Abstract Background The role of temporary ovarian suppression with gonadotropin-releasing hormone analogs (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients remains highly controversial. This option is considered experimental by the ASCO and ESMO guidelines on fertility preservation in cancer patients. The present pooled analysis aimed at elucidating the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients. Patients and methods This study included individual patient data from 5 trials (PROMISE-GIM6, POEMS/SWOG S0230, Anglo Celtic Group OPTION, GBG-37 ZORO, Moffitt-led trial) in which premenopausal women with early breast cancer were randomized to receive (neo)adjuvant chemotherapy alone or with concurrent administration of GnRHa. Efficacy endpoints were premature ovarian insufficiency (POI, according to the definition used as primary endpoint in the included trials), 1- and 2-year amenorrhea rates and post-treatment pregnancy rate. Safety endpoints were disease-free survival (DFS) and overall survival (OS). Odds ratio (OR), incidence rate ratio (IRR) and hazard ratio (HR) with 95% confidence intervals (CI) were calculated for the effect of adding GnRHa to chemotherapy alone. As each study represents a cluster, statistical analysis has been performed using a random effects model. The study is registered with the PROSPERO registration number CRD42014015638. Results A total of 873 patients from 5 randomized trials were included. Median age was 38 years (interquartile range: 34-42 years). POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted OR 0.38; 95% CI 0.26-0.57; p < 0.001). The incidence of 1-year amenorrhea was 36.8% in the GnRHa group and 40.4% in the control group (adjusted OR 0.92; 95% CI 0.66-1.28; p = 0.623). The incidence of 2-year amenorrhea was 18.2% in the GnRHa group and 30.0% in the control group (adjusted OR 0.51; 95% CI 0.31-0.85; p = 0.009). A total of 37 patients had at least one post-treatment pregnancy in the GnRHa group and 20 in the control group (IRR 1.83; 95% CI 1.06-3.15; p = 0.030). There were no significant differences in DFS (adjusted HR 1.01; 95% CI 0.72-1.42; p = 0.999) or OS (adjusted HR 0.67; 95% CI 0.42-1.06; p = 0.083) between the GnRHa and control groups. Subgroup analyses of both efficacy and safety endpoints according to age of the patients, hormone receptor status, type and duration of chemotherapy will be presented at the conference. Conclusions This study provides level 1A of evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy in premenopausal early breast cancer patients. Given the findings of this pooled analysis, temporary ovarian suppression with GnRHa during chemotherapy should be considered as a new standard option to reduce the likelihood of chemotherapy-induced POF and possibly improve future fertility in premenopausal early breast cancer patients. Citation Format: Lambertini M, Moore HCF, Leonard RCF, Loibl S, Munster P, Bruzzone M, Boni L, Unger JM, Anderson RA, Mehta K, Minton S, Poggio F, Albain KS, Adamson DJA, Gerber B, Cripps A, Bertelli G, Seiler S, Ceppi M, Partridge AH, Del Mastro L. Pooled analysis of five randomized trials investigating temporary ovarian suppression with gonadotropin-releasing hormone analogs during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-01.

Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal women remains controversial. This systematic review and meta-analysis using individual patient-level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer.

Background: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense ; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. Methods: Patients were randomised (2 : 1) to IMM-101 (10 mg ml −l intradermally)+GEM (1000 mg m −2 intravenously; n =75), or GEM alone ( n =35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. Results: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44–1.04, P =0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33–0.87, P =0.01). Conclusions: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.

Introduction: Surgical management of axilla in patients with breast cancer (BC) after neoadjuvant chemotherapy (NAC) remains a clinical challenge. The aim of this study was to explore the effects of NAC on axillary lymph nodes to identify a subset of patients who may be spared axillary node clearance (ANC).

Background: The Ovarian Protection Trial In Premenopausal Breast Cancer Patients "OPTION" trial (NCT00427245) was a prospective, multicenter, randomised, open label study evaluating the frequency of primary ovarian insufficiency (POI) at 12 months in women randomised to 6-8 cycles of (neo)adjuvant chemotherapy (CT) +/ goserelin (G). Here we report the results of a secondary endpoint analysis of the effects of CT +/-G on markers of bone turnover.Methods: Serum for bone alkaline phosphatase (BALP) and urine for N-terminal telopeptide (NTX) were collected at baseline, 6, 12, 18, 24 and 36 months. Changes in median levels of bone turnover markers were evaluated for the overall population, according to age stratification at randomisation (<= 40 vs > 40 years) and with exploratory analysis according to POI rates at 12 months.Results: In the overall population, there was a significant increase in NTX at 6 months compared to baseline in patients treated with CT+G (40.81 vs 57.82 p = 0.0074) with normalisation of levels thereafter. BALP was significantly increased compared to baseline at 6 months and 12 months in those receiving CT+G, but normalised thereafter. BALP remained significantly higher compared to baseline at 12, 24 and 36 months in patients receiving CT, resulting in a significant difference between treatment groups at 36 months (CT+G 5.845 vs CT 8.5 p =0.0006). These changes were predominantly seen in women > 40 years. Women with POI at 12 months showed altered bone formation compared to baseline levels for a longer duration than women who maintained menses.Conclusion: Addition of G to CT increases bone turnover during treatment with normalisation after cessation of treatment suggesting G may offer sufficient ovarian protection against CT induced POI to negate longstanding altered bone turnover associated with POI. (C) 2016 Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license.

Objective To quantify the journeys and CO2 emissions if women with breast cancer are treated with risk-adapted single-dose targeted intraoperative radiotherapy (TARGIT) rather than several weeks' course of external beam whole breast radiotherapy (EBRT) treatment.Setting (1) TARGIT-A randomised clinical trial (ISRCTN34086741) which compared TARGIT with traditional EBRT and found similar breast cancer control, particularly when TARGIT was given simultaneously with lumpectomy, (2) 2 additional UK centres offering TARGIT.Participants 485 UK patients (249 TARGIT, 236 EBRT) in the prepathology stratum of TARGIT-A trial (where randomisation occurred before lumpectomy and TARGIT was delivered simultaneously with lumpectomy) for whom geographical data were available and 22 patients treated with TARGIT after completion of the TARGIT-A trial in 2 additional UK breast centres.Outcome measures The shortest total journey distance, time and CO2 emissions from home to hospital to receive all the fractions of radiotherapy.Methods Distances, time and CO2 emissions were calculated using Google Maps and assuming a fuel efficiency of 40mpg. The groups were compared using the Student t test with unequal variance and the non-parametric Wilcoxon rank-sum (Mann-Whitney) test.Results TARGIT patients travelled significantly fewer miles: TARGIT 21681, mean 87.1 (SE 19.1) versus EBRT 92591, mean 392.3 (SE 30.2); had lower CO2 emissions 24.7kg (SE 5.4) vs 111kg (SE 8.6) and spent less time travelling: 3h (SE 0.53) vs 14h (SE 0.76), all p<0.0001. Patients treated with TARGIT in 2 hospitals in semirural locations were spared much longer journeys (753 miles, 30h, 215kg CO2 per patient).Conclusions The use of TARGIT intraoperative radiotherapy for eligible patients with breast cancer significantly reduces their journeys for treatment and has environmental benefits. If widely available, 5 million miles (8000000km) of travel, 170000 woman-hours and 1200 tonnes of CO2 (a forest of 100hectares) will be saved annually in the UK.Trial registration number ISRCTN34086741; Post-results.

BACKGROUNDGuidelines on the use of haematopoietic colony-stimulating factors for patients having adjuvant chemotherapy for breast cancer are designed to minimise the risk of neutropaenic infection (Smith TJ, Khatcheressian J, Lyman GH et al. Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 3: 187-205; Aapro MS, Bohlius J, Cameron DA et al. Effect of primary prophylactic G-CSF use on systemic therapy administration for elderly breast cancer patients. Breast Cancer Res Treat 2011; 47: 8-32; Carlson RW, Allred DC, Anderson BO et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2009; 7: 122-192). Non-randomised data suggest that the achievement of planned dose intensity (DI) may have an important effect on survival. This trial compared the effects of granulocyte colony-stimulating factor, GCSF, against standard management following a first neutropaenic event (NE) in achieving planned DI.PATIENTS AND METHODSAdult patients receiving adjuvant or neoadjuvant chemotherapy were randomised following a first NE, defined as hospitalisation due to neutropaenic fever, an absolute neutrophil count (ANC) ≤1.5 × 10(9)/l requiring treatment delay or dose reduction of 15% or more of planned dose. The study was initially planned to enrol 816 patients to detect a difference of 10%. This was difficult to achieve in the timeframe and the trial size was amended. Thus, 407 patients were randomly assigned to filgrastim for 7 days or pegfilgrastim versus standard care. The amended study was designed to have 80% power to detect an absolute difference of 14% of planned DI between the two groups.RESULTSMost regimens were anthracycline-based many of which included a sequential taxane and/or were in clinical trials. Around 82.7% had an NE in the first three cycles. A total of 401 had calculable relative dose intensity (RDI) data. A target of 85% planned RDI was achieved in only 50% of patients in the control arm compared with 75% in the GCSF arm (P < 0.0001). A secondary end point revealed a reduction in post-randomisation NEs, 65.7% controls versus 18.2% with GCSF.CONCLUSIONSSecondary intervention with GCSF showed a statistically significant improvement in the achievement of adequate RDI in non-intensive regimens. This may have important clinical implications for outcome.

PURPOSE:To evaluate the outcomes of patients with gastric cancer bleeding who had been treated with palliative radiotherapy with haemostatic intent.METHODS AND MATERIALS:Fifty-two gastric cancer patients aged 52-92 years (median 78 years) with active bleeding or anaemia resulting from inoperable gastric cancer were treated with short-course radiotherapy. Responses to radiotherapy treatment were evaluated based on the changes of haemoglobin level, number of transfusions received before and after radiotherapy, and overall median survival.RESULTS:Thirty-nine (75%) patients received single 8 Gy fraction, and 13 (25%) patients received 20 Gy in five daily fractions. The need for transfusion was evaluable in 44 patients, and the response rate was 50%, with less requirement for blood transfusions within four weeks of radiotherapy. There was also an increase in mean haemoglobin level (0.66 ± 1.12 g/dl, p < 0.01) after radiotherapy in 35 evaluable patients. The overall median survival (calculated from last day of treatment to date of death) was 160 days (95% CI of 119-201 days), making actuarial 12-month survival 15%.CONCLUSION:Palliative short-course radiotherapy is a reasonably effective treatment that can provide durable palliation of bleeding in gastric cancer.

In this paper we use a hybrid multiscale mathematical model that incorporates both individual cell behaviour through the cell-cycle and the effects of the changing microenvironment through oxygen dynamics to study the multiple effects of radiation therapy. The oxygenation status of the cells is considered as one of the important prognostic markers for determining radiation therapy, as hypoxic cells are less radiosensitive. Another factor that critically affects radiation sensitivity is cell-cycle regulation. The effects of radiation therapy are included in the model using a modified linear quadratic model for the radiation damage, incorporating the effects of hypoxia and cell-cycle in determining the cell-cycle phase-specific radiosensitivity. Furthermore, after irradiation, an individual cell's cell-cycle dynamics are intrinsically modified through the activation of pathways responsible for repair mechanisms, often resulting in a delay/arrest in the cell-cycle. The model is then used to study various combinations of multiple doses of cell-cycle dependent chemotherapies and radiation therapy, as radiation may work better by the partial synchronisation of cells in the most radiosensitive phase of the cell-cycle. Moreover, using this multi-scale model, we investigate the optimum sequencing and scheduling of these multi-modality treatments, and the impact of internal and external heterogeneity on the spatio-temporal patterning of the distribution of tumour cells and their response to different treatment schedules.

Previous studies from our laboratory have identified a link between intracellular topoisomerase IIα (topo IIα) levels and chromosomal radiosensitivity, as measured by the frequencies of chromatid breaks in the so-called G2-assay. Lower topo IIα levels were associated with reduced chromosomal radiosensitivity in cultured human cells. These findings supported a model, in which it is proposed that such chromatid breaks are the result of radiation-induced errors made by topoisomerase IIα during decatenation of chromatids. Studies from our and other laboratories, using the G2-assay, have shown that phytohaemagglutinin (PHA)-stimulated peripheral blood T-lymphocytes from 40% of female breast cancer cases show elevated chromatid break frequencies when exposed to a small standard dose of ionizing radiation, i.e. elevated above the 90th percentile of a group of female control samples. In the present study we have used a modified G2-assay to test whether elevated frequency of chromatid breaks in breast cancer cases is linked with elevated intracellular topo IIα level in PHA-stimulated T-lymphocytes, and also whether there is a general correlation between chromosomal radiosensitivity and topo IIα level. Our results confirm previous studies that 40% of breast cancer cases show elevated radiosensitivity as compared with controls. Also, the mean chromatid break frequency in breast cancer cases was significantly higher than in controls (P = 0.0001). We found that the mean topo IIα level in the cohort of breast cancer cases studied was significantly raised, as compared with controls (P = 0.0016), which could indicate a genetic propensity towards a raised intracellular production of topo IIα in these individuals. There was no direct correlation between chromosomal radiosensitivity and topo IIα level for individual samples either in the breast cancer cohort or in controls. However, a comparison between control and breast cancer samples shows a higher mean topo IIα level in breast cancer samples that correlates with the elevated mean chromatid break frequency seen in these patient samples. We found no meaningful correlations between either chromatid break frequency or topo IIα level and either tumour grade or hormone status. We conclude that elevated intracellular topo IIα level is likely to be a significant factor in determining the chromosomal response of stimulated T-lymphocytes from certain breast cancer cases.

Introduction Oesophageal cancer patients often experience dysphagia due to the blockage of the gullet by the tumour, resulting in severe restrictions on food intake, physical activity, social functioning and quality of life. One of the more effective treatments to improve swallowing is the insertion of a metal stent (SEMS), which then self expands to open up the gullet. The addition of radiotherapy may also help to improve the problems causes by dysphagia and provide an additional survival benefit. Aims and Methods To add radiotherapy to SEMS and examine the impact on: i) duration of improvement of swallow; ii) quality of life; iii) survival. A pragmatic, randomised controlled trial of external beam radiotherapy plus SEMS versus SEMS alone in 396 patients with oesophageal cancer. Radiotherapy will be given as an outpatient either as five treatments over one week, or ten treatments over two weeks. Questionnaires assessing quality of life and cost effectiveness will be completed at weeks two, four, eight and twelve and then monthly for up to one year. Semi-structured interviews will be held with: i) trial participants to explore their experiences while on the trial; ii) patients who decide not to take part in the trial to explore reasons for non-consent. Results This trial will provide data on the time to progression of dysphagia, quality of life, morbidity and re-intervention rates, survival, patient attitude to treatment and cost-effectiveness of the treatment. Conclusion Achieving funding for large scale trials capable of answering important symptom control questions is feasible using a pragmatic approach.

We report on a new method for the study of radiation-induced chromatid breaks in stimulated human peripheral blood T lymphocytes, involving a combination of a 1-h colcemid block and a short (15 min) calyculin A treatment. We find that this procedure eliminates the problem of centromere splitting when calyculin A is used alone for a longer period and produces metaphase spreads with superior quality. By this procedure, the chromosomes and the chromatid breaks are expanded and thereby make for improved break scoring. In a comparison of the new technique with the conventional colcemid block method, we show a close proportionality between the frequencies of chromatid breaks scored with the two methods. The frequency of chromatid breaks with the new method was found to be significantly higher than that with colcemid alone, adding a higher sensitivity to the assay as an additional advantage.

The CA 19-9 tumour marker is increasingly used to monitor response to therapy in patients with pancreatic adenocarcinoma. Serum CA 19-9 levels have also been shown to correlate with survival. However, their role in cholangiocarcinoma is less clear.