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In a continuously aging population, the burden of colorectal cancer (CRC) is rising among older patients. Despite the fact that almost half of the cases occur in patients over 75 years, this age group is subjected to disparities regarding diagnostic and therapeutic options. So far, exclusion of older patients from randomized clinical trials has resulted in a lack of evidence-based guidelines. Nevertheless, newer data from studies specifically targeting older patients and subgroup analyses indicate that proper treatment planning and specific medical and geriatric assessment can achieve a safe and beneficial treatment result in older patients, often with similar outcomes to their younger counterparts. Resection of the primary tumour, if feasible, should be the primary goal of surgery aiming for cure, although it should be avoided under emergency conditions. Chronological age per se should not be an exclusion criterion for adjuvant or palliative chemotherapy, or targeted therapies. Careful patient selection, dose adjustments, close monitoring and early intervention in the event of side effects are essential. The benefits of treatment must be balanced with potential effects of treatment and patients’ wishes.

Gastric cancer is one of the commonest malignancies with high rates of mortality worldwide. Older patients represent a substantial proportion of cases with this diagnosis. However, there are very few ‘elderly-specific’ trials in this setting. In addition, the inclusion rate of such patients in randomised clinical trials is poor, presumably due to concerns about increased toxicity, co-existing comorbidities and impaired performance status. Therapeutic strategies for this patient group are therefore mostly based on retrospective subgroup analysis of randomised clinical trials. Review of currently available evidence suggests that older gastric cancer patients who are fit for trial inclusion may benefit from surgical intervention and peri-operative systemic chemotherapy strategies. For patients with metastatic disease, management has been revolutionized by the use of anti-HER2 directed therapies as well as immune checkpoint inhibitors with or without chemotherapy. Early data suggest that fit older patients may also benefit from these therapeutic interventions. However, once again there may be limitations in extrapolating these data to everyday clinical practice with older patients being less likely to have a good performance status and an intact immune system. Therefore, determining the functional age and not just the chronological age of a patient prior to initiating therapy becomes very important. The functional decline including reduced organ function that may occur in older patients makes the integration of some form of geriatric assessment in routine clinical practice very relevant.

Objective We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled. Design To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included. Results Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV. Conclusions No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.

Lynch syndrome is the most common form of hereditary colorectal cancer and is caused by germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Mutation carriers have an increased lifetime risk of developing colorectal cancer as well as other extracolonic tumours. The aim of the current study was to evaluate the frequency and distribution of mutations in the MLH1, MSH2 and MSH6 genes within a cohort of Cypriot families that fulfilled the revised Bethesda guidelines. The study cohort included 77 patients who fulfilled at least one of the revised Bethesda guidelines. Mutational analysis revealed the presence of 4 pathogenic mutations, 3 in the MLH1 gene and 1 in the MSH2 gene, in 5 unrelated individuals. It is noted that out of the 4 pathogenic mutations detected, one is novel (c.1610delG in exon 14 of the MLH1) and has been detected for the first time in the Cypriot population. Overall, the pathogenic mutation detection rate in our patient cohort was 7%. This percentage is relatively low but could be explained by the fact that the sole criterion for genetic screening was compliance to the revised Bethesda guidelines. Larger numbers of Lynch syndrome families and screening of the two additional predisposition genes, PMS2 and EPCAM, are needed in order to decipher the full spectrum of mutations associated with Lynch syndrome predisposition in Cyprus.

Objective: To analyze the factors associated with overall survival (OS) and progression-free survival (PFS) in patients with ovarian cancer in Cyprus. Methods: We retrospectively analyzed data from patients with histologically confirmed epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC). Results: A total of 106 women diagnosed with ovarian cancer were included, with a median age at diagnosis of 58 years. The Kaplan–Meier survival analysis showed a median OS of 41 months (95% C.I = 36.9, 45.1), and the FIGO stage (p < 0.001), type of surgery (p < 0.001) and performance status (p < 0.001) were identified as statistically significant prognostic factors for OS. PFS analysis revealed the FIGO stage (p = 0.006) and the performance status (p < 0.001) as significant prognostic factors. Additionally, a Cox regression analysis for median OS was performed for patients with high-grade serous carcinoma, identifying the performance status, FIGO stage, and type of surgery as prognostic factors in univariate analysis. However, in the subsequent multivariate analysis, the performance status and the FIGO stage were confirmed to be the only statistically significant prognostic factors for OS (p < 0.05). Conclusions: This study confirms that the FIGO stage, performance status, and surgery type were considered as prognostic factors for OS in ovarian cancer.

Gastric cancer remains one of the most common malignancies worldwide. Despite the significant advances in surgical treatment and multimodality strategies, prognosis has modestly improved over the last two decades. Locoregional relapse remains one of the main issues and the combined chemoradiation treatment seems to be one of the preferred approaches. However, more than ten years after the hallmark INT-0116 trial, minimal progress has been made both in terms of effectiveness and toxicity. Moreover, new regimens added to combined therapy failed to prove favourable results. Herein, we attempt a thorough literature review comparing pros and cons of all relative studies and potential bias, targeting well-designed future approaches.

Abstract Introduction The rising incidence of early-onset gastrointestinal (GI) cancer has made the impact of treatments on fertility of high significance. While there is abundant evidence on oncofertility outcomes in breast cancer and hematological malignancies, data regarding these perspectives in GI cancers is lacking. We sought to evaluate current practices of fertility preservation (FP) among GI oncologists across Europe. Methods A cross-sectional survey was distributed through the Gastrointestinal Tract Cancer Group (GITCG) of the EORTC network and affiliated cooperative groups and cancer centers using a 10-item electronic survey regarding oncofertility practices. The target population was oncologists who routinely treat GI cancers. A statistical analysis was performed based on country, patient volume, and tumor type. Results Two hundred and twenty-six GI oncologists from 27 countries completed the survey, the majority from high volume cancer centers. Fifty seven percent of the participating oncologists routinely discuss the impact of treatment on fertility in any patient <40 years, while 36% discuss this only in the curative setting. Fifty-nine percent refer female patients to standard FP options (embryo/oocyte preservation), while 24% chose to refer to ovarian cryopreservation. Of note, 17% indicated they would not refer a curative patient for FP at all due to time or resource issues. Sixty five percent routinely refer male patients to sperm preservation. Use of Gonadotropin Releasing Hormone analogues (GnRHa) in CRC patients is recommended by 34% of oncologists. In the setting of pelvic radiation, 65% refer a female patient for ovarian transposition before pelvic irradiation; 32% would consider uterine transposition. Sixty one percent would consider a nonradiation protocol as perioperative chemotherapy as a valid option for young female patients. We observed heterogeneity upon country but not upon physician gender. Conclusion Our study indicates a substantial diversity in current practices in Europe with regard to FP in young cancer patients with GI malignancies, which is not always aligned with current guidelines. There is a need to disseminate and educate GI oncologists on oncofertility perspectives and contemporary data. Additionally, there is a need to establish evidence on the utility of fertility preservation options for patients with GI cancers.

Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre- KRAS selection era. 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. 40·0% (299/747) of the tumours harboured a KRAS mutation, 14·5% (108/743) harboured a PIK3CA mutation (of which 68·5% [74/108] were located in exon 9 and 20·4% [22/108] in exon 20), 4·7% (36/761) harboured a BRAF mutation, and 2·6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6·7% (17/253) versus 35·8% (126/352; odds ratio [OR] 0·13, 95% CI 0·07–0·22; p<0·0001), a median PFS of 12 weeks versus 24 weeks (hazard ratio [HR] 1·98, 1·66–2·36; p<0·0001), and a median overall survival of 32 weeks versus 50 weeks (1·75, 1·47–2·09; p<0·0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8·3% (2/24) in carriers of BRAF mutations versus 38·0% in BRAF wild types (124/326; OR 0·15, 95% CI 0·02–0·51; p=0·0012); and 7·7% (1/13) in carriers of NRAS mutations versus 38·1% in NRAS wild types (110/289; OR 0·14, 0·007–0·70; p=0·013). PIK3CA exon 9 mutations had no effect, whereas exon 20 mutations were associated with a worse outcome compared with wild types, with a response rate of 0·0% (0/9) versus 36·8% (121/329; OR 0·00, 0·00–0·89; p=0·029), a median PFS of 11·5 weeks versus 24 weeks (HR 2·52, 1·33–4·78; p=0·013), and a median overall survival of 34 weeks versus 51 weeks (3·29, 1·60–6·74; p=0·0057). Multivariate analysis and conditional inference trees confirmed that, if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutations (in that order) gives additional information about outcome. Objective response rates in our series were 24·4% in the unselected population, 36·3% in the KRAS wild-type selected population, and 41·2% in the KRAS, BRAF, NRAS, and PIK3CA exon 20 wild-type population. While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS, and PIK3CA exon 20 mutations are significantly associated with a low response rate. Objective response rates could be improved by additional genotyping of BRAF, NRAS, and PIK3CA exon 20 mutations in a KRAS wild-type population. Belgian Federation against Cancer (Stichting tegen Kanker).

Colorectal cancer (CRC) largely affects patients >75 years old, yet no evidence-based guidelines are available for this age group. In this article, Riccardo Audisio and Demetris Papamichael discuss the various treatment options available for older patients with CRC and suggest that treatment should be tailored to the individual patient. Colorectal cancer (CRC) largely affects older individuals; almost half of cases occur in patients >75 years old. The incidence increases with advancing age, doubling every 7 years in patients aged ≥50 years. The medical and societal burdens of CRC will probably worsen over the coming decades as the number of older individuals (>70) continues to grow. No evidence-based guidelines are available for this age group, as older patients with CRC are generally excluded from randomized clinical trials and the fit ones who are recruited are not representative of the general elderly population. When feasible, surgery is the most successful treatment option for eradicating the primary lesion, as well as any metastases. The operative risk under elective conditions is not markedly different in older than in younger patients; however, the acute setting is to be avoided as it is associated with high operative death rates. Well-selected older patients can tolerate chemotherapy, but benefits need to be balanced against potentially limited life expectancy and reduced quality of life. The use of combination chemotherapy is an area of much controversy, but this treatment should not necessarily be withheld because of the age of the patient. Careful monitoring of toxicities and early intervention is essential in older patients undergoing chemotherapy. Key Points Most cases of colorectal cancer (CRC) occur in patients >75 years old and active treatment should not be withheld because of a patient's age No evidence-based guidelines are available, as older patients (≥70) with CRC are generally excluded from randomized controlled trials and fit patients who are recruited are not representative of the elderly population Surgery is the most successful treatment option, when feasible The operative risk under elective conditions is not notably different in older patients than in young patients; however, emergency surgery should be avoided as it has high death rates Older patients can tolerate chemotherapy, and toxicity is not a major issue in appropriately selected patients; however, benefits must be balanced against the limited life expectancy and reduced quality of life The use of geriatric assessment is mandatory for appropriate treatment planning, obtaining patient consent, comparing series, designing trials and sharing data

Currently, no consensus exists regarding the definition of oligometastatic pancreatic ductal adenocarcinoma, its necessary diagnostic measures, and potential treatment approaches. To address these knowledge gaps, the OligoPanc project brought together an interdisciplinary group of experts to establish consensus using a modified Delphi process and clinical vignettes. Participants agreed that the number of metastatic lesions and the number of affected organs are key elements in defining oligometastatic pancreatic ductal adenocarcinoma. Specifically, up to three lesions in a single organ, either the liver or the lung, define oligometastatic pancreatic ductal adenocarcinoma and could be either synchronous or metachronous. Necessary diagnostics include a triple-phase contrast-enhanced CT scan of the chest and abdomen and MRI of the liver with a hepatocyte-specific contrast agent. In unclear cases, [18F]fluorodeoxyglucose-PET CT or MRI can be considered. A multidisciplinary tumour board is essential. Patient-intrinsic factors, including age, do not define oligometastatic disease but should be considered for any treatment decision. Systemic treatment before any local consolidative treatment, including surgery, stereotactic ablative radiotherapy, or other locally ablative techniques, is mandatory. The proposed definition should be incorporated into future trials to improve comparability and enable validation.