oncology/European Society for Paediatric Oncology (ESMO/SIOPE) AYA Working Group aims to describe the burden of cancers in AYAs in Europe and across European Union (EU) countries. PATIENTS AND METHODS: We used data available on the Global Cancer Observatory. We retrieved crude and age-standardised (World Standard Population) incidence and mortality rates. We reported about AYA cancer burden in Europe and between 28 EU member states. We described incidence and mortality for all cancers and for the 13 cancers most relevant to the AYA population. RESULTS: Incidence and mortality varied widely between countries with the highest mortality observed in Eastern EU countries. Cancers of the female breast, thyroid and male testis were the most common cancers across countries followed by melanoma of skin and cancers of the cervix. Variations in cancer incidence rates across different populations may reflect different distribution of risk factors, variations in the implementation or uptake of screening as well as overdiagnosis. AYA cancer mortality disparities may be due to variation in early-stage diagnoses, different public education and awareness of cancer symptoms, different degrees of access or availability of treatment. CONCLUSIONS: Our results highlight the future health care needs and requirements for AYA-specialised services to ensure a homogeneous treatment across different countries as well as the urgency for preventive initiatives that can mitigate the increasing burden.

Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations.

BACKGROUND: The European Society for Medical Oncology Precision Medicine Working Group (ESMO PMWG) was reconvened to update its 2018/19 recommendations on follow-up of putative germline variants detected on tumour-only sequencing, which were based on an analysis of 17 152 cancers. METHODS: We analysed an expanded dataset including 49 264 paired tumour-normal samples. We applied filters to tumour-detected variants based on variant allele frequency, predicted pathogenicity and population variant frequency. For 58 cancer-susceptibility genes, we then examined the proportion of filtered tumour-detected variants of true germline origin [germline conversion rate (GCR)]. We conducted subanalyses based on the age of cancer diagnosis, specific tumour types and 'on-tumour' status (established tumour-gene association). RESULTS: Analysis of 45 472 nonhypermutated solid malignancy tumour samples yielded 21 351 filtered tumour-detected variants of which 3515 were of true germline origin. 3.1% of true germline pathogenic variants were absent from the filtered tumour-detected variants. For genes such as BRCA1, BRCA2 and PALB2, the GCR in filtered tumour-detected variants was >80%; conversely for TP53, APC and STK11 this GCR was <2%. CONCLUSION: Strategic germline-focused analysis can prioritise a subset of tumour-detected variants for which germline follow-up will produce the highest yield of most actionable true germline variants. We present updated recommendations around germline follow-up of tumour-only sequencing including (i) revision to 5% for the minimum per-gene GCR, (ii) inclusion of actionable intermediate penetrance genes ATM and CHEK2, (iii) definition of a set of seven 'most actionable' cancer-susceptibility genes (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6 and RET) in which germline follow-up is recommended regardless of tumour type.

Risk-adapted modulation through de-intensification of cancer treatments: an ESMO classification.

BACKGROUND: The landscape of clinical trials testing risk-adapted modulations of cancer treatments is complex. Multiple trial designs, endpoints, and thresholds for non-inferiority have been used; however, no consensus or convention has ever been agreed to categorise biomarkers useful to inform the treatment intensity modulation of cancer treatments. METHODS: An expert subgroup under the European Society for Medical Oncology (ESMO) Precision Medicine Working Group shaped an international collaborative project to develop a classification system for biomarkers used in the cancer treatment de-intensification, based on a tiered approach. A group of disease-oriented clinical, translational, methodology and public health experts, and patients' representatives provided an analysis of the status quo, and scanned the horizon of ongoing clinical trials. The classification was developed through multiple rounds of expert revisions and inputs. RESULTS: The working group agreed on a univocal definition of treatment de-intensification. Evidence of reduction in the dose-density, intensity, or cumulative dose, including intermittent schedules or shorter treatment duration or deletion of segment(s) of the standard regimens, compound(s), or treatment modality must be demonstrated, to define a treatment de-intensification. De-intensified regimens must also portend a positive impact on toxicity, quality of life, health system burden, or financial toxicity. ESMO classification categorises the biomarkers for treatment modulation in three tiers, based on the level of evidence. Tier A includes biomarkers validated in prospective, randomised, non-inferiority clinical trials. The working group agreed that in non-inferiority clinical trials, boundaries are highly dependent upon the disease scenario and endpoint being studied and that the absolute differences in the outcomes are the most relevant measures, rather than relative differences. Biomarkers tested in single-arm studies with a threshold of non-inferiority are classified as Tier B. Tier C is when the validation occurs in prospective-retrospective quality cohort investigations. CONCLUSIONS: ESMO classification for the risk-guided intensity modulation of cancer treatments provides a set of evidence-based criteria to categorise biomarkers deemed to inform de-intensification of cancer treatments, in risk-defined patients. The classification aims at harmonising definitions on this matter, therefore offering a common language for all the relevant stakeholders, including clinicians, patients, decision-makers, and for clinical trials.

Current landscape of ESMO/ASCO Global Curriculum adoption and medical oncology recognition: a global survey.

BACKGROUND: With the implementation of multidisciplinary treatment and development of multiple novel anticancer drugs in parallel with expanding knowledge of supportive and palliative care, a need for separate training and specialisation in medical oncology emerged. A Global Curriculum (GC) in medical oncology, developed and updated by a joint European Society for Medical Oncology/American Society of Clinical Oncology (ESMO/ASCO) GC Task Force/Working Group (GC WG), greatly contributed to the recognition of medical oncology worldwide. MATERIAL AND METHODS: ESMO/ASCO GC WG carried out a global survey on medical oncology recognition and GC adoption in 2019. RESULTS: Based on our survey, medical oncology is recognised as a separate specialty or sub-specialty in 47/62 (75%) countries participating in the survey; with a great majority of them (39/47, 83%) recognising medical oncology as a standalone specialty. Additionally, in 9 of 62 (15%) countries, medical oncology is trained together with haematology as a specialty in haemato-oncology or together with radiotherapy as a specialty in clinical oncology. As many as two-thirds of the responding countries reported that the ESMO/ASCO GC has been either fully or partially adopted or adapted in their curriculum. It has been adopted in a vast majority of countries with established training in medical oncology (28/41; 68%) and adapted in 12 countries with mixed training in haemato-oncology, clinical oncology or other specialty responsible for training on systemic anticancer treatment. CONCLUSIONS: With 75% of participating countries reporting medical oncology as a separate specialty or sub-specialty and as high as 68% of them reporting on GC adoption, the results of our survey on global landscape are reassuring. Despite a lack of data for some regions, this survey represents the most comprehensive and up-to-date information about recognition of medical oncology and GC adoption worldwide and will allow both societies to further improve the dissemination of the GC and global recognition of medical oncology, thus contributing to better cancer care worldwide.

Adolescents and young adults (AYA) with cancer: a position paper from the AYA Working Group of the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE).

It is well recognised that adolescents and young adults (AYA) with cancer have inequitable access to oncology services that provide expert cancer care and consider their unique needs. Subsequently, survival gains in this patient population have improved only modestly compared with older adults and children with cancer. In 2015, the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE) established the joint Cancer in AYA Working Group in order to increase awareness among adult and paediatric oncology communities, enhance knowledge on specific issues in AYA and ultimately improve the standard of care for AYA with cancer across Europe. This manuscript reflects the position of this working group regarding current AYA cancer care, the challenges to be addressed and possible solutions. Key challenges include the lack of specific biological understanding of AYA cancers, the lack of access to specialised centres with age-appropriate multidisciplinary care and the lack of available clinical trials with novel therapeutics. Key recommendations include diversifying interprofessional cooperation in AYA care and specific measures to improve trial accrual, including centralising care where that is the best means to achieve trial accrual. This defines a common vision that can lead to improved outcomes for AYA with cancer in Europe.

Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group.

Next-generation sequencing (NGS) allows sequencing of a high number of nucleotides in a short time frame at an affordable cost. While this technology has been widely implemented, there are no recommendations from scientific societies about its use in oncology practice. The European Society for Medical Oncology (ESMO) is proposing three levels of recommendations for the use of NGS. Based on the current evidence, ESMO recommends routine use of NGS on tumour samples in advanced non-squamous non-small-cell lung cancer (NSCLC), prostate cancers, ovarian cancers and cholangiocarcinoma. In these tumours, large multigene panels could be used if they add acceptable extra cost compared with small panels. In colon cancers, NGS could be an alternative to PCR. In addition, based on the KN158 trial and considering that patients with endometrial and small-cell lung cancers should have broad access to anti-programmed cell death 1 (anti-PD1) antibodies, it is recommended to test tumour mutational burden (TMB) in cervical cancers, well- and moderately-differentiated neuroendocrine tumours, salivary cancers, thyroid cancers and vulvar cancers, as TMB-high predicted response to pembrolizumab in these cancers. Outside the indications of multigene panels, and considering that the use of large panels of genes could lead to few clinically meaningful responders, ESMO acknowledges that a patient and a doctor could decide together to order a large panel of genes, pending no extra cost for the public health care system and if the patient is informed about the low likelihood of benefit. ESMO recommends that the use of off-label drugs matched to genomics is done only if an access programme and a procedure of decision has been developed at the national or regional level. Finally, ESMO recommends that clinical research centres develop multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development, and prospectively capture the data that could further inform how to optimise the use of this technology.

Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group.

It is increasingly common in oncology practice to perform tumour sequencing using large cancer panels. For pathogenic sequence variants in cancer susceptibility genes identified on tumour-only sequencing, it is often unclear whether they are of somatic or constitutional (germline) origin. There is wide-spread disparity regarding both the extent to which systematic 'germline-focussed analysis' is carried out upon tumour sequencing data and for which variants follow-up analysis of a germline sample is carried out. Here we present analyses of paired sequencing data from 17 152 cancer samples, in which 1494 pathogenic sequence variants were identified across 65 cancer susceptibility genes. From these analyses, the European Society of Medical Oncology Precision Medicine Working Group Germline Subgroup has generated (i) recommendations regarding germline-focussed analyses of tumour-only sequencing data, (ii) indications for germline follow-up testing and (iii) guidance on patient information-giving and consent.

A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT).

Background: In order to facilitate implementation of precision medicine in clinical management of cancer, there is a need to harmonise and standardise the reporting and interpretation of clinically relevant genomics data. Methods: The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to propose a classification system for molecular aberrations based on the evidence available supporting their value as clinical targets. A group of experts from several institutions was assembled to review available evidence, reach a consensus on grading criteria and present a classification system. This was then reviewed, amended and finally approved by the ESMO TR and PM WG and the ESMO leadership. Results: This first version of the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT) defines six levels of clinical evidence for molecular targets according to the implications for patient management: tier I, targets ready for implementation in routine clinical decisions; tier II, investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed; tier III, clinical benefit previously demonstrated in other tumour types or for similar molecular targets; tier IV, preclinical evidence of actionability; tier V, evidence supporting co-targeting approaches; and tier X, lack of evidence for actionability. Conclusions: The ESCAT defines clinical evidence-based criteria to prioritise genomic alterations as markers to select patients for targeted therapies. This classification system aims to offer a common language for all the relevant stakeholders in cancer medicine and drug development.

Monitoring levels of nephrotoxicity of different aminoglycosides during febrile neutropenia caused by nephrotoxic chemotherapy: a single centre study.

PURPOSE: To investigate the possible existence of increased nephrotoxicity caused by once-daily aminoglycosides in febrile neutropenic patients who were previously treated with cisplatin-based nephrotoxic chemotherapy. METHODS: Thirty-one patients with metastatic tumors received chemotherapy and, as a result, developed febrile neutropenia. Patients were stratified with regard to chemotherapy with cisplatin (n=15) or without cisplatin (n=16). Both groups received i.v. empiric antibiotic treatment which included combinations of once-daily aminoglycosides (amikacin vs. gentamicin) with beta-lactams. RESULTS: Increased nephrotoxicity due to administered aminoglycosides appeared significantly more frequently (p<0.05) in patients who received cisplatin-based chemotherapy. Increased nephrotoxicity differed significantly between various aminoglycosides regimens (p<0.05), being greater in the gentamicin group. CONCLUSION: These results showed that cisplatin-based chemotherapy followed by a once-daily aminoglycosides regimen caused increased renal toxicity, which was more pronounced in patients treated with gentamicin vs. those treated with amikacin.

Biweekly oxaliplatin, fluorouracil and leucovorin versus cisplatin, fluorouracil and leucovorin in patients with advanced gastric cancer.

PURPOSE: To compare a bi-weekly infusion of leucovorin (LV) 5-fluorouracil (5-FU) for 2 days, plus oxaliplatin (LV5- FU2-oxaliplatin) and LV5-FU2-cisplatin (CDDP) regimens with respect to toxicity, objective response rates, time to progression (TTP) and overall survival (OS) in patients with advanced gastric cancer. PATIENTS AND METHODS: Patients received LV5-FU2- oxaliplatin (oxaliplatin 85 mg/m(2), day 1; folinic acid 200 mg/m(2), days 1-2; 5-FU 400 mg/m(2), i.v. bolus, days 1-2; 5-FU 600 mg/m(2), 22-hour continuous infusion, days 1-2) or LV5- FU2-CDDP (CDDP 50 mg/m(2), day 1; plus LV5-FU2). A total of 72 patients were enrolled into this study (36 vs. 36). RESULTS: A total of 305 cycles were administered in the LV5-FU2-oxaliplatin arm (median 8) and 272 cycles in the LV5-FU2-CDDP arm (median 8). Grades 3-4 toxicity were as follows (LV5-FU2-oxaliplatin %/LV5-FU2-CDDP %; p<0.05): neutropenia 5/49, thrombocytopenia 2/6, anemia 6/16 nausea/vomiting 2/15, and mucositis 0/3. Response rate of LV5-FU2-oxaliplatin was 41% (partial response/PR 41%, stable disease/SD 31%, progressive disease/PD 28%; 95% confidence internal/95% CI 27-58) and of LV5-FU2-CDDP was 25% (PR 25%, SD 36%, PD 39%; 95% CI 14-41; p =0.013). The median TTP of the patients in the LV5-FU2-oxaliplatin arm was 8 months and 6 months for those in the LV5- FU2-CDDP arm (p=0.073). The median survival time of the patients in the LV5-FU2-oxaliplatin arm was 10 months and 7 months for those in the LV5-FU2-CDDP arm (p=0.003). CONCLUSION: Our study showed that oxaliplatin may be substituted for cisplatin with LV5-FU2 with favorable safety and efficacy profile. The encouraging results from our study support the effectiveness of oxaliplatin-fluoropyrimidine- containing chemotherapy in gastric cancer and could provide a new core on which to add other agents in future investigations.

Bimonthly 24 h infusion of high-dose 5-fluorouracil vs EAP regimen in patients with advanced gastric cancer. A randomized phase II study.

BACKGROUND: To investigate the activity and toxicity of high dose (HD) infusional 5-FU in comparison to EAP regimen as first-line chemotherapy in patients with advanced gastric cancer. PATIENTS AND METHODS: Histologically confirmed measurable advanced gastric cancer, age < 72 yr, ECOG performance status 0-2, no prior chemo- and radiotherapy, adequate organ functions. TREATMENT: EAP arm: doxorubicin (40 mg/m(2)), etoposide (360 mg/m(2)), and cisplatin (80 mg/m(2)) every 28 d; HD 5-FU arm: 5-FU 2.6 g/m(2) 24 h infusion, biweekly. RESULTS: Sixty patients were randomized. Patient characteristics (arms EAP/HD 5-FU): Median age 57/55 yr, median PS 1/1, LAD (patients) 3/8, M1 (patients) 27/22. Median number of cycles (range): EAP arm 4 (2-8), HD 5-FU arm 2 (1-8). Worst toxicity per cycle (grade 3 and 4 in%): Neutropenia 20/3, thrombocytopenia 9/0, anemia 9/13, diarrhea 3/10, nausea 17/7, vomiting 10/0 for EAP and HD 5-FU arms, respectively. All patients were eligible for response in both arms. Confirmed response rate (95%CI): EAP arm 34% [16-50%]/HD 5-FU arm 10% (0-21%), no change: 46/40%, progression of disease: 20/50, respectively. Overall survival (range): EAP arm A 7 mo [3-27], HD 5-FU arm 6 mo (4-25). CONCLUSIONS: Infusional HD 5-FU showed a low incidence of severe toxicity. But given the low efficacy of 5-FU in the dosage we applied in the study, it cannot be recommended as a single treatment for further studies. Assessment of higher dose intensity and/or dose density of 5-FU, with introduction of other active drugs in combination, could be an option for further studies.

Chemoembolization for liver metastases from colorectal carcinoma: risk or a benefit.

Results from clinical trials do not allow definitive conclusions about the role of chemoembolization (ChE) in the treatment of colorectal cancer (CRC) liver metastases. The aim of present phase II study was to investigate toxicity and efficacy of ChE for patients, with unresectable colorectal liver metastases after failure of 5-FU based chemotherapy. Secondary endpoint was clinical benefit measurement. Eleven patients were enrolled in first stage (two-stage Simon design), 2 males/9 females, median age 60 (46-71). Performance status was I in 8 patients and II in 3 patients. All patients had radical surgery, 7 of them adjuvant chemotherapy and 4 systemic chemotherapy. The ChE regimen consisted of an injection of iodinated oil Lipiodol with mitomycin C (3 mg/ml). Repeated treatments were performed at 9- to 12-week intervals. We applied 17 ChE (median 1/pts.). Clinical benefit was a composite of measurements of pain, ECOG performance status, weight and tumor fever. Study was stopped after first stage because non of the patients (pts) achieved objective response (RECIST). Stable disease occurred in 5 pts (45%). Median time to progression was 3 months (range 3-9 months). Median survival was 9 months (range 4-16 months). A decrease of the baseline carcinoembryonic antigen level occurred in 0% of the cases. Clinical benefit was recorded in one patient. Common toxicity included a "postembolization syndrome," which consisted of fever, pain in the right upper quadrant, nausea, and vomiting. Grades 3-4 toxicity (NCI-CTC) followed transaminases 6/11, LDH 4/11. In addition, a drop in F V levels was noted in 5 pts, F VII in 9, F IX in 2 and F X in 10 pts. Decrease in At III levels occurred in 6 pts and FDP appeared in one. Thus, The ChE as performed in the present study did not appear to bring any benefit; furthermore, significant liver toxicity compromises the safety of such procedure.