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The optimal follow-up (FU) strategy for patients treated for localised renal cell carcinoma (RCC) remains unclear. Using the RECUR database, we studied imaging intensity utilised in contemporary FU to evaluate its association with outcome after detection of disease recurrence. Consecutive patients with nonmetastatic RCC (n = 1612) treated with curative intent at 12 institutes across eight European countries between 2006 and 2011 were included. Recurrence occurred in 336 patients. Cross-sectional (computed tomography, magnetic resonance imaging) and conventional (chest X-ray, ultrasound) methods were used in 47% and 53%, respectively. More intensive FU imaging (more than twofold) than recommended by the European Association of Urology (EAU) was not associated with improved overall survival (OS) after recurrence. Overall, per patient treated for recurrence remaining alive with no evidence of disease, the number of FU images needed was 542, and 697 for high-risk patients. The study results suggest that use of more imaging during FU than that recommended in the 2017 EAU guidelines is unlikely to improve OS after recurrence. Prospective studies are needed to design optimal FU strategies for the future. Patient summary: After curative treatment for localised kidney cancer, follow-up is necessary to detect any recurrence. This study illustrates that increasing the imaging frequency during follow-up, even to double the number of follow-up imaging procedures recommended by the European Association of Urology guidelines, does not translate into improved survival for those with recurrence. After curative treatment for localised kidney cancer, a more intensive follow-up regimen than that recommended in the 2017 European Association of Urology guidelines did not improve overall survival among those experiencing recurrence, irrespective of the risk of recurrence. This suggests that an increase in follow-up imaging frequency is not cost-efficient. Prospective studies to identify more optimal follow-up strategies are needed.

Summary Background The optimal chemotherapy backbone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracyclines would improve pathological complete response compared with a carboplatin–taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab. Methods The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands. We recruited patients aged 18 years or older with previously untreated, histologically confirmed stage II–III HER2-positive breast cancer. Patients were randomly allocated using central randomisation software (1:1 ratio) with minimisation without a random component, stratified by tumour stage, nodal stage, oestrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m 2 ), epirubicin (90 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) every 3 weeks for three cycles followed by paclitaxel (80 mg/m 2 on days 1 and 8) and carboplatin (area under the concentration–time curve [AUC] 6 mg/mL per min on day 1 or optionally, as per hospital preference, AUC 3 mg/mL per min on days 1 and 8) every 3 weeks for six cycles, or to receive nine cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group. Patients in both study groups received trastuzumab (6 mg/kg, loading dose 8 mg/kg) and pertuzumab (420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles. The primary endpoint was the proportion of patients who achieved a pathological complete response in breast and axilla (ypT0/is ypN0) in the intention-to-treat population. Safety was analysed in patients who received at least one treatment cycle according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT01996267, and follow-up for long-term outcome is ongoing. Findings Between Dec 9, 2013, and Jan 14, 2016, 438 patients were enrolled and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the primary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group). The median follow-up for all patients was 19 months (IQR 16–23 months). A pathological complete response was recorded in 141 (67%, 95% CI 60–73) of 212 patients in the anthracycline group and in 140 (68%, 61–74) of 206 in the non-anthracycline group (p=0·95). One patient randomly allocated to the non-anthracycline group did receive anthracyclines and was thus included in the anthracycline group for safety analyses; therefore, for the safety analyses there were 220 patients in the anthracycline group and 218 in the non-anthracycline group. Serious adverse events were reported in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group. The most common adverse events of any cause were grade 3 or worse neutropenia (in 131 [60%] of 220 patients in the anthracycline group vs 118 [54%] of 218 in the non-anthracycline group), grade 3 or worse diarrhoea (26 [12%] vs 37 [18%]), and grade 2 or worse peripheral neuropathy (66 [30%] vs 68 [31%]), with no substantial differences between the groups. Grade 3 or worse febrile neutropenia was more common in the anthracycline group than in the non-anthracycline group (23 [10%] vs three [1%], p vs 0 of 218). One patient in the anthracycline group died because of a pulmonary embolism, which was possibly treatment related. Interpretation In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results. Funding Roche Netherlands.

Background Preservation of erectile function is an important postoperative quality of life concern for patients after robot-assisted radical prostatectomy (RARP) for prostate cancer. Although erectile function may recover, many men continue to suffer from erectile dysfunction (ED). Aim This study aims to determine whether satisfaction with sexual life improves in patients with ED after RARP and which factors are associated with satisfaction during follow-up. Methods A review was carried out of a prospectively maintained database of patients with prostate cancer who underwent a RARP between 2006 and 2019. The “International Index of Erectile Function” questionnaire was used to describe ED (range 5-25), overall satisfaction with sexual life and sexual desire (range for both: 2-10). Patients with ED due to RARP were compared with those without ED after RARP. Mixed effect model was used to test differences in satisfaction over time. Mann-Whitney U tests and multiple logistic regression were used to assess factors associated with being satisfied at 24 and 36 months. Outcomes The main outcomes of this study are the overall satisfaction with sexual life score over time and factors which influence sexual satisfaction. Results Data of 2808 patients were reviewed. Patients whose erectile function was not known (n = 643) or who had ED at the baseline (n = 1281) were excluded. About 884 patients were included for analysis. They had an overall satisfaction score of 8.4. Patients with ED due to RARP had mean overall satisfaction scores of 4.8, 4.8, 4.9, and 4.6 at 6 mo, 12 mo, 24 mo, and 36 mo. These scores were significantly lower than those of patients without ED at every time point. In multiple regression analysis, higher overall satisfaction score at the baseline and higher sexual desire at 24 and 36 months' follow-up were associated with satisfaction with sexual life at 24 and 36 months’ follow-up. No association was found for erectile function. Clinical implications Interventions focusing on adjustment to the changes in sexual functioning might improve sexual satisfaction; especially for those men who continue to suffer from ED. Strengths & Limitations Strengths of this study are the large number of patients, time of follow-up, and use of multiple validated questionnaires. Our results must be interpreted within the limits of retrospectively collected, observational data. Conclusion Satisfaction with sexual life in men with ED due to RARP may take a long time to improve. One could counsel patients that sexual satisfaction is based on individual baseline sexual satisfaction and the return of sexual desire after RARP. Albers LF, Tillier CN, van Muilekom HAM, et al. Sexual Satisfaction in Men Suffering From Erectile Dysfunction After Robot-Assisted Radical Prostatectomy for Prostate Cancer: An Observational Study. J Sex Med 2021;18:339–346.

Background: The addition of bevacizumab to chemotherapy conferred a modest progression-free survival (PFS) benefit in metastatic triple-negative breast cancer (mTNBC). However, no overall survival (OS) benefit has been reported. Also, its combination with carboplatin-cyclophosphamide (CC) has never been investigated. Methods: The Triple-B study is a multicenter, randomized phase IIb trial that aims to prospectively validate predictive biomarkers, including baseline plasma vascular endothelial growth factor receptor-2 (pVEGFR-2), for bevacizumab benefit. mTNBC patients were randomized between CC and paclitaxel (P) without or with bevacizumab (CC ± B or P ± B). Here we report on a preplanned safety and preliminary efficacy analysis after the first 12 patients had been treated with CC+B and on the predictive value of pVEGFR-2. Results: In 58 patients, the median follow-up was 22.1 months. Toxicity was manageable and consistent with what was known for each agent separately. There was a trend toward a prolonged PFS with bevacizumab compared to chemotherapy only (7.0 vs. 5.2 months; adjusted HR = 0.60; 95% CI 0.33–1.08; p = 0.09), but there was no effect on OS. In this small study, pVEGFR-2 concentration did not predict a bevacizumab PFS benefit. Both the intention-to-treat analysis and the per-protocol analysis did not yield a significant treatment-by-biomarker test for interaction (pinteraction = 0.69). Conclusions:CC and CC+B are safe first-line regimens for mTNBC and the side effects are consistent with those known for each individual agent. pVEGFR-2 concentration did not predict a bevacizumab PFS benefit.

Item does not contain fulltext IMPORTANCE: Currently, preoperative radiotherapy for all soft-tissue sarcomas is identical at a 50-Gy dose level, which can be associated with morbidity, particularly wound complications. The observed clinical radiosensitivity of the myxoid liposarcoma subtype might offer the possibility to reduce morbidity. OBJECTIVE: To assess whether a dose reduction of preoperative radiotherapy for myxoid liposarcoma would result in comparable oncological outcome with less morbidity. DESIGN, SETTING, AND PARTICIPANTS: The Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcomas (DOREMY) trial is a prospective, single-group, phase 2 nonrandomized controlled trial being conducted in 9 tertiary sarcoma centers in Europe and the US. Participants include adults with nonmetastatic, biopsy-proven and translocation-confirmed myxoid liposarcoma of the extremity or trunk who were enrolled between November 24, 2010, and August 1, 2019. Data analyses, using both per-protocol and intention-to-treat approaches, were conducted from November 24, 2010, to January 31, 2020. INTERVENTIONS: The experimental preoperative radiotherapy regimen consisted of 36 Gy in once-daily 2-Gy fractions, with subsequent definitive surgical resection after an interval of 4 or more weeks. MAIN OUTCOMES AND MEASURES: As a short-term evaluable surrogate for local control, the primary end point was centrally reviewed pathologic treatment response. The experimental regimen was regarded as a success when 70% or more of the resection specimens showed extensive treatment response, defined as 50% or greater of the tumor volume containing treatment effects. Morbidity outcomes consisted of wound complications and late toxic effects. RESULTS: Among the 79 eligible patients, 44 (56%) were men and the median (interquartile range) age was 45 (39-56) years. Two patients did not undergo surgical resection because of intercurrent metastatic disease. Extensive pathological treatment response was observed in 70 of 77 patients (91%; posterior mean, 90.4%; 95% highest probability density interval, 83.8%-96.4%). The local control rate was 100%. The rate of wound complication requiring intervention was 17%, and the rate of grade 2 or higher toxic effects was 14%. CONCLUSIONS AND RELEVANCE: The findings of the DOREMY nonrandomized clinical trial suggest that deintensification of preoperative radiotherapy dose is effective and oncologically safe and is associated with less morbidity than historical controls, although differences in radiotherapy techniques and follow-up should be considered. A 36-Gy dose delivered in once-daily 2-Gy fractions is proposed as a dose-fractionation approach for myxoid liposarcoma, given that phase 3 trials are logistically impossible to execute in rare cancers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02106312.

BackgroundThe added value of surgery in breast cancer patients with pathological complete response (pCR) after neoadjuvant systemic therapy (NST) is uncertain. The accuracy of imaging identifying pCR for omission of surgery, however, is insufficient. We investigated the accuracy of ultrasound-guided biopsies identifying breast pCR (ypT0) after NST in patients with radiological partial (rPR) or complete response (rCR) on MRI.MethodsWe performed a multicenter, prospective single-arm study in three Dutch hospitals. Patients with T1–4(N0 or N +) breast cancer with MRI rPR and enhancement ≤ 2.0 cm or MRI rCR after NST were enrolled. Eight ultrasound-guided 14-G core biopsies were obtained in the operating room before surgery close to the marker placed centrally in the tumor area at diagnosis (no attempt was made to remove the marker), and compared with the surgical specimen of the breast. Primary outcome was the false-negative rate (FNR).ResultsBetween April 2016 and June 2019, 202 patients fulfilled eligibility criteria. Pre-surgical biopsies were obtained in 167 patients, of whom 136 had rCR and 31 had rPR on MRI. Forty-three (26%) tumors were hormone receptor (HR)-positive/HER2-negative, 64 (38%) were HER2-positive, and 60 (36%) were triple-negative. Eighty-nine patients had pCR (53%; 95% CI 45–61) and 78 had residual disease. Biopsies were false-negative in 29 (37%; 95% CI 27–49) of 78 patients. The multivariable associated with false-negative biopsies was rCR (FNR 47%; OR 9.81, 95% CI 1.72–55.89;p = 0.01); a trend was observed for HR-negative tumors (FNR 71% in HER2-positive and 55% in triple-negative tumors; OR 4.55, 95% CI 0.95–21.73;p = 0.058) and smaller pathological lesions (6 mm vs 15 mm; OR 0.93, 95% CI 0.87–1.00;p = 0.051).ConclusionThe MICRA trial showed that ultrasound-guided core biopsies are not accurate enough to identify breast pCR in patients with good response on MRI after NST. Therefore, breast surgery cannot safely be omitted relying on the results of core biopsies in these patients.

Purpose: To identify an MTD of olaparib, a PARP inhibitor, in combination with loco-regional radiotherapy with/without cisplatin for the treatment of non–small cell lung cancer (NSCLC). Patients and Methods: Olaparib dose was escalated in two groups: radiotherapy (66 Gy/24 fractions in 2.75 Gy/fraction) with and without daily cisplatin (6 mg/m2), using time-to-event continual reassessment method with a 1-year dose-limiting toxicity (DLT) period. The highest dose level with a DLT probability Results: Twenty-eight patients with loco-regional or oligometastatic disease (39%) were treated: 11 at olaparib 25 mg twice daily and 17 at 25 mg once daily. The lowest dose level with cisplatin was above the MTD due to hematologic and late esophageal DLT. The MTD without cisplatin was olaparib 25 mg once daily. At a latency of 1–2.8 years, severe pulmonary adverse events (AE) were observed in 5 patients across all dose levels, resulting in 18% grade 5 pulmonary AEs. Exploratory analyses indicate an association with the radiation dose to the lungs. At the MTD, olaparib reduced PAR levels by more than 95% and abolished radiation-induced PARylation. Median follow-up of survivors was 4.1 years. Two-year loco-regional control was 84%, median overall survival in patients with locally advanced NSCLC was 28 months. Conclusions: Combined mildly hypofractionated radiotherapy and low-dose daily cisplatin and olaparib was not tolerable due to esophageal and hematologic toxicity. Severe pulmonary toxicity was observed as well, even without cisplatin. More conformal radiotherapy schedules with improved pulmonary and esophageal sparing should be explored.

Background: Histotype specific neoadjuvant therapy response data is scarce in soft tissue sarcomas. This study aimed to assess the impact of a moderate radiotherapy (RT) dose on resectability and to correlate MRI parameters to pathological treatment response in Myxoid Liposarcoma (MLS).Methods: This prospective, multicenter, single-arm, phase 2 trial assessed the radiological effects of 36 Gy of preoperative radiotherapy in primary non-metastatic MLS (n=34). Distance of the tumor to the neurovascular bundle, tumor dimensions, fat fraction, enhancing fraction were determined on MRI scans at baseline, after 8 and 16 fractions, and preoperatively. Pathological response was established by central pathology review.Results: Preoperative radiotherapy resulted in a median increase of 2 mm (IQR 0 to 6) of the distance of the tumor to the neurovascular bundle. As compared to baseline, the median change of the tumor volume, craniocaudal diameter and axial diameter at preoperative MRI were -60% (IQR -74 to -41), -19% (IQR -23 to -7) and -20% (IQR -29 to -12), respectively. The median fat fraction of 0.1 (IQR 0.0-0.1) and enhancing fraction of 0.8 (IQR 0.6 to 0.9) at baseline, changed to 0.2 (IQR 0.1 to 0.5) and to 0.5(IQR 0.4 to 0.9) preoperatively, respectively. Radiological signs of response in terms of volume, enhancing fraction and fat fraction were correlated with specific pathological signs of response like hyalinization, necrosis and fatty maturation.Conclusions: A moderate dose of preoperative radiotherapy may improve resectability in MLS and could facilitate achievement of clear margins and function preservation. MRI features which were predictive for expressions of pathological response, can play a role in further personalization of neoadjuvant treatment strategies in order to improve outcome in MLS. (C) 2021 Elsevier Ltd, BASO - The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Background For advanced non-small cell lung cancer anti-PD-1 treatment has become standard care in first and second line treatment in recent years. Because many of the clinical trials with anti-PD-1 drugs have only recently been completed, long term follow up data of patients treated with these agents is scarce, even more so of patients treated in real life clinical care. We present long term follow up of patients treated with nivolumab. Methods Two hundred forty-eight patients with pre-treated, advanced NSCLC who received nivolumab between August 2015 and December 2018 were included in this retrospective cohort study. Overall survival and progression free survival rates were calculated for the total cohort and for subgroups defined by clinical characteristics, responses to treatment, and other parameters. Data on further lines of treatment and characteristics of long term survivors were also collected. Results Median overall survival in the total cohort was 8.1 months, median progression free survival was 2.8 months. Overall survival after two and three years was 23.8% and 17.1%, respectively. Good ECOG performance scores, absence of liver metastases, experiencing treatment-related toxicity, and response to nivolumab were significantly associated with longer overall survival and progression free survival. Three-year survival rate among patients with an objective response was 55.3%. Survival for more than two years without subsequent therapy after nivolumab was observed in 13.3% of patients. Conclusions The results from our study confirm that long term survival rates of patients treated with nivolumab for advanced NSCLC in a real world clinical setting are comparable to survival rates shown in clinical trials.

Aim Oligometastatic breast cancer (OMBC) is a disease-entity with potential for long-term remission in selected patients. Those with truly limited metastatic load (rather than occult widespread metastatic disease) may benefit from multimodality treatment including local ablative therapy of distant metastases. In this systematic review, we studied factors associated with long-term survival in patients with OMBC. Methods Eligible studies included patients with OMBC who received a combination of local and systemic therapy as multimodal approach and reported overall survival (OS) or progression-free survival (PFS), or both. The Quality in Prognosis Studies (QUIPS) tool was used to assess the quality of each included study. Independent prognostic factors for OS and/or PFS are summarized. Results Of 1271 screened abstracts, 317 papers were full-text screened and twenty studies were included. Eleven of twenty studies were classified as acceptable quality. Definition of OMBC varied between studies and mostly incorporated the number and/or location of metastases. The 5-year OS ranged between 30 and 79% and 5-year PFS ranged between 25 and 57%. Twelve studies evaluated prognostic factors for OS and/or PFS in multivariable models. A solitary metastasis, >24 months interval between primary tumor and OMBC, no or limited involved axillary lymph nodes at primary diagnosis, and hormone-receptor positivity were associated with better outcome. HER2-positivity was associated with worse outcome, but only few patients received anti-HER2 therapy. Conclusions OMBC patients with a solitary distant metastasis and >24 months disease-free interval have the best OS and may be optimal candidates to consider a multidisciplinary approach.

This nonrandomized controlled trial evaluates the resection margin rates as well as the safety and usability of a newly developed image-guided navigation technique among patients who underwent a rectal cancer resection., Key Points Question Is there an association between image-guided navigation and complete surgical resection rates in locally advanced rectal cancer and recurrent rectal cancer? Findings In this nonrandomized controlled trial of 33 patients with locally advanced or recurrent rectal cancer, image-guided navigation was found to be a feasible and safe technique in advanced rectal cancer resection. Patients with recurrent cancer who underwent image-guided resection had higher rates of successful resection than a historical cohort who received resection without navigation; however, there was no difference between groups for patients with primary locally advanced cancer. Meaning Image-guided navigation appeared to be associated with an increase in radical resection margin rates in recurrent rectal cancer resection and thereby may improve patient outcomes., Importance The percentage of tumor-positive surgical resection margin rates in patients treated for locally advanced primary or recurrent rectal cancer is high. Image-guided navigation may improve complete resection rates. Objective To ascertain whether image-guided navigation during rectal cancer resection improves complete resection rates compared with surgical procedures without navigation. Design, Setting, and Participants This prospective single-center nonrandomized controlled trial was conducted at the Netherlands Cancer Institute—Antoni van Leeuwenhoek in Amsterdam, the Netherlands. The prospective or navigation cohort included adult patients with locally advanced primary or recurrent rectal cancer who underwent resection with image-guided navigation between February 1, 2016, and September 30, 2019, at the tertiary referral hospital. Clinical results of this cohort were compared with results of the historical cohort, which was composed of adult patients who received rectal cancer resection without image-guided navigation between January 1, 2009, and December 31, 2015. Intervention Rectal cancer resection with image-guided navigation. Main Outcomes and Measures The primary end point was the complete resection rate, measured by the amount of tumor-negative resection margin rates. Secondary outcomes were safety and usability of the system. Safety was evaluated by the number of navigation system–associated surgical adverse events. Usability was assessed from responses to a questionnaire completed by the participating surgeons after each procedure. Results In total, 33 patients with locally advanced or recurrent rectal cancer were included (23 men [69.7%]; median [interquartile range] age at start of treatment, 61 [55.0-69.0] years). With image-guided navigation, a radical resection (R0) was achieved in 13 of 14 patients (92.9%; 95% CI, 66.1%-99.8%) after primary resection of locally advanced tumors and in 15 of 19 patients (78.9%; 95% CI, 54.4%-94.0%) after resection of recurrent rectal cancer. No navigation system–associated complications occurred before or during surgical procedures. In the historical cohort, 142 patients who underwent resection without image-guided navigation were included (95 men [66.9%]; median [interquartile range] age at start of treatment, 64 [55.0-70.0] years). In these patients, an R0 resection was accomplished in 85 of 101 patients (84.2%) with locally advanced rectal cancer and in 20 of 41 patients (48.8%) with recurrent rectal cancer. A significant difference was found between the navigation and historical cohorts after recurrent rectal cancer resection (21.1% vs 51.2%; P = .047). For locally advanced primary tumor resection, the difference was not significant (7.1% vs 15.8%; P = .69). Surgeons stated in completed questionnaires that the navigation system improved decisiveness and helped with tumor localization. Conclusions and Relevance Findings of this study suggest that image-guided navigation used during rectal cancer resection is safe and intuitive and may improve tumor-free resection margin rates in recurrent rectal cancer. Trial Registration Netherlands Trial Register Identifier: NTR7184

Background Awareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration. In this article, we discuss how to design and deliver a trial using this method, from the grant application stage through to dissemination, using two radiotherapy trials as examples. Methods The TiTE-CRM encapsulates the dose-toxicity relationship with a statistical model. The model incorporates observed toxicities and uses a weight to account for the proportion of completed follow-up of participants without toxicity. This model uses all available data to determine the next participant’s dose and subsequently declare the maximum tolerated dose. We focus on two trials designed by the authors to illustrate practical issues when designing, setting up, and running such studies. Results In setting up a TiTE-CRM trial, model parameters need to be defined and the time element involved might cause complications, therefore looking at operating characteristics through simulations is essential. At the grant application stage, we suggest resources to fund statisticians’ time before funding is awarded and make recommendations for the level of detail to include in funding applications. While running the trial, close contact of all involved staff is required as a dose decision is made each time a participant is recruited. We suggest ways of capturing data in a timely manner and give example code in R for design and delivery of the trial. Finally, we touch upon dissemination issues while the trial is running and upon completion. Conclusion Model-based designs can be complex. We hope this paper will help clinical trial teams to demystify the conduct of TiTE-CRM trials and be a starting point for using this methodology in practice.

Purpose Capecitabine is an oral pre-pro-drug of the anti-cancer drug 5-fluorouracil (5-FU). The biological activity of the 5-FU degrading enzyme, dihydropyrimidine dehydrogenase (DPD), and the target enzyme thymidylate synthase (TS), are subject to circadian rhythmicity in healthy volunteers. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of capecitabine therapy adapted to this circadian rhythm (chronomodulated therapy). Methods Patients aged ≥18 years with advanced solid tumours potentially benefitting from capecitabine therapy were enrolled. A classical dose escalation 3 + 3 design was applied. Capecitabine was administered daily without interruptions. The daily dose was divided in morning and evening doses that were administered at 9:00 h and 24:00 h, respectively. The ratio of the morning to the evening dose was 3:5 (morning: evening). PK and PD were examined on treatment days 7 and 8. Results A total of 25 patients were enrolled. The MTD of continuous chronomodulated capecitabine therapy was established at 750/1250 mg/m2/day, and was generally well tolerated. Circadian rhythmicity in the plasma PK of capecitabine, dFCR, dFUR and 5-FU was not demonstrated. TS activity was induced and DPD activity demonstrated circadian rhythmicity during capecitabine treatment. Conclusion The MTD of continuous chronomodulated capecitabine treatment allows for a 20% higher dose intensity compared to the approved regimen (1250 mg/m2 bi-daily on day 1–14 of every 21-day cycle). Chronomodulated treatment with capecitabine is promising and could lead to improved tolerability and efficacy of capecitabine.

BACKGROUND: Presence of lymph node metastases (LNM) is an important prognostic factor for cancer-specific survival (CSS) in patients with upper tract urothelial carcinoma (UTUC). In various neoplasms, 18F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT) is an established modality for preoperative lymph node (LN) staging. In UTUC, the diagnostic value of FDG-PET/CT for LN staging is unknown.OBJECTIVE: To determine the diagnostic value of FDG-PET/CT for LN staging in patients with UTUC.DESIGN, SETTING, AND PARTICIPANTS: Data of 152 patients with UTUC who underwent FDG-PET/CT followed by surgical treatment in eight centers between 2007 and 2017 were retrospectively collected. Patients receiving neoadjuvant chemotherapy were excluded.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: FDG-PET/CT results were compared with histopathology after lymph node dissection (LND). Recurrence-free survival (RFS), CSS, and overall survival (OS) were analyzed using Kaplan-Meier estimates, and compared for patients with and without suspicious LNs on FDG-PET/CT.RESULTS AND LIMITATIONS: We included 117 patients, of whom 62 underwent LND. Seventeen patients had LNM at histopathological evaluation. Sensitivity and specificity of FDG-PET/CT for diagnosis of LNM were 82% (95% confidence interval [CI]: 57-96) and 84% (95% CI: 71-94), respectively. RFS was significantly worse in patients with LN-positive FDG-PET/CT than in those with LN-negative FDG-PET/CT (p=0.03). CSS (p=0.11) and OS (p=0.5) were similar between groups. This study is limited by its retrospective design and by its sample size. Our results warrant further validation.CONCLUSIONS: FDG-PET/CT has 82% sensitivity and 84% specificity for the detection of LNM in patients with UTUC. Presence of suspicious LNs on FDG-PET/CT is associated with worse RFS.PATIENT SUMMARY: In patients with upper tract urothelial cancer, positron emission tomography with computed tomography (PET/CT) scans can detect lymph node metastases with noteworthy accuracy. Presence of suspicious lymph nodes on 18F-fluorodeoxyglucose PET/CT is associated with worse recurrence-free survival.

Background and purpose To investigate associations of early post-treatment 18Fluorodeoxyglucose-positron-emission-tomography (FDG-PET)-scans with local (LF), regional (RF), distant failure (DF) and overall survival (OS) in locally advanced non-small cell lung cancer (LA-NSCLC)-patients treated with concurrent chemoradiotherapy. Materials and methods Forty-seven stage IIIA-B NSCLC-patients included in a randomized phase II-trial (NTR2230) received 66 Gy (24x2.75 Gy) with low dose Cisplatin +/− Cetuximab. FDG-PET-scans were performed at baseline and 4 weeks post-treatment (range, 1.6–10.1). SUVmax, SUVmean, metabolic tumor volume (MTV), total lesion glycolysis (TLG) and gross tumor volume were calculated separately for the primary tumor and the involved lymph nodes to generate baseline, post-treatment, and relative response metrics defined as (metricpre-metricpost)/metricpre. Univariable cox regression analyses were performed to investigate associations between PET-metrics and outcomes. Results Metrics resulted from the post-treatment scan and relative response were associated with outcome, but baseline metrics were not. Primary tumor metrics were stronger associated with all outcomes than lymph node metrics. Both the volumetric (TLG/MTV) and intensity (SUVmax/SUVmean) PET-metrics were associated with OS. The intensity metrics were associated with LF, while the volumetric PET-metrics were associated with RF/DF. This was in contrast to the nodal metrics, demonstrating only an association between RF and the relative response of TLG/MTV. No preference was found between PET volumetric and intensity metrics associated with outcome. Conclusion Early post-treatment PET-metrics are associated with treatment outcome in LA-NSCLC patients treated with chemoradiotherapy. Both volumetric and intensity PET-metrics are useful, but more for the primary tumor than for lymph nodes.

BACKGROUND AND PURPOSE: Radical cystectomy (RC) is considered standard treatment for muscle-invasive bladder cancer (BC) and high-risk non-muscle invasive BC. In selected cases, bladder-sparing treatment using brachytherapy can be offered. We examined the outcome after brachytherapy in comparison to RC in terms of survival, complications and bladder preservation in patients with cT1G3-T2N0M0 BC.MATERIALS AND METHODS: Between 1988 and 2016, 301 patients underwent brachytherapy in two centres. Overall survival (OS) and disease specific survival (DSS) after brachytherapy and RC were assessed using Kaplan-Meier curves. Cox proportional hazards modelling was used to determine variables associated with OS and DSS. Local recurrences, bladder preservation and salvage cystectomy (SC) after brachytherapy were reported. Complications after brachytherapy, RC and SC were compared using CTCAE criteria.RESULTS: Median follow-up was 9.6 years (95% confidence interval (CI): 8.8-10.4) after brachytherapy and 10.6 years (95% CI: 10.0-11.2) after RC. Five/10-year OS was 66%/49% after brachytherapy and 68%/53% after RC (p = 0.4). Five/10-year DSS was 73%/67% after brachytherapy and 75%/65% after RC (p = 0.8). Intravesical recurrence occurred in 58/259 brachytherapy patients after which salvage cystectomy was performed in 32 patients. In total, 84% of brachytherapy-treated patients preserved their bladder. The brachytherapy cohort experienced less high grade complications than the RC cohort (p = 0.02).CONCLUSION: In selected patients with solitary, ≤5 cm cT1G3-T2N0M0 bladder tumours brachytherapy is a bladder-sparing therapy with good survival outcome and with a favourable complication rate compared to RC.

Introduction: Uretero-ileal strictures (UES) following urinary diversion are therapeutically challenging. We compared the efficacy, safety and renal outcome following therapeutic endo-urological techniques (EUTs) and open surgical revision of the anastomosis (SRA) for UES. Material and Methods: We retrospectively analysed all EUTs and SRAs performed for UES in 2 hospitals between 1987 and 2015. Restenosis was defined as recurrent radiographically diagnosed hydronephrosis and re-intervention. Renal function (estimated glomerular filtration rate [eGFR]) decrease was correlated with the number of EUTs per patient. Results: Eighty-five UES were treated with 105 EUTs and 31 open revisions. Due to total obstruction, 28 (27%) EUTs were aborted. During a median follow-up of 33 months, restenosis occurred following 53 out of 77 (69%) completed EUTs and 4 out of 31 (13%) SRAs (p < 0.001 on univariable and multivariable analyses). No serious (Clavien ≥3b) EUT-related complications occurred vs. 5 (19%) related to SRA (p < 0.001). The number of finalised EUTs was independently associated with eGFR loss (β = 12.3 mL/min/1.73 m2 loss per EUT, p = 0.008), with a significant cutoff value of >1 EUTs. SRA did not affect renal function (β = 6.8 mL/min/1.73 m2 loss, p = 0.276). Conclusions: Although EUTs are less invasive, they have an inferior efficacy to SRA. Our results suggest that a maximum of one EUT may be attempted without significantly compromising renal function.

Objectives The objective of this study is to compare long-term outcomes between younger and older (70 y and above) esophageal cancer patients treated with curative intent. Materials and methods Overall survival (OS), disease-free survival (DFS), and locoregional recurrence-free interval were compared between older (70 y and above) and younger (below 70 y) esophageal cancer patients treated between 1998 and 2013. Treatment consisted of neoadjuvant chemoradiotherapy with surgery or definitive chemoradiotherapy: 36 to 50.4 Gy in 18 to 28 fractions combined with 5-fluorouracil/cisplatin or carboplatin/paclitaxel. Results The study comprised 253 patients, of whom 76 were 70 years and older. Median age was 64 years (range, 41 to 83). Most patients had stage II-IIIA disease (83%). Planned treatment was neoadjuvant chemoradiotherapy with surgery for 169 patients (41 patients aged 70 y and older) and definitive chemoradiotherapy for 84 patients (31 patients aged 70 y and older). The compliance to radiotherapy was 92%, with no difference between older and younger patients. In 33 patients (13 patients aged 70 y and older) planned surgery was not performed. Median follow-up was 4.9 years. Three-year OS was 42%. The multivariable analysis showed no statistical difference in OS or in DFS comparing older and younger patients: OS (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.61-1.28), DFS (HR, 0.87; 95% CI, 0.60-1.25). Elderly showed a longer locoregional recurrence-free interval; HR, 0.53 (95% CI, 0.30-0.92; P=0.02) and a higher pathologic complete response rate (50% vs. 25%; P=0.02). Conclusions Long-term outcomes of older esophageal cancer patients (70 y and above) selected for treatment with neoadjuvant chemoradiotherapy followed by surgery or definitive chemoradiotherapy were comparable with the outcomes of their younger counterparts. Advanced age alone should not be a contraindication for potentially curative chemoradiotherapy-based treatment in esophageal cancer patients.

To this day, targeted treatment options for patients with triple negative metastatic breast cancer (TNBC) are still virtually absent. Previously, we showed that elevated expression of the tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/TNBC patients. Here, we show that high FER levels are also associated with improved outcome after adjuvant taxane-based combination chemotherapy, in high-risk, HER2-negative patients. In TNBC cells, we observed a causal relation between high FER levels and sensitivity to taxanes. Our proteomics and mechanistic studies demonstrated that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identified DCTN2 as a novel FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for tubular recycling domains development in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients. Citation Format: Sandra Tavares, Nalan Liv, Milena Pasolli, Mark Opdam, Max Ratze, Manuel Saornil, Lilian Sluimer, Rutger Hengeveld, Robert van Es, Erik van Werkhoven, Harmjan Vos, Holger Rehmann, Boudewijn Burgering, Hendrika Oosterkamp, Susanne Lens, Judith Klumperman, Sabine Linn, Patrick Derksen. FER regulates endosomal recycling and is a candidate predictor for taxane benefit in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB203.

Importance Primary analysis of the TRAIN-2 study showed high pathologic complete response rates after neoadjuvant chemotherapy with or without anthracyclines plus dualERBB2(formerlyHER2) blockade. Objective To evaluate 3-year event-free survival (EFS) and overall survival (OS) of an anthracycline-free and anthracycline-containing regimen with dualERBB2blockade in patients with stage II and IIIERBB2-positive breast cancer. Design, Setting, and Participants A total of 438 patients with stage II and IIIERBB2-positive breast cancer were enrolled in this randomized, clinical, open-label phase 3 trial across 37 hospitals in the Netherlands from December 9, 2013, until January 14, 2016. Follow-up analyses were performed after a median follow-up of 48.8 months (interquartile range, 44.1-55.2 months). Analysis was performed on an intention-to-treat basis. Interventions Participants were randomly assigned on a 1:1 basis, stratified by age, tumor stage, nodal stage, and estrogen receptor status, to receive 3 cycles of fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2), followed by 6 cycles of paclitaxel and carboplatin or 9 cycles of paclitaxel (80 mg/m2days 1 and 8) and carboplatin (area under the concentration-time curve, 6 mg/mL/min). Both groups received trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg intravenously; loading dose 840 mg) every 3 weeks. Main Outcomes and Measures Three-year EFS, OS, and safety. Results A total of 438 women were randomized, with 219 per group (anthracycline group, median age, 49 years [interquartile range, 43-55 years]; and nonanthracycline group, median age, 48 years [interquartile range, 43-56 years]). A total of 23 EFS events (10.5%) occurred in the anthracycline group and 21 EFS events (9.6%) occurred in the nonanthracycline group (hazard ratio, 0.90; 95% CI, 0.50-1.63; favoring nonanthracyclines). Three-year EFS estimates were 92.7% (95% CI, 89.3%-96.2%) in the anthracycline group and 93.6% (95% CI, 90.4%-96.9%) in the nonanthracycline group and 3-year OS estimates were 97.7% (95% CI, 95.7%-99.7%) in the anthracycline group and 98.2% (95% CI, 96.4%-100%) in the nonanthracycline group. The results were irrespective of hormone receptor and nodal status. A decline in left ventricular ejection fraction of 10% or more from baseline to less than 50% was more common in patients who received anthracyclines than those who did not (17 of 220 [7.7%] vs 7 of 218 [3.2%];P = .04). Two patients treated with anthracyclines developed acute leukemia. Conclusions and Relevance This follow-up analysis of the TRAIN-2 study shows similar 3-year EFS and OS estimates with or without anthracyclines in patients with stage II and IIIERBB2-positive breast cancer. Anthracycline use is associated with increased risk of febrile neutropenia, cardiotoxic effects, and secondary malignant neoplasms. Trial Registration ClinicalTrials.gov Identifier:NCT01996267

Dose redistribution, where radio-resistant parts of the tumour are boosted while the border of the planning target volume receives a lower dose has the potential to increase local control in advanced head and neck squamous cell carcinoma (HNSCC). In this treatment planning study for 20 patients, standard radiotherapy (RT) of 70 Gy, was compared to redistributed RT following the ARTFORCE trial protocol (NCT01504815), i.e., a fluorodeoxyglucose-positron emission tomography (FDG-PET) based heterogeneous simultaneous-integrated-boost to a total dose of 64–84 Gy. Redistribution marginally increased the mean ipsilateral ⧹contralateral parotid dose by 1.55⧹0.55 Gy but not dose to other organs at risk. Keywords: Head and neck cancer, Radiotherapy, Dose-painting, Treatment planning

Background The discovery of novel biomarkers that predict treatment response in advanced cancer patients requires acquisition of high-quality tumor samples. As cancer evolves over time, tissue is ideally obtained before the start of each treatment. Preferably, samples are freshly frozen to allow analysis by next-generation DNA/RNA sequencing (NGS) but also for making other emerging systematic techniques such as proteomics and metabolomics possible. Here, we describe the first 469 image-guided biopsies collected in a large collaboration in The Netherlands (Center for Personalized Cancer Treatment) and show the utility of these specimens for NGS analysis. Patients and Methods Image-guided tumor biopsies were performed in advanced cancer patients. Samples were fresh frozen, vital tumor cellularity was estimated, and DNA was isolated after macrodissection of tumor-rich areas. Safety of the image-guided biopsy procedures was assessed by reporting of serious adverse events within 14 days after the biopsy procedure. Results Biopsy procedures were generally well tolerated. Major complications occurred in 2.1%, most frequently consisting of pain. In 7.3% of the percutaneous lung biopsies, pneumothorax requiring drainage occurred. The majority of samples (81%) contained a vital tumor percentage of at least 30%, from which at least 500 ng DNA could be isolated in 91%. Given our preset criteria, 74% of samples were of sufficient quality for biomarker discovery. The NGS results in this cohort were in line with those in other groups. Conclusion Image-guided biopsy procedures for biomarker discovery to enable personalized cancer treatment are safe and feasible and yield a highly valuable biobank.

Background: The head and neck region has rich regional lymphatic network, with a theoretical risk on contralateral metastasis from oropharyngeal cancer (OPC). There is a long-standing convention to irradiate the great majority of these tumors electively to both sides of the neck to reduce the risk of contralateral regional failure (cRF), but this can induce significant toxicity. We aimed to identify patient groups where elective contralateral irradiation may safely be omitted. Methods: PubMed and EMBASE were searched for original full-text articles in English with a combination of search terms related to the end points: cRF in OPC primarily treated by radiotherapy only to the ipsilateral neck and identifying predictive factors for increased incidence of cRF. The data from the identified studies were pooled, the incidence of cRF was calculated and the correlation with different predictive factors was investigated. Results: Eleven full-text articles met the inclusion criteria. In these studies, 1116 patients were treated to the ipsilateral neck alone. The mean incidence of cRF was 2.42% (range 0-5.9%, 95% CI 1.6-3.5%). The incidence of cRF correlated only with T-stage (p = 0.008), and involvement of midline (p = 0.001). However, the significant correlation with T-stage can be explained by the very low incidence of cRF among T1 (0.77%), and disappeared when the incidence of cRF was compared between T2, T3,and T4 (p = 0.344). Conclusion: The incidence of cRF in patients with OPC is very low, with involvement of midline providing the most significant prognosticator. These results call for trials on unilateral elective irradiation in selected groups. (C) 2017 Elsevier Ltd. All rights reserved

Objectives To guide decision making in preventing over- or under-treatment in older breast cancer patients who have undergone breast conserving surgery, we analyzed prognostic factors and risk of recurrence in a consecutive series of patients ≥ 65 years old with breast cancer and identified subgroups that may benefit or not from more intensive treatment. Methods Patients ≥65 years of age with breast cancer (pT1-2/pN0-2) treated with breast conserving surgery and postoperative radiation therapy at the Netherlands Cancer Institute (NKI) between 1980 and 2008 were identified. Endpoints were locoregional recurrence (LRR), distant metastasis (DM) and overall survival (OS). Multivariable analyses were performed using Cox proportional hazards models. Results 1922 patients with a median age of 70 years were analyzed. The 5- and 10- years LRR rates were 2% and 3% respectively. In multivariable analysis there was no significant factor influencing LRR risk. Patients with low risk tumors (node negative patients with T1 and ER positive, grade 1 or 2) had lower risk of DM (HR 0.26) and better OS (HR 0.65) compared to patients with higher risk tumors (grade 3 and/or node positive). Conclusion In elderly breast cancer patients the risk of LRR and DM is low. In patients with less favorable characteristics the risk of LRR is equally low, with a higher risk to develop DM and worse OS. Treatment in the low risk group may be minimized, while for the higher risk group adjuvant treatment could be intensified.

Background: Optimal follow-up (FU) strategy to detect potentially curable (PC) recurrences after treatment of localised clear cell renal cell carcinoma (ccRCC) is unclear. This study retrospectively analysed a large international database to determine recurrence patterns and overall survival (OS), as part of a wider project to issue recommendations on FU protocols. Objective: To analyse associations between RCC recurrences in patients with ccRCC, their risk group stratifications, treatments, and subsequent outcomes. Design, setting, and participants: Nonmetastatic ccRCC patients treated with curative intent between 1 January 2006 and 31 December 2011, with at least 4 yr of FU, were included. Patient, tumour and recurrence characteristics, Leibovich score, and management and survival data were recorded. Isolated local, solitary, and oligometastatic (three or fewer lesions at a single site) recurrences were considered PC, while all others were probably incurable (PI). Intervention: Primarily curative surgical treatment of ccRCC while at recurrence detection metastasectomy, systemic therapy, best supportive care, or observation. Outcome measurements and statistical analysis: Incidence, time to recurrence (TTR), and OS were measured. Competing risk analysis, Kaplan-Meier, and Cox regression models were used. Results and limitation: Of 1265 patients with ccRCC, 286 had a recurrence, with 131 being PC and 155 PI. Five-year cumulative risks of recurrence for low- (n = 53), intermediate- (n = 105), and high-risk (n = 128) patients were, respectively, 7.2%, 23.2%, and 61.6%, of whom 52.8%, 37.1%, and 30.5% were PC, respectively. Median TTR was 25.0 for PC patients versus 17.3 mo for PI patients (p = 0.004). Median OS was longer in PC compared with that in PI patients (p< 0.001). Competing risk analysis showed highest risk of ccRCC-related death in younger and high-risk patients. Limitations were no data on comorbidities, retrospective cohort, and insufficient data excluding 12% of cohort. Conclusions: Low-risk group recurrences are rare and develop later. Treatment of recurrences with curative intent is disappointing, especially in high-risk patients. An age- and risk score-dependent FU approach is suggested. Patient summary: We analysed data from eight European countries, and found that the incidence of the kidney cancer recurrence and patient survival correlated with clinical factors known to predict cancer recurrence reliably and age. We conclude that these factors should be used to design follow-up strategies. Renal cell carcinoma recurrences are rare in low-risk patients. Potentially curable recurrences are more frequent in high-risk patients, but local treatment is unlikely to be curative. Competing risk analyses suggest age and risk score as important factors in developing follow-up strategies.

Presence of lymph node metastases (LNM) is an important prognostic factor for cancer-specific survival (CSS) in patients with upper tract urothelial carcinoma (UTUC). In various neoplasms,To determine the diagnostic value of FDG-PET/CT for LN staging in patients with UTUC.Data of 152 patients with UTUC who underwent FDG-PET/CT followed by surgical treatment in eight centers between 2007 and 2017 were retrospectively collected. Patients receiving neoadjuvant chemotherapy were excluded.FDG-PET/CT results were compared with histopathology after lymph node dissection (LND). Recurrence-free survival (RFS), CSS, and overall survival (OS) were analyzed using Kaplan-Meier estimates, and compared for patients with and without suspicious LNs on FDG-PET/CT.We included 117 patients, of whom 62 underwent LND. Seventeen patients had LNM at histopathological evaluation. Sensitivity and specificity of FDG-PET/CT for diagnosis of LNM were 82% (95% confidence interval [CI]: 57-96) and 84% (95% CI: 71-94), respectively. RFS was significantly worse in patients with LN-positive FDG-PET/CT than in those with LN-negative FDG-PET/CT (p=0.03). CSS (p=0.11) and OS (p=0.5) were similar between groups. This study is limited by its retrospective design and by its sample size. Our results warrant further validation.FDG-PET/CT has 82% sensitivity and 84% specificity for the detection of LNM in patients with UTUC. Presence of suspicious LNs on FDG-PET/CT is associated with worse RFS.In patients with upper tract urothelial cancer, positron emission tomography with computed tomography (PET/CT) scans can detect lymph node metastases with noteworthy accuracy. Presence of suspicious lymph nodes on

To investigate associations of early post-treatmentForty-seven stage IIIA-B NSCLC-patients included in a randomized phase II-trial (NTR2230) received 66 Gy (24x2.75 Gy) with low dose Cisplatin +/- Cetuximab. FDG-PET-scans were performed at baseline and 4 weeks post-treatment (range, 1.6-10.1). SUVMetrics resulted from the post-treatment scan and relative response were associated with outcome, but baseline metrics were not. Primary tumor metrics were stronger associated with all outcomes than lymph node metrics. Both the volumetric (TLG/MTV) and intensity (SUVEarly post-treatment PET-metrics are associated with treatment outcome in LA-NSCLC patients treated with chemoradiotherapy. Both volumetric and intensity PET-metrics are useful, but more for the primary tumor than for lymph nodes.

There is a clear and unmet clinical need for biomarkers to predict responsiveness to chemotherapy for cancer. We developed an in vitro test based on patient-derived tumor organoids (PDOs) from metastatic lesions to identify nonresponders to standard-of-care chemotherapy in colorectal cancer (CRC). In a prospective clinical study, we show the feasibility of generating and testing PDOs for evaluation of sensitivity to chemotherapy. Our PDO test predicted response of the biopsied lesion in more than 80% of patients treated with irinotecan-based therapies without misclassifying patients who would have benefited from treatment. This correlation was specific to irinotecan-based chemotherapy, however, and the PDOs failed to predict outcome for treatment with 5-fluorouracil plus oxaliplatin. Our data suggest that PDOs could be used to prevent cancer patients from undergoing ineffective irinotecan-based chemotherapy.

Highlights • SBRT for liver metastases is a safe alternative for surgical resection or ablation. • High dose (>100 Gy) SBRT provides better local control than low dose (≤100 Gy) SBRT. • Toxicity rates of SBRT are low and do not increase after dose escalation. • Dose escalation is positively associated with overall survival., Introduction Stereotactic Body Radiation Therapy (SBRT) is a treatment option for patients with liver metastases. This study evaluated the impact of high versus low dose image-guided SBRT of hepatic metastases. Methods and materials This is a single-center retrospective study of patients with liver metastases treated with SBRT. For analyses, patients were divided into two groups: ≤100 Gy and >100 Gy near-minimum Biological Effective Doses (BED98%). The main outcomes were local control (LC), toxicity and overall survival (OS). Cox regression analyses were performed to determine prognostic variables on LC and OS. Results Ninety patients with 97 liver metastases (77% colorectal) were included. Median follow-up was 28.6 months. The two-year LC rates in the ≤100 Gy and >100 Gy BED98% group were 60% (CI: 41–80%) and 90% (CI: 80–100%), respectively (p = 0.004). Grade 3 toxicity occurred in 7% vs 2% in the ≤100 Gy and >100 Gy group (p = 0.23). Two-year OS rates in the ≤100 Gy and >100 Gy group were 48% (CI: 32–65%) and 85% (CI: 73–97%), respectively (p = 0.007). In multivariable Cox regression analyses, group dose and tumor volume were significantly correlated with LC (HR: 3.61; p = 0.017 and HR: 1.01; p = 0.005) and OS (HR: 2.38; p = 0.005 and HR: 1.01; p =

Objective: Modality and frequency of image-based renal cell carcinoma (R.C.C.) follow-up strategies are based on risk of recurrence. Using the R.E.C.U.R.-database, frequency of imaging was studied in regard to prognostic risk groups. Furthermore, it was investigated whether imaging modality utilized in contemporary follow-up were associated with outcome after detection of recurrence. Moreover, outcome was compared based on whether the assessment of potential curability was a pre-defined set of criteria’s (per-protocol) or stated by the investigator. Materials and methods: Consecutive non-metastatic R.C.C. patients (n = 1,612) treated with curative intent at 12 institutes across eight European countries between 2006 and 2011 were included. Leibovich or U.I.S.S. risk group, recurrence characteristics, imaging modality, frequency and survival were recorded. Primary endpoints were overall survival (O.S.) after detection of recurrence and frequency of features associated with favourable outcome (non-symptomatic recurrences and detection within the follow-up-programme). Results: Recurrence occurred in 336 patients. Within low, intermediate and high risk for recurrence groups, the frequency of follow-up imaging was highest in the early phase of follow-up and decreased significantly over time (p < 0.001). However, neither the image modality for detection nor ≥ 50% cross-sectional imaging during follow-up were associated with improved O.S. after recurrence. Differences between per protocol and investigator based assessment of curability did not translate into differences in O.S. Conclusions: As expected, the frequency of imaging was highest during early follow-up. Cross-sectional imaging use for detection of recurrences following surgery for localized R.C.C. did not improve O.S. post-recurrence. Prospective studies are needed to determine the value of imaging in follow-up.

Purpose Oropharynx cancer (OPC) is heterogeneous; human papillomavirus (HPV)-positive and HPV- tumors represent 2 disease entities with a different prognosis. Earlier studies investigating the prognostic value of pretreatment 18F-FDG PET in OPC are small or included patients with unknown HPV status. This study assessed the prognostic value of PET variables, in a large cohort with balanced HPV status. Methods Retrospectively, primary tumor SUVmax, SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were extracted from baseline FDG PET/CT of patients with OPC treated with (chemo)radiation. The Pearson correlation between the PET variables was calculated. With linear regression, the correlation between the PET variables and HPV status, age, smoking status, T stage, N stage, and American Joint Committee on Cancer stage was calculated. Univariable and multivariable Cox models analyzed local control, overall survival, and disease-free survival (DFS). Results Of 201 patients, 109 were HPV+. Metabolic tumor volume and TLG correlated (r = 0.96), as did SUVpeak and SUVmax (r = 0.97). The PET variables correlated strongest with HPV status and T stage. These two accounted for 40% of the variance of MTV and 33% of TLG. Human papillomavirus-negative tumors had a significantly higher SUVmax, SUVpeak, MTV, and TLG. In univariable analysis, all PET variables were significantly associated with local control, overall survival, and DFS. In multivariable analysis, TLG was significantly associated to DFS in patients with HPV- OPC (hazard ratio, 1.005; 95% confidence interval, 1.001-1.010; P = 0.03). However, we did not observe this in HPV+ patients. Conclusions Increased baseline TLG is associated with worse DFS in HPV- OPC and might be used as biomarker for risk stratification in these patients. Interestingly, we could not identify this association in HPV+ patients.

Purpose: In breast cancer, pathologic complete response (pCR) to neoadjuvant systemic therapy (NST) is associated with favorable long-term outcome. Trastuzumab emtansine as additional adjuvant therapy improves recurrence-free survival of patients with HER2-positive breast cancer without pCR, but it is uncertain whether all patients without pCR need additional therapy. We evaluated the prognostic value of residual disease after trastuzumab-based NST in patients with HER2-positive breast cancer using Residual Cancer Burden (RCB), Neoadjuvant Response Index (NRI), and Neo-Bioscore. Experimental Design: We included patients with stage II or III HER2-positive breast cancer treated with trastuzumab-based NST and surgery at The Netherlands Cancer Institute between 2004 and 2016. RCB, NRI, and Neo-Bioscore were determined. Primary endpoint was 5-year recurrence-free interval (RFI). A 3% difference compared with the pCR group was considered acceptable as noninferiority margin on the 5-year RFI estimate, based on a proportional hazards model, and its lower 95% confidence boundary. Results: A total of 283 women were included. Median follow-up was 67 months (interquartile range 44–100). A total of 157 patients (56%) with pCR (breast and axilla) had a 5-year RFI of 92% (95% CI, 88–97); patients without pCR had a 5-year RFI of 80% (95% CI, 72–88). Patients with an RCB = 1 (N = 40, 15%), an NRI score between 0.75 and 0.99 (N = 30, 11%), or a Neo-Bioscore of 0 to 1 (without pCR; N = 28, 11%) have a 5-year RFI that falls within a predefined noninferiority margin of 3% compared with patients with pCR. Conclusions: The RCB, NRI, and Neo-Bioscore can identify patients with HER2-positive breast cancer with minimal residual disease (i.e., RCB = 1, NRI ≥ 0.75, or Neo-Bioscore = 0–1) after NST who have similar 5-year RFI compared with patients with pCR.

Background: Fluoropyrimidine therapy including capecitabine or 5-fluorouracil can result in severe treatment-related toxicity in up to 30% of patients. Toxicity is often related to reduced activity of dihydropyrimidine dehydrogenase, the main metabolic fluoropyrimidine enzyme, primarily caused by genetic DPYD polymorphisms. In a large prospective study, it was concluded that upfront DPYD-guided dose individualisation is able to improve safety of fluoropyrimidine-based therapy. In our current analysis, we evaluated whether this strategy is cost saving.Methods: A cost-minimisation analysis from a health-care payer perspective was performed as part of the prospective clinical trial (NCT02324452) in which patients prior to start of fluoropyrimidine-based therapy were screened for the DPYD variants DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A and received an initial dose reduction of 25% (c.2846A>T, c.1236G>A) or 50% (DPYD*2A, c.1679T>G). Data on treatment, toxicity, hospitalisation and other toxicity-related interventions were collected. The model compared prospective screening for these DPYD variants with no DPYD screening. One-way and probabilistic sensitivity analyses were also performed.Results: Expected total costs of the screening strategy were (sic)2599 per patient compared with (sic)2650 for non-screening, resulting in a net cost saving of (sic)51 per patient. Results of the probabilistic sensitivity and one-way sensitivity analysis demonstrated that the screening strategy was very likely to be cost saving or worst case cost-neutral.Conclusions: Upfront DPYD-guided dose individualisation, improving patient safety, is cost saving or cost-neutral but is not expected to yield additional costs. These results endorse implementing DPYD screening before start of fluoropyrimidine treatment as standard of care. (C) 2018 Elsevier Ltd. All rights reserved.

Background The addition of pertuzumab to neoadjuvant trastuzumab-based chemotherapy improves pathologic complete response rates in HER2-positive breast cancer. However, increased toxicity has been reported with the addition of pertuzumab, and this may differ between various chemotherapy backbone regimens. We evaluated toxicities of pertuzumab when added to either FEC-T (5-fluorouracil, epirubicin, cyclophosphamide, trastuzumab) or weekly paclitaxel, trastuzumab, carboplatin (PTC). Methods The TRAIN-2 study is a neoadjuvant randomized controlled trial in stage II and III HER2-positive breast cancer (NCT01996267). Patients are randomly assigned to receive either three cycles of FEC-T plus pertuzumab or three cycles of PTC plus pertuzumab, followed by six cycles of PTC plus pertuzumab in both arms. Toxicities are described per treatment arm according to the Common Toxicity Criteria for Adverse Events version 4.03. Results This analysis includes 110 patients balanced over both treatment arms. Neutropenia was the most common hematologic toxicity, with grade 3–4 occurring in 53% in the FEC-T-arm and in 51% in the PTC-arm. Febrile neutropenia occurred in 9% in the FEC-T arm and did not occur in the PTC-arm. Secondary G-CSF prophylaxis was used in 35–40% of patients. Asymptomatic ejection fraction decrease grade 2 was observed in 24% in the FEC-T-arm and 11% in the PTC-arm. The most common grade 3–4 non-hematologic toxicity was diarrhea (5% in the FEC-T-arm and 18% in the PTC-arm). Conclusions Pertuzumab in combination with FEC-T mostly causes neutropenia, and when added to PTC mostly causes diarrhea. Significant cardiac toxicity is rare with both regimens, and toxicity is overall well manageable.

Het doel van deze studie was het bepalen van de klinische relevantie van incidentele prostaatopname (IPO) op een FDG-PET/CT-scan. We analyseerden 108 mannelijke patienten met blaascarcinoom (BCa) die een FDG-PET/CT-scan ondergingen en vervolgens een cystoprostatectomie, in de periode 2009–2014. IPO had een slechte voorspellende waarde voor de aanwezigheid van prostaatcarcinoom (PCa). Diagnostische nauwkeurigheid verbeterde niet wanneer een nucleair geneeskundige de laesies classificeerde op basis van de mate van verdenking op PCa. Gebaseerd op deze resultaten, zouden artsen bij IPO op een FDG-PET/CT-scan terughoudend moeten zijn met het toepassen van invasieve diagnostiek naar PCa.

3633 Background: Extensive molecular profiling in cancer regularly reveals targets for which approved drugs are available in tumor types outside the registered label. Efficacy of off-label use of these drugs is unavailable. Access to these drugs for pts is challenging. In the Drug Rediscovery Protocol (DRUP, Van der Velden et al, Nature 2019), pts are treated based on their tumor molecular profile. Here, we present the results of the successful cohort “Olaparib for tumors with BRCA1/2 alterations”. Methods: Twenty five adult cancer patients (pts) who exhausted all treatment options and had BRCA1/2 loss of function (LoF) mutations (found in routine diagnostics) were included. No pts were eligible for on-label treatment with PARP inhibitors. Pts were treated with olaparib until disease progression or unacceptable toxicity. The primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥ 16 weeks). Pts were enrolled using a Simon-like two-stage model, with 8 pts in stage 1 and up to 24 pts in stage 2 if at least 1 pt had CB in stage 1. A fresh frozen biopsy was obtained from each pt for whole genome sequencing (WGS) and target confirmation. Results: Fourteen pts (56%) had CB. The objective response rate was 32%. Nine different cancer types were included: prostate (n=11), breast (n=4), ovarian (n=2), pancreatic (n=3), colorectal (n=2), biliary tract (n=2), kidney (n=1), adrenal gland (n=1) and endometrial (n=1). WGS could be performed on 58% of baseline tumor biopsies, confirming the original BRCA1/2 mutations in 86%. CB was observed in pts with both somatic and germline BRCA alterations and across tumor types. CB was only observed in cases with biallelic loss of BRCA1/2 in the tumor and when classified as HRD by a pan-cancer homologous recombination deficiency classifier (CHORD), which relies on genome-wide SNV, indel, and SV mutational footprints for HRD detection. No evidence of complete BRCA loss and HRD was observed in 5 pts with PD, while 4 patients with effective BRCA complete loss and HRD also had PD. WGS analysis of these pts suggested resistance mechanisms due to other oncogenic drivers (e.g FGFR1 amplification, CTNNB1 stabilization, KEAP1 inactivation). Conclusions: Olaparib seems to be an effective treatment option for pts with BRCA1/2 LoF mutated malignancies, regardless of histology, for both germline and somatic alterations, which needs confirmation in an independent cohort. CB of olaparib was observed in malignancies showing biallelic loss of BRCA1/2 and when classified as HRD, indicating the importance of the BRCA/HRD signature status. Clinical trial information: NCT02925234 .

501 Background: The multicenter phase III TRAIN-2 study showed high pathological complete response (pCR) rates after neoadjuvant chemotherapy with and without anthracylines plus dual HER2-blockade in stage II-III HER2-positive breast cancer patients (67% vs 68%, p = 0.95) (NCT01996267). Here we report 3-year efficacy and safety outcomes. Methods: Patients were randomly assigned (1:1) to receive 3 cycles 5-fluoruoracil (500mg/m2), epirubicin (90mg/m2), and cyclophosphamide (500mg/m2) followed by 6 cycles paclitaxel (80mg/m2 day 1 and 8) and carboplatin (AUC = 6mg/ml·min) (FEC-PC) or 9 cycles paclitaxel and carboplatin (PC). Both regimens were combined with trastuzumab (T; 6mg/kg, loading dose 8mg/kg) and pertuzumab (Ptz; 420mg, loading dose 840mg). Patients completed one year of trastuzumab, radiotherapy and endocrine therapy as indicated. The primary endpoint pCR was previously reported. Secondary efficacy endpoints reported here are event-free-survival (EFS) defined as time from randomization to first event (disease progression resulting in inoperability, recurrence [contralateral DCIS excluded], secondary primary malignancies, or death) and overall survival (OS), both in the intention-to-treat population. Safety endpoints are reported for patients treated with at least one dose of study medication. Results: 438 patients were randomized (219/arm) and evaluable for long-term efficacy endpoints. After a median follow-up of 48.8 months 23 EFS events occurred in the FECT-PTC-Ptz-arm and 21 in the PTC-Ptz-arm (HR 0.90; 95% CI 0.50-1.63). Three-year EFS estimates were 92.7% (95% CI: 89.3-96.2) for FECT-PTC-Ptz and 93.6% (95% CI: 90.4-96.9) for PTC-Ptz. Three-year OS estimates were 97.7% (95% CI: 95.7-99.7) for FECT-PTC-Ptz and 98.2% (95% CI: 96.4-100) for PTC-Ptz. These results were irrespective of hormone receptor and nodal status. LVEF decline ≥10% from baseline and < 50% was more common in patients who received anthracyclines than in the PTC-Ptz arm (8.6% vs. 3.2%, p = 0.021). Two patients in the FECT-PTC-Ptz arm developed acute leukemia. No other new safety concerns were seen. Conclusions: The 3-year follow-up of the TRAIN-2 study confirms the results of the primary outcome that anthracylines do not improve efficacy and are associated with clinically relevant toxicity. A neoadjuvant carboplatin-taxane based regimen with dual HER2-blockade can be considered in all stage II-III breast cancer patients, regardless of hormone receptor and nodal status. Clinical trial information: NCT01996267 .

7037 Background: Fluoropyrimidines (FP) are the cornerstone of chemotherapy in many solid tumors and linked to cardiotoxicity (CarTx) in about 5% (Polk, Cancer Treat Rev 2013), often leading to FP discontinuation. CarTx may be less common with S-1 and successful switch from other FP has been reported (Kwakman, EJC 2017). Methods: This 6-country, 12-center, cohort study included patients with solid tumors (ICD10 C15-C21, C24-25, C50, C80) who experienced FP-related CarTx. Primary endpoint was recurrent (R) CarTx during S-1 therapy after switch from any other FP. Results: CarTx during capecitabine (n = 124), continuous (n = 13) or bolus 5-fluorouracil (n = 4) was reported for 141 patients who switched to S-1 therapy. CarTx was chest pain including vasospasm without cardiac findings (55%), acute coronary syndrome or myocardial infarction (32%), atrial fibrillation (4%), heart failure/cardiomyopathy (4%), tachy-/bradycardia (3%), and/or other (15%). CarTx was grade 3-4 in 55%, appeared on cycle 1-2 in 89%, and at median 4 days (range 0-466) from FP initiation (Table). Causality was judged related in 26%, probable in 60%, and possible in 14%. Action with FP causing CarTx was permanent discontinuation in 91%. Treatment intent was curative in 70%. Cumulative incidence of RCarTx with S-1 was 3.5% (CI95%, 1.2-8.4%) and median time to R-CarTx was 11 (range 6-195) days. Four (out of 141) had grade 1 and one grade 2 R-CarTx. Three were judged possibly related to S-1 and 2 not related. S-1 was discontinued in one patient and continued in 4 (for 63-252 days) without action (n = 2), with dose reduction (n = 1), or delay (n = 1). There were no differences in demographic or risk factors regarding R-CarTx on S-1 (Table). Conclusions: FP-related CarTx is often severe, occurs early, and leads to permanent FP discontinuation. Switching to S-1-based therapy is safe, with, at the most, grade 1-2 R-CarTx in only 3.5%, and rarely leads to treatment discontinuation (0.7%), allowing patients to continue on an FP-based regimen. Clinical trial information: NCT04260269 . [Table: see text]

Background Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], and c.1236G>A [rs56038477, E412E, in haplotype B3]) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care. Methods In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (>= 18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade >= 3) overall fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete. Findings Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 [39%] of 85 patients) than in wild-type patients (231 [23%] of 1018 patients; p=0.0013). The RR for severe fluoropyrimidine-related toxicity was 1.31 (95% CI 0.63-2.73) for genotype-guided dosing compared with 2.87 (2.14-3.86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4.30 (2.10-8.80) in c.1679T>G carriers, 2.00 (1.19-3.34) compared with 3.11 (2.25-4.28) for c.2846A>T carriers, and 1.69 (1.18-2.42) compared with 1.72 (1.22-2.42) for c.1236G>A carriers. Interpretation Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

Mesenchymal stem cells (MSCs) can play a vital role in tumor progression and anticancer therapy response, as demonstrated by various in vitro and in vivo model systems. Their ability to home to developing tumors and modulate the tumor microenvironment, by suppressing T-cell responses and contributing to the tumor stroma, is suggested to have a significant impact on disease progression, metastasis formation, and therapy response. Most evidence, however, is derived from artificial models using exogenously administered MSCs. The contribution of endogenous MSCs to tumor progression is currently unclear. Furthermore, few studies have been conducted in humans. A prospective biomarker study was therefore undertaken in 40 human cancer patients and 10 healthy controls of similar age, aimed at (i) exploring and quantifying circulating MSC levels in healthy volunteers and patients with advanced malignancies, (ii) determining the variability of MSC levels between healthy volunteers and cancer patients with different histologic tumor types, and (iii) exploring biomarkers associated with MSC levels. Significantly increased levels of circulating MSC-like cells were observed in cancer patients when compared to healthy individuals (1.72 fold difference, 95% CI 1.03–2.81%, p = 0.03). In addition, prior systemic therapy was associated with a significant increase in MSC-like cells (1.73 fold difference, 95% CI 1.02–2.95, p = 0.04). These results indicate that the amount of endogenously circulating MSCs in humans is increased in response to cancer, and that systemic anticancer treatment can influence MSC levels. Further research is needed to determine whether MSCs have a predictive value.

The fluoropyrimidines act by inhibiting thymidylate synthase (TS). Recent studies have shown that patients' risk of severe fluoropyrimidine-associated toxicity is affected by polymorphisms in the 5′-untranslated region of TYMS, the gene encoding TS. A G>C substitution in the promoter enhancer region of TYMS, rs183205964 (known as the 2RC allele), markedly reduces TS activity in vitro, but its clinical relevance is unknown. We determined rs183205964 in 1605 patients previously enrolled in a prospective multicenter study. Associations between putative low TS expression genotypes (3RC/2RC, 2RG/2RC, and 2RC/2RC) and severe toxicity were investigated using univariable and multivariable logistic regression. Activity of TS and TYMS gene expression were determined in peripheral blood mononuclear cells (PBMCs) of a patient carrying genotype 2RC/2RC and of a control group of healthy individuals. Among 1,605 patients, 28 patients (1.7%) carried the 2RC allele. Twenty patients (1.2%) carried a risk-associated genotype (2RG/2RC, n=13; 3RC/2RC, n=6; and 2RC/2RC, n=1), the eight remaining patients had genotype 3RG/2RC. Early severe toxicity and toxicity-related hospitalization were significantly more frequent in risk-associated genotype carriers (OR 3.0, 95%CI 1.04-8.93, p=0.043 and OR 3.8, 95%CI 1.19-11.9, p=0.024, respectively, in multivariable analysis). The patient with genotype 2RC/2RC was hospitalized twice and had severe febrile neutropenia, diarrhea, and hand-foot syndrome. Baseline TS activity and gene expression in PBMCs of this patient, and a healthy individual with the 2RC allele, were found to be within the normal range. Our study suggests that patients carrying rs183205964 are at strongly increased risk of severe, potentially life-threatening, toxicity when treated with fluoropyrimidines. What's new? Fluoropyrimidines are among the most commonly used anticancer drugs. Fluoropyrimidines act by inhibiting thymidylate synthase, encoded by the gene TYMS. A G>C substitution in the promoter enhancer region of TYMS, rs183205964, has been shown to reduce TS activity in vitro, but its effect in patients is unknown. We determined the clinical relevance of this variant as a predictor of severe fluoropyrimidine-induced toxicity in a cohort of 1605 patients treated with fluoropyrimidine-based chemotherapy, and demonstrate for the first time that rs183205964 is associated with risk of early severe toxicity.

Keywords: Head and neck cancer; larynx cancer; organ preservation; total laryngectomy; imaging; tumor volume;prognosis; outcome Objectives/Hypothesis Tumor volume has been postulated to be an important prognostic factor for oncological outcome after radiotherapy or chemoradiotherapy. This postulate was retrospectively investigated in a consecutively treated cohort of T3-T4 larynx cancer patients. Study Design Retrospective cohort study. Methods For 166 patients with T3-T4 larynx cancer (1999-2008), pretreatment computed tomography and magnetic resonance imaging scans were available for tumor volume delineation. Patients were treated with radiotherapy, chemoradiotherapy, or total laryngectomy with postoperative radiotherapy. Both a dedicated head and neck radiologist and the first author determined all tumor volumes. Statistical analysis was by Kaplan-Meier plots and Cox proportional hazard models. Results Patients with T3 larynx cancer had significantly smaller tumor volumes than patients with T4 larynx cancer (median = 8.1 cm3 and 15.8 cm3, respectively; P < .0001). In the group treated with total laryngectomy and postoperative radiotherapy, no association was found between tumor volume and local or locoregional control or overall survival. In the group treated with radiotherapy, a nonsignificant trend was observed between local control and tumor volume. In the chemoradiotherapy group, however, a significant impact of tumor volume was found on local control (hazard ratio = 1.07; 95% confidence interval = 1.01-1.13; P = .028). Conclusions Tumor volume was not significantly associated with local control, locoregional control, or overall survival in the surgically treated group. In the group treated with radiotherapy, there was no statistically significant association, but a trend was observed between local control and tumor volume. Only in patients treated with concurrent chemoradiotherapy was a significant impact of tumor volume on local control found. Level of Evidence 4. Laryngoscope, 126:E60-E67, 2016

Purpose: The incidence of penile cancer is increasing, and is suggested to be explained by changes in sexual practice and increased exposure of men to sexually transmitted high risk human papillomavirus infection. In penile cancers from a Dutch population treated in 1963 to 2001 we found a high risk human papillomavirus prevalence of about 30%. In this study we assessed the prevalence of high risk human papillomavirus-DNA in a more recent, contemporary penile cancer cohort and its association with patient survival.Materials and Methods: High risk human papillomavirus-DNA presence was assessed by GP5+6+ polymerase chain reaction in 212 formalin fixed, paraffin embedded invasive penile tumor specimens of patients treated between 2001 and 2009. The 5-year disease specific survival was calculated using the Kaplan-Meier method with the log rank test and Cox regression.Results: High risk human papillomavirus-DNA was detected in a subset of penile cancer cases (25%, 95% CI 19–31). HPV16 was the predominant type,...

Introduction/Background Neoadjuvant taxane-based combination chemotherapy has shown promising results in unresectable squamous cell carcinoma of the head and neck area, and the penis. Our primary aim was to assess the objective response in penile cancer patients neoadjuvantly treated with taxane-based combination chemotherapy. Secondary outcomes were progression-free survival (PFS), disease-specific survival (DSS), and toxicity. Patients and Methods Twenty-six patients were treated within the framework of a nonrandomized institutional registration study with 4 courses of TPF (docetaxel, cisplatin, and 5-fluorouracil) for advanced penile cancer between 2008 and 2012. Response was measured using computed tomography (CT) and/or fluorodeoxyglucose positron emission tomography/CT according to Response Evaluation Criteria in Solid Tumours 1.1 criteria and European Organisation for Research and Treatment of Cancer recommendations, respectively. Toxicity, PFS, and DSS were analyzed using either the Common Toxicity Criteria of Adverse Events version 4.0 or the Kaplan-Meier methods. To analyze possible association with survival, univariable and multivariable Cox regression analyses were performed for tumor differentiation, N-category, recurrent disease, tumor margins, and administration of radiotherapy. Results During a median follow-up of 30 months, an imaging-based response was obtained in 60% (95% confidence interval [CI], 39%-79%) (15/25) of patients. However, pathologic complete response was observed in 1 of 25 evaluable patients (4%; 95% CI, 0%-20%). Toxicity was considerable with registered toxicity in every patient. The 2-year PFS and DSS probability were 12% and 28%, respectively. Patients responsive to chemotherapy had significantly better survival than nonresponsive patients. Conclusion Despite a fairly good response percentage, TPF chemotherapy was poorly tolerated with disappointing survival rates. Therefore, other treatment options should be considered.

Summary Background The standard of care for operable, stage I, non-small-cell lung cancer (NSCLC) is lobectomy with mediastinal lymph node dissection or sampling. Stereotactic ablative radiotherapy (SABR) for inoperable stage I NSCLC has shown promising results, but two independent, randomised, phase 3 trials of SABR in patients with operable stage I NSCLC (STARS and ROSEL) closed early due to slow accrual. We aimed to assess overall survival for SABR versus surgery by pooling data from these trials. Methods Eligible patients in the STARS and ROSEL studies were those with clinical T1–2a ( Findings 58 patients were enrolled and randomly assigned (31 to SABR and 27 to surgery). Median follow-up was 40·2 months (IQR 23·0–47·3) for the SABR group and 35·4 months (18·9–40·7) for the surgery group. Six patients in the surgery group died compared with one patient in the SABR group. Estimated overall survival at 3 years was 95% (95% CI 85–100) in the SABR group compared with 79% (64–97) in the surgery group (hazard ratio [HR] 0·14 [95% CI 0·017–1·190], log-rank p=0·037). Recurrence-free survival at 3 years was 86% (95% CI 74–100) in the SABR group and 80% (65–97) in the surgery group (HR 0·69 [95% CI 0·21–2·29], log-rank p=0·54). In the surgery group, one patient had regional nodal recurrence and two had distant metastases; in the SABR group, one patient had local recurrence, four had regional nodal recurrence, and one had distant metastases. Three (10%) patients in the SABR group had grade 3 treatment-related adverse events (three [10%] chest wall pain, two [6%] dyspnoea or cough, and one [3%] fatigue and rib fracture). No patients given SABR had grade 4 events or treatment-related death. In the surgery group, one (4%) patient died of surgical complications and 12 (44%) patients had grade 3–4 treatment-related adverse events. Grade 3 events occurring in more than one patient in the surgery group were dyspnoea (four [15%] patients), chest pain (four [15%] patients), and lung infections (two [7%]). Interpretation SABR could be an option for treating operable stage I NSCLC. Because of the small patient sample size and short follow-up, additional randomised studies comparing SABR with surgery in operable patients are warranted. Funding Accuray Inc, Netherlands Organisation for Health Research and Development, NCI Cancer Center Support, NCI Clinical and Translational Science Award.