Local Recurrence-free Interval Research Articles

High-dose-rate brachytherapy at 3 Gy per fraction for lip carcinoma: Treatment outcomes and toxicity at 5-years

PURPOSELow-dose-rate brachytherapy (LDR-BT) is a well-established treatment for lip cancer. High-dose-rate (HDR)-BT is a promising alternative to LDR-BT, but data are limited. In this context, we retrospectively evaluated treatment outcomes in a series of patients who underwent HDR-BT for lip carcinoma between 2003 and 2021. MATERIALS AND METHODSA total of 32 patients were included in this study, with a median age of 73.5 years (range, 61 – 88). The indications for HDR-BT were as follows: primary treatment (n = 17), adjuvant treatment (n = 3), and recurrent disease after surgery (n = 12). The prescribed dose was 18 fractions of 3 Gy administered twice daily. RESULTSAt a median followup of 45 months (range, 12 -232), the 5-year local recurrence-free interval was 96.9% (95% CI: 90.9–100%), the disease-free interval was 85% (95% CI: 70.9–99.1), and 5-year overall survival was 64.7% (95% CI: 44.7–84.8). Eleven patients died, all on age related comorbidities. Acute toxicity manifested as G1 dry desquamation in 6 patients (18.8%), G2 erythema in 10 patients (31.2%) and G3 confluent moist desquamation in 16 patients (50%). Late complications included G1 fibrosis (100% of cases). G1 and G2 depigmentation was observed in 8 (25%) and 6 (18%) patients, G1 telangiectasia occurred in 5 patients (16%). CONCLUSIONSThese data support the use of HDR-BT for lip cancer. The dose and fractionation schedule used in this study (18 fractions x 3 Gy twice daily) seems to be effective and safe.

Abstract P3-05-18: Unravelling the clinicopathological and functional significance of Replication Protein A (RPA) heterotrimeric complex in sporadic breast cancers

Abstract Unravelling the clinicopathological and functional significance of Replication Protein A (RPA) heterotrimeric complex in sporadic breast cancers Mashael Algethami1, Michael S Toss 1,4, Juliette Brownlie 1, Corinne L Woodcock 1,2, Chandar Jaipal1, Ahmed Shoqafi 1, Katia A Mesquita1, Adel Alblihy1,3, Andrew R Green1, Nigel P Mongan 1,5, Emad A Rakha 1,4, Jennie N Jeyapalan 1,2 and Srinivasan Madhusudan1,6 1 Nottingham Biodiscovery Institute, Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham, University Park, Nottingham NG7 2RD, UK. 2 Faculty of Medicine and Health Sciences, Centre for Cancer Sciences, University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Leicestershire LE12 5RD, UK 3 Medical Center, King Fahad Security College (KFSC), Riyadh 11461, Saudi Arabia. 4 Department of Pathology, Nottingham University Hospital, City Campus, Hucknall Road, Nottingham NG5 1PB, UK. 5 Department of Pharmacology, Weill Cornell Medicine, New York, NY, 10065, USA 6 Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK. Introduction: Replication Protein A (RPA) is a critical single-stranded DNA (ssDNA)-binding protein that coats and protects exposed ssDNA from endogenous nucleases. RPA is a heterotrimeric complex consisting of RPA1 (70kDa), RPA2 (32kDa), and RPA3 (14kDa) subunits. RPA provides a platform for recruitment of factors required during replication, checkpoint regulation, DNA repair [including homologous recombination (HR), nucleotide excision repair (NER), base excision repair (BER) and mismatch repair (MMR)], telomere maintenance and retro-transposition. To understand the role of RPA in breast cancer pathogenesis we conducted a comprehensive genomic, transcriptomic, bioinformatic, proteomic and preclinical study. Patients and methods: RPA1, RPA2 and RPA3 protein expression was evaluated in 4221 primary invasive breast carcinomas and 776 breast ductal carcinoma in situ (DCIS). Transcriptomic investigation was completed in the METABRIC cohort (n=1980). Detailed bioinformatics was conducted in the TCGA cohort (n=1090). RPA deficient breast cancer cell lines were tested for Cisplatin, Palbociclib and Olaparib sensitivity. Results: RPA1, RPA2 and RPA3 loss is frequent in DCIS and linked to aggressive phenotype (including high grade, ER and PR negativity) (all p values < 0.01). DCIS with low RPA1 was also associated with poor local recurrence-free interval (p< 0.00001). In invasive breast cancers, low RPA1, low RPA2 and low RPA3 were all associated with larger size, lympho-vascular invasion, higher histological grade, high stage, ER negativity and poor breast cancer specific survival. Transcriptomic alterations in low RPA tumors included those genes involved in steroid hormone biosynthesis, chemical carcinogenesis, and drug metabolism. Pre-clinically, RPA deficient breast cancer cells were sensitive to Cisplatin and Palbociclib (CDK4/6 inhibitor) therapy compared to controls. Additionally, the PARP1 inhibitor Olaparib was synthetically lethal in RPA1 and RPA2 deficient cells compared to controls. Increased Olaparib sensitivity was associated with double strand breaks, S-phase cell cycle arrest and increased apoptosis. Conclusions: We provide the first comprehensive evidence that RPA loss is an early event during breast cancer pathogenesis and promotes aggressive phenotypes. Pre-clinically RPA deficient breast cancer cells were selectively toxic to Cisplatin, Palbociclib and Olaparib. Citation Format: Mashael A. Algethami, Michael Toss, Juliette Brownlie, Corinne L. Woodcock, Chandar Jaipal, AHMED SHOQAFI, Katia Mesquita, Adel Alblihy, Nigel Mongan, Emad Rakha, Jennie N. Jeyapalan, Srinivasan Madhusudan, Andrew R. Green. Unravelling the clinicopathological and functional significance of Replication Protein A (RPA) heterotrimeric complex in sporadic breast cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-18.

Lesion Site Is the Key Prognostic Factor for Keloid Patients Receiving Surgery With Adjuvant Radiotherapy.

Keloid is a benign tumor with high recurrence rate; accordingly, complete surgical excision with adjuvant radiotherapy is one of the most effective treatments. This study reviewed outcomes of keloid patients receiving surgery and adjuvant radiotherapy in Kaohsiung Medical University Hospital. All patients received radiation dose with 15 Gy, with their first radiotherapy within 24 hours after surgical excision. The end points were recurrence rate and local recurrence-free interval (LRFI), defined clinically as palpable gross tumor over the treatment site and duration from the last day of radiotherapy to disease recurrence. From May 2017 to July 2020, 32 patients with 40 keloid lesions were included. The mean age for these patients was 37.6 years, and the median follow-up time was 15.3 months. The overall recurrence rate was 52.5%, and the median LRFI was 9.7 months. Recurrence rates for males and females were 46.7% and 56% ( P = 0.567), respectively; for head and ear, chest, shoulder and upper extremities, and abdomen and back were 12.5%, 61.5%, 63.6%, and 62.5% ( P = 0.093); for lesions over 20 cm 2 and below 20 cm 2 were 62.5% and 50% ( P = 0.527); and for megavoltage electron beam and kilovoltage photon beam were 56.7% and 40% ( P = 0.361), respectively. Patients were further classified into 2 groups by lesion sites, which showed lower recurrence rate ( P = 0.011) and longer LRFI ( P = 0.028) with lesions over the head and ear than other sites. We found that lesion site might be a prognostic factor for keloid recurrence. Adjuvant radiation dose escalation for high-recurrence risk areas (other than the head and ear) might be required.

The impact of radiotherapy on survival after surgical resection of chordoma with minimum five-year follow-up

BACKGROUND CONTEXTLocal control remains a vexing problem in the management of chordoma despite advances in operative techniques and radiotherapy (RT) protocols. Existing studies show satisfactory local control rates with different treatment modalities. However, those studies with minimum follow-up more than 4 years demonstrate increasing rates of local failure. Therefore, mid-term local survival rates may be inadvertently elevated by studies with less than 4 years follow-up. PURPOSEThe purpose of this study is to report the mid-term results of primary spinal chordoma treated with en bloc resection and proton-based RT with minimum 5 years of follow-up. STUDY DESIGN/SETTINGRetrospective, single-center, cohort study. PATIENT SAMPLEPatients undergoing primary surgical excision of a spine or sacral chordoma tumor between 1990 and 2016 at a single-institution were included. Patients were included if they had a local failure at any time, or they had a minimum of 5 years of follow up with no local failure. Patients were excluded if a prior surgical excision was performed or metastases were present at the time of referral. OUTCOME MEASURESThe outcome measures were local recurrence-free interval (LRFI) and overall survival (OS). METHODSDemographic, clinical, oncologic and surgical variables, including margin status, as well as radiation doses and schedule (neoadjuvant, adjuvant, or both) were compared using Wilcoxon rank-sum or chi-squared testing. The goal RT dose was 70 Gray (total) and patients were stratified based on completing (C70) or receiving incomplete (I70) dosing. Overall survival (OS) and local-recurrence free interval (LRFI) were calculated using the Kaplan-Meier method. FUNDING STATEMENTNo funding was obtained for this work. RESULTSSeventy-six patients were included in the final analysis. All patients had a minimum of 5-year follow-up (median 9.3 years, range 5.1–24.7 years). There were no significant clinical differences between the C70 and I70 RT groups. OS was greater for the C70 RT group (5-year OS 82% vs. 63%, p=.001). There was similar OS for the positive margin group (5-year OS 70% vs. 61%, p=.266). LRFI was greater for the C70 RT group (5-year OS 93% vs. 78%, p=.017). There was similar LRFI for the positive margin group (5-year OS 90% versus 87%, p=.810). CONCLUSIONChordoma outcomes trend towards diminishing LRFI rates in the literature. Here we report the results of the operative management of primary spinal chordoma with minimum five year follow-up, the addition of C70 RT to surgical excision conferred a benefit to OS and local recurrence.

Comparison of Different Systemic Therapeutic Regimes in Resectable Soft-Tissue Sarcoma-Results of a Network Meta-Analysis.

Simple SummaryThis analysis was conducted to compare different systemic treatment options in the therapy of localized and resectable soft-tissue sarcoma. We tested these in a network against the current standard of resection with or without radiotherapy, which allowed direct and indirect comparisons. Chemotherapy given after the local therapy and chemotherapy added to regional hyperthermia before the operation were associated with a longer survival and likeliness of being disease free and alive. Chemotherapy tailored to the specific subtype of sarcoma did not improve outcomes. Adjuvant chemotherapy might be more helpful in male rather than female patients.Background: The standard treatment of high-risk soft-tissue sarcoma consists of surgical resection followed by risk-adapted radiation therapy. Further treatment options that may improve local and systemic tumor control, including chemotherapy, are not well established. Due to the heterogeneity of the disease, different systemic approaches as well as their application at different time points have been attempted. Methods: We conducted a systematic literature search for randomized clinical trials in the treatment of localized, resectable high-risk adult soft-tissue sarcoma comparing different treatment modalities according to the PRISMA guidelines. We extracted published hazard ratios and number of events for the endpoints overall and disease-free survival (OS; DFS) as well as local and distant recurrence-free interval (LRFI; DRFI). The different modalities were compared in a network meta-analysis against the defined standard treatment surgery ± radiotherapy using the inverse-variance heterogeneity model. Results: The literature search identified 25 trials including 3453 patients. Five different treatment modalities were compared in the network meta-analysis. The addition of adjuvant chemotherapy significantly improved OS compared to surgery ± radiotherapy alone (HR = 0.86; CI-95%: 0.75–0.97; p = 0.017). Likewise, neoadjuvant chemotherapy combined with regional hyperthermia (naCTx + HTx) also led to superior OS (HR = 0.45; CI-95%: 0.20–1.00; p = 0.049). Both neoadjuvant chemotherapy alone (naCTx) and perioperative chemotherapy (periCTx) did not improve OS (HR = 0.61; CI-95%: 0.29–1.29; p = 0.195 and HR = 0.66; CI-95%: 0.30–1.48; p = 0.317, respectively). Histology-tailored chemotherapy (htCTx) also did not improve survival compared to surgery ± radiotherapy (HR = 1.08; CI-95%: 0.45–2.61; p = 0.868). The network analysis of DFS, LRFI, and DRFI revealed a similar pattern between the different treatment regimens. Adjuvant chemotherapy significantly improved DFS, LRFI, and DRFI compared to surgery ± radiotherapy. In direct comparison, this advantage of adjuvant chemotherapy was restricted to male patients (HR = 0.78; CI-95%: 0.65–0.92; p = 0.004) with no effect for female patients (HR = 1.08; CI-95%: 0.90–1.29; p = 0.410). Conclusions: Standardized chemotherapy in high-risk soft-tissue sarcoma appears to be of added value irrespective of timing. The benefit of adjuvant chemotherapy seems to be restricted to male patients. The addition of regional hyperthermia to neodjuvant chemotherapy achieved the best effect sizes and might warrant further investigation.

The Biological and Clinical Significance of Glutaminase in Luminal Breast Cancer.

Simple SummaryCertain nutrients are needed by cancers to grow. Some breast cancers need the nutrient glutamine to grow and without it they don’t grow as quickly. In this study, we wanted to know the role of an enzyme, glutaminase, which is a substance produced by the body that breaks down glutamine so it can be used by cancers to grow. This enzyme occurs as two different types but we don’t know what their roles are in breast cancer. We therefore looked at the two types of enzyme in over 7000 breast cancers. We found that patients with high amounts of enzyme in early forms of breast cancer died earlier. Therefore, this enzyme has an important role in breast cancer and could be used to identify cancers which will get worse. We also think that using a drug to stop this enzyme will stop cancers growing. More studies are needed to confirm this.The glutamine metabolism has a key role in the regulation of uncontrolled tumour growth. This study aimed to evaluate the expression and prognostic significance of glutaminase in luminal breast cancer (BC). The glutaminase isoforms (GLS/GLS2) were assessed at genomic/transcriptomic levels, using METABRIC (n = 1398) and GeneMiner datasets (n = 4712), and protein using immunohistochemistry in well-characterised cohorts of Oestrogen receptor-positive/HER2-negative BC patients: ductal carcinoma in situ (DCIS; n = 206) and invasive breast cancer (IBC; n = 717). Glutaminase expression was associated with clinicopathological features, patient outcome and glutamine-metabolism-related genes. In DCIS, GLS alone and GLS+/GLS2- expression were risk factors for shorter local recurrence-free interval (p < 0.0001 and p = 0.001, respectively) and remained prognostic factors independent of tumour size, grade and comedo necrosis (p = 0.0008 and p = 0.003, respectively). In IBC, GLS gene copy number gain with high mRNA expression was associated with poor patient outcome (p = 0.011), whereas high GLS2 protein was predictive of a longer disease-free survival (p = 0.006). Glutaminase plays a role in the biological function of luminal BC, particularly GLS in the early non-invasive stage, which could be used as a potential biomarker to predict disease progression and a target for inhibition. Further validation is required to confirm these observations, and functional assessments are needed to explore their specific roles.

Comparison of Different Systemic Therapeutic Regimes in Resectable Soft Tissue Sarcoma – Results of a Network Meta-Analysis

Background: The standard treatment of high-risk soft tissue sarcoma consists of surgical resection followed by risk-adapted radiation therapy. Further treatment options which may improve local and systemic tumor control, including chemotherapy, are not well established. Due to the heterogeneity of the disease, different systemic approaches as well as their application at different time points have been attempted. Methods: We conducted a systematic literature search for randomized clinical trials in the treatment of localized, resectable high-risk adult soft tissue sarcoma comparing different treatment modalities according to the PRISMA guidelines. We extracted published hazard ratios and number of events for the endpoints overall and disease-free survival (OS; DFS) as well as local and distant recurrence-free interval (LRFI; DRFI). The different modalities were compared in a network meta-analysis against the defined standard treatment surgery ± radiotherapy using the inverse-variance heterogeneity model. Results: The literature search identified 25 trials including 3453 patients. Five different treatment modalities were compared in the network meta-analysis. The addition of adjuvant chemotherapy significantly improves OS compared to surgery ± radiotherapy alone (HR =0.86; CI-95%: 0.75-0.97; p=0.017). Likewise, neoadjuvant chemotherapy combined with regional hyperthermia (naCTx+HTx) also led to superior OS (HR =0.45; CI-95%: 0.20-1.00; p=0.049). Neoadjuvant chemotherapy alone (naCTx) and perioperative chemotherapy (periCTx) both did not improve OS (HR =0.61; CI-95%: 0.29-1.29; p=0.195) and (HR=0.66; CI-95%: 0.30-1.48; p=0.317), respectively. Histology-tailored chemotherapy (htCTx) also did not improve survival compared to surgery ± radiotherapy (HR =1.08; CI-95%: 0.45-2.61; p=0.868). The network analysis of DFS, LRFI and DRFI revealed a similar pattern between the different treatment regimens. Adjuvant chemotherapy significantly improved DFS, LRFI and DRFI compared to surgery ± radiotherapy The subgroup analysis of adjuvant chemotherapy was In direct comparison this advantage of adjuvant chemotherapy was restricted to male patients (HR=0.78; CI-95%: 0.65-0.92; p=0.004) with no effect for female patients (HR=1.08; CI-95%: 0.90-1.29; p=0.410). Conclusions: Standardized chemotherapy in high-risk soft tissue sarcoma appears to be of added value irrespective of timing. The benefit of adjuvant chemotherapy seems to be restricted to male patients. The addition of regional hyperthermia to neodjuvant chemotherapy achieved the best effect sizes and might warrant further investigation. Funding: None to declare. Declaration of Interest: None to declare.

Breast-Conserving Therapy in Patients with cT3 Breast Cancer with Good Response to Neoadjuvant Systemic Therapy Results in Excellent Local Control: A Comprehensive Cancer Center Experience.

Many cT3 breast cancer patients are treated with mastectomy, regardless of response to neoadjuvant systemic therapy (NST). We evaluated local control of cT3 patients undergoing breast-conserving therapy (BCT) based on magnetic resonance imaging (MRI) evaluation post-NST. In addition, we analyzed predictive characteristics for positive margins after breast-conserving surgery (BCS). All cT3 breast cancer patients who underwent BCS after NST between 2002 and 2015 at the Netherlands Cancer Institute were included. Local recurrence-free interval (LRFI) was estimated using the Kaplan-Meier method, and predictors for positive margins were analyzed using univariable analysis and multivariable logistic regression. Of 114 patients undergoing BCS post-NST, 75 had negative margins, 16 had focally positive margins, and 23 had positive margins. Of those with (focally) positive margins, 12 underwent radiotherapy, 6 underwent re-excision, and 21 underwent mastectomy. Finally, 93/114 patients were treated with BCT (82%), with an LRFI of 95.9% (95% confidence interval [CI] 91.5-100%) after a median follow-up of 7 years. Predictors for positive margins in univariable analysis were hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) subtype, lobular carcinoma, and non-mass enhancement (NME) on pre-NST MRI. MRI response was not correlated to positive margins. In multivariable regression, the odds of positive margins were decreased in patients with HER2-positive (HER2+; odds ratio [OR] 0.27, 95% CI 0.10-0.73; p=0.01) and TN tumors (OR 0.17, 95% CI 0.03-0.82; p=0.028). A trend toward positive margins was observed in patients with NME (OR 2.38, 95% CI 0.98-5.77; p=0.055). BCT could be performed in 82% of cT3 patients in whom BCT appeared feasible on post-NST MRI. Local control in these patients was excellent. In those patients with HR+/HER2- tumors, NME on MRI, or invasive lobular carcinoma, the risk of positive margins should be considered preoperatively.

Distance to isocenter is not associated with an increased risk for local failure in LINAC-based single-isocenter SRS or SRT for multiple brain metastases

PurposeTo evaluate the impact of the distance between treatment isocenter and brain metastases on local failure in patients treated with a frameless linear-accelerator-based single-isocenter volumetric modulated arc (VMAT) SRS/SRT for multiple brain metastases. Methods and materialsPatients treated with SRT for brain metastases (BM) between April 2014 and May 2019 were included in this retrospective study. BM treated with a single-isocenter multiple-target (SIMT) SRT were evaluated for local recurrence-free intervals in dependency to their distance to the treatment isocenter. A Cox-regression model was used to investigate different predictor variables for local failure. Results were compared to patients treated with a single-isocenter-single-target (SIST) approach. ResultsIn total 315 patients with a cumulative number of 1087 BM were analyzed in this study of which 140 patients and 708 BM were treated with SIMT SRS/SRT. Median follow-up after treatment was 13.9 months for SIMT approach and 11.9 months for SIST approach. One-year freedom from local recurrence was 87% and 94% in the SIST and SIMT group, respectively. Median distance to isocenter (DTI) was 4.7 cm (range 0.2–10.5) in the SIMT group. Local recurrence-free interval was not associated with the distance to the isocenter in univariable or multivariable Cox-regression analysis. Multivariable analysis revealed only volume as an independent significant predictor for local failure (p-value <0.05). ConclusionSRS/SRT using single-isocenter VMAT for multiple targets achieved high local metastases control rates irrespective of distance to the isocenter, supporting efficacy of single-isocenter stereotactic radiation therapy for multiple brain metastases.

Predictive Factors of Early Recurrence in Patients with Phyllodes Tumor of the Breast.

Phyllodes tumor (PT) is a rare entity accounting for 1% of breast neoplasms with a high propensity of recurrence. This study aimed to identify factors that are predictive of early recurrence in patients with PT. This study reviewed clinical data of patients with PT (n=57) treated at our tertiary care referral center in South India between February 2010 and December 2019. The Pearson χ2 test was used to investigate the relationship between patient's clinical features and tumor histotypes. Survival curves were obtained using the Kaplan-Meier method based on the log-rank test. Multivariate Cox regression analyses were performed to identify predictors of early recurrence or local recurrence-free-interval (LRFI). The mean age was 38.3 [standard deviation (SD)=13.6] years, and the mean follow-up was 18 (SD=13.5) months. The median tumor size was 5 cm (interquartile range 3 and range: 3-22 cm). Moreover, 64.9% (n=37) of the tumors were benign, 21.1% (n=12) were borderline, and 14% (n=8) were malignant. Of the 57 patients, 17 (29.8%) developed local recurrence and one developed distant metastasis. Of the 17 patients, three were unwilling to undergo completion surgery. The median LRFI was 20 (range: 7-60) months. Multivariate cox regression analyses showed that mitotic rate >10/high power field [hazard ratio (HR) 0.147; p=0.04], stromal overgrowth (HR: 4.904; p=0.05), margin status (HR: 0.037; p<0.001), and preoperative neutrophil-to-lymphocyte ratio [(NLR), HR: 4.891; p=0.04)] were significant predictors of LRFI. A high mitotic rate, positive margin, stromal overgrowth, and NLR >3.5 were associated with early recurrence. These attributes mandate stringent follow-up, especially in a resource-limited setting.

20-year assessment of metastatic latency and subsequent time to death after proton therapy for uveal melanomas.

The aim of this study was to evaluate metastatic latency and survival after the occurrence of metastases in patients with choroidal/ciliary body melanoma treated with proton therapy. This was a retrospective cohort study. All consecutive patients with choroidal/ciliary body melanoma treated with proton therapy between 1991 and 2010 were included. Overall survival, specific survival (SS), local recurrence-free interval, and metastasis-free interval (MFI) were calculated. There were 508 patients. The mean follow-up was 239.4 months. Overall survival and SS rates were 57.2 and 67.6% at 10 years. Pre-equatorial tumor location, advanced tumor stage, and initial exudative retinal detachment were associated independently with SS. Thirty-three percent of the patients (n = 169) had metastases. Local recurrence-free interval and MFI were 91.3 and 65.7% at 10 years, respectively. MFI was shorter in pre-equatorial, large tumors, and/or tumors with exudative retinal detachment. After the occurrence of metastases, the median survival time was 1.25 years and survival probabilities were 62.1% at 1 year, 26.0% at 2 years, and 6.0% at 5 years. Except for age, none of the baseline clinical factors was associated with survival after metastasis occurrence. SS after metastasis occurrence was longer for metastasis occurring more than 10 years after tumor diagnosis (P =0.010). Death after metastasis is independent of initial tumor characteristics. Small tumors still have a risk for metastases after 10 years. Thus, lifelong follow-up is necessary for uveal melanoma patients. Larger series of metastatic patients are needed to evaluate aggressive multimodal treatments of metastases. Death after metastasis is independent of the initial tumor characteristics. Small tumors contraintuitively have a long-life risk of metastases. MFI is associated independently with pre-equatorial location, tumor stage, and retinal detachment.

Results of laparoscopic resection in high-risk rectal cancer patients.

Obesity, neoadjuvant-radiotherapy, tumour proximity to the anal verge and previous abdominal surgery are factors that might increase the intra-operative difficulty of laparoscopic rectal cancer surgery. However, whether patients with these 'high-risk' characteristics are subject to worse short- or long-term outcomes is debated. The aim of this study is to examine the short- and long-term clinical and oncological outcomes of patients receiving laparoscopic rectal surgery with any of these high-risk characteristics and compare them with patients that do not possess any of these high-risk features. For the purpose of this study data from consecutive patients receiving laparoscopic rectal cancer resections between 2006 and 2016 from two centres were analysed. High-risk patients were defined as patients with either one of the following characteristics: BMI ≥ 30, neoadjuvant chemoradiotherapy, tumour < 8cm from the anal verge and previous abdominal surgery. A total of 313 patients were identified (227 high risk, 86 low risk). Short-term outcomes were similar between the two groups with the exception of blood loss and length of stay, which were higher in the high-risk group (10 vs 2.5ml, p = 0.045; 7 vs 5days, p = 0.001). There were no statistically significant differences in 5-year overall survival (79.7% vs 79.8%, p = 0.757), disease-free survival (76.8% vs 69.3%, p = 0.175), distant disease-free interval (84.8% vs 79.7%, p = 0.231) and local recurrence-free interval (100%, 97.4%, p = 0.162) between the two groups. Similar short- and long-term outcomes can be achieved in high-risk and low-risk patients receiving laparoscopic rectal surgery. The presented data support the suitability of laparoscopic surgery for this group of patients.

Comparison of different systemic therapeutic regimes in resectable high-risk soft tissue sarcoma: Results of a network meta-analysis.

11549 Background: The treatment of high-risk soft tissue sarcoma of the trunk or the extremities consists of surgical resection with risk-adapted radiation therapy. Further treatment options which can significantly improve local and systemic tumor control including chemotherapy are not well established. Due to the heterogeneity of disease different systemic approaches as well as their application during different time points have been attempted. Methods: We conducted a literature search for randomized clinical trials in the treatment of localized, resectable high-risk soft tissue sarcoma comparing different treatment modalities according to the PRISMA guidelines. We extracted published hazard ratios and number of events for the endpoints of overall and disease-free survival (OS; DFS) as well as local and distant recurrence-free interval (LRFI; DRFI). The different modalities were compared in a network meta-analysis against the defined standard treatment surgery ± radiotherapy using the inverse-variance heterogeneity model (ivhet) with the help of the Microsoft Excel add-in Meta-XL V5.3. Results: The literature search identified 25 studies including 3489 patients. The network analysis showed that adjuvant chemotherapy (adjCTx) results in a significant improvement in overall survival (HR = 0.86; CI-95%: 0.75-0.97; p = 0.017) compared to the standard treatment of surgery ± radiatherapy alone. Combined treatment with regional hyperthermia and neoadjuvant chemotherapy (HTx+nadjCTx) also improves OS (HR = 0.45; CI-95%: 0.20-1.00; p = 0.049). Preoperative chemotherapy alone (nadjCTx) as well as perioperative chemotherapy (periopCTx) resulted both in non-statistically significant improvements in OS (HR = 0.61; CI-95%: 0.29-1.29; p = 0.195) and (HR = 0.48; CI-95%: 0.15-1.55; p = 0.218). Histology-tailored neoadjuvant chemotherapy (tNaCTx) also showed no effect on overall survival (HR = 1.08; CI-95%: 0.45-2.61; p = 0.868). The analysis of DFS, LRFI and DRFI disclosed a similar pattern between the different treatment regimens. Conclusions: The addition of cytotoxic chemotherapy in resectable high-risk soft tissue sarcomas provides a measurable benefit in overall survival. Shifting of systemic therapy to the neoadjuvant setting and combination with regional hyperthermia might be favored. Predictive clinical and molecular markers are needed to evaluate and limit potentional risks prospectively going forward.

Collagen (XI) alpha-1 chain is an independent prognostic factor in breast ductal carcinoma in situ

Collagen11A1 (COL11A1) is a fibrillary type collagen constituting a minor component of the extracellular matrix and plays role in tissue tensile strength. Overexpression of COL11A1 expression is associated with aggressive behavior and poor outcome in several human malignancies. In this study, we evaluated the association between COL11A1 expression and clinicopathological parameters of the breast ductal carcinoma in situ (DCIS) and its prognostic value. COL11A1 protein expression was assessed immunohistochemically in a large well-characterized cohort of DCIS including pure (n = 776) and DCIS associated with invasive carcinoma (DCIS-mixed, n = 239). COL11A1 expression was assessed in tumor cells and surrounding stromal cells, and correlated with clinicopathological parameters, immunoprofile and disease outcome. In pure DCIS, high COL11A1 expression was observed in tumor cells and surrounding stromal cells in 25 and 13% of cases, respectively. Higher COL11A1 expression within the stromal cells was associated with hormone receptor negative, HER2 enriched and triple negative molecular subtypes and showed a positive linear correlation with proliferation index, dense tumor infiltrating lymphocytes and hypoxia-inducible factor 1 alpha. COL11A1 expression in tumor and stromal cells was significantly higher in DCIS associated with invasive carcinoma than in pure DCIS, and within the DCIS-mixed cohort, the invasive component showed higher COL11A1 expression than the DCIS component (all, p < 0.0001). Overexpression of stromal COL11A1 was an independent predictor of shorter local recurrence-free interval for all recurrences (HR = 13.2, 95% CI = 6.9–25.4, p < 0.0001) and for invasive recurrences (HR = 11.2, 95% CI = 4.9–25.8, p < 0.0001). When incorporated with other risk factors, stromal COL11A1 provided better patient risk stratification. DCIS with higher stromal COL11A1 expression showed poor outcome even with adjuvant radiotherapy management. In conclusion, overexpression of stromal COL11A1 is associated with invasive recurrence in DCIS and is a potential marker to predict the response to radiotherapy.

Legumain is an independent predictor for invasive recurrence in breast ductal carcinoma in situ

Legumain is a proteolytic enzyme that plays a role in the regulation of cell proliferation in invasive breast cancer. Studies evaluating its role in ductal carcinoma in situ (DCIS) are lacking. Here, we aimed to characterize legumain protein expression in DCIS and evaluate its prognostic significance. Legumain was assessed immunohistochemically in a tissue microarray of a well-characterized cohort of DCIS (n = 776 pure DCIS and n = 239 DCIS associated with invasive breast cancer (DCIS-mixed)). Legumain immunoreactivity was scored in tumor cells and surrounding stroma and related to clinicopathological parameters and patient outcome. High legumain expression was observed in 23% of pure DCIS and was associated with features of high-risk DCIS including higher nuclear grade, comedo necrosis, hormone receptor negativity, HER2 positivity, and higher proliferation index. Legumain expression was higher in DCIS associated with invasive breast cancer than in pure DCIS (p < 0.0001). In the DCIS-mixed cohort, the invasive component showed higher legumain expression than the DCIS component (p < 0.0001). Legumain was an independent predictor of shorter local recurrencefree interval for all recurrences (p = 0.0003) and for invasive recurrences (p = 0.002). When incorporated with other risk factors, legumain provided better patient risk stratification. High legumain expression is associated with poor prognosis in DCIS and could be a potential marker to predict DCIS progression to invasive disease.

Prolyl-4-hydroxylase \u0391 subunit 2 (P4HA2) expression is a predictor of poor outcome in breast ductal carcinoma in situ (DCIS)

BackgroundExtracellular matrix (ECM) plays a crucial role in tumour behaviour. Prolyl-4-hydroxlase-A2 (P4HA2) is a key enzyme in ECM remodelling. This study aims to evaluate the prognostic significance of P4HA2 in breast ductal carcinoma in situ (DCIS).MethodsP4HA2 expression was assessed immunohistochemically in malignant cells and surrounding stroma of a large DCIS cohort comprising 481 pure DCIS and 196 mixed DCIS and invasive carcinomas. Outcome analysis was evaluated using local recurrence free interval (LRFI).ResultsHigh P4HA2 expression was detected in malignant cells of half of pure DCIS whereas its expression in stroma was seen in 25% of cases. Higher P4HA2 expression was observed in mixed DCIS cases compared to pure DCIS both in tumour cells and in stroma. High P4HA2 was associated with features of high risk DCIS including younger age, higher grade, comedo necrosis, triple negative and HER2-positive phenotypes. Interaction between P4HA2 and radiotherapy was also observed regarding the outcome. High P4HA2 expression was an independent prognostic factor in predicting shorter LRFI.ConclusionP4HA2 plays a role in DCIS progression and can potentially be used to predict DCIS outcome. Incorporation of P4HA2 with other clinicopathological parameters could refine DCIS risk stratification that can potentially guide management decisions.

Gamma knife radiosurgery for residual or recurrent intracranial hemangiopericytomas

Residual or recurrent hemangiopericytoma (HPC) has been treated with radiosurgery; however, its long-term outcome is not well known. This study is to investigate the long-term outcome of gamma knife radiosurgery (GKS) for residual or recurrent HPCs. We conducted a retrospective analysis of 18 patients who underwent gamma knife radiosurgery for residual or recurrent HPCs. Of the 18 patients, 10 patients had high-grade HPCs (27 tumors) and 8 had low-grade HPCs (13 tumors). Median overall survival (OS) after the first GKS was 134.7months and actuarial survival rate at 1, 5, and 10years was 85.6%, 85.6%, and 37.4%, respectively. At the last follow-up, local tumor control was achieved in 32 (80.0%) of the 40 GKS-treated tumors. New lesions developed out of initial GKS target in 8 patients (44.4%). They were also treated with additional GKS. The actuarial local control rate of 40 tumors at 1-, 3-, and 5-years was 89.3%, 60.9%, and 37.5%, respectively. The median local recurrence-free interval of 40 tumors after initial GKS for each lesion was 86.1months for low-grade and 40.5months for high-grade tumors (p=0.010). Extracranial metastases developed in 7 (38.9%) patients with high-grade pathology and became a cause of death in 3 patients. Intracranial tumor control can be achieved over the long term, though additional GKS is frequently necessary. Extracranial metastasis is common in HPC of high-grade pathology. Close surveillance and aggressive treatment is recommended not only for intracranial tumor but also for possible extracranial metastases.

Stereotactic radiation therapy for liver metastases: factors affecting local control and survival.

PurposeTo report on outcome and toxicity of stereotactic body radiotherapy (SBRT) for liver metastases in patients not eligible for surgery.MethodsFrom 2000 to 2009, 74 patients with 91 liver metastases from different primaries have been treated with SBRT at our institution. Median planning target volume was 123 ccm (range: 10.6-1074 ccm). Treatment consisted of 3–5 fractions with 5–12.5 Gy/ fraction prescribed to the surrounding 60-95% isodose with daily image guidance. Regular follow-up included CT or MRI imaging until tumor progression.ResultsMedian local recurrence-free interval was 23 months with a local control rate of 74.7%, 48.3% and 48.3% after 1, 2 and 3 years. Only minimum biologically effective dose (BED) to gross tumor volume (GTV) remained as independent significant factor for local control in multivariate analysis. No local recurrences were observed in lesions (n = 12) which received a minimal BED to the GTV of 120 Gy. Including 26 local recurrences, 67 patients (91%) showed disease progression after SBRT with a median time of 5 months. Median overall survival was 27 months with survival rates of 77%, 30% and 27% at 1, 3 and 5 years. On multivariate analysis only GTV volume remained as independent significant prognostic factor for overall survival (p = 0.002). No grade 3 to 5 acute toxicity and no grade 4 or 5 late toxicity occurred.ConclusionSBRT for liver metastases was well tolerated in this non-selected patient cohort and yielded good local control despite the considerable size of most lesions treated. Long-term survival is possible after SBRT.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-015-0369-9) contains supplementary material, which is available to authorized users.

A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil–epirubicine–cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000)

BackgroundStandard adjuvant chemotherapy regimens for patients with node positive (N+) breast cancer consisted of anthracycline followed by taxane. The European Association for Research in Oncology embarked in 2000 on a phase III trial comparing 6 cycles of FEC100 versus 4 FEC100 followed by 4 Taxol. Primary end-point was disease free survival. Secondary end-points were overall survival, local recurrence free interval, metastases free interval and safety. Patients and methodsBetween March 2000 and December 2002, 837 patients were randomised between 6FEC100 for 6 cycles (417patients) or FEC100 for 4 cycles then Taxol 175mg/m2/3 weeks for 4 cycles (4FEC100-4T) (420 patients). One thousand patients had been planned initially but the trial was closed earlier due to slow accrual. ResultsHazard ratios (HRs) were 0.99 for disease-free survival (DFS) (95%CI: 0.77–1.26; p=0.91), and 0.85 for overall survival (OS) (95%CI: 0.62–1.15; p=0.29). Nine-year DFS were 62.9% versus 62.5% for 6FEC100 and 4FEC100-4T, respectively. Nine-year OS were 73.9% versus 77% for 6FEC100 and 4FEC100-4T, respectively. Toxicity analyses based on 803 evaluable patients showed that overall grade 3–4 toxicities were similar in both arms (63% versus 58% for 6FEC100 arm and 4FEC100-4T arm, respectively; p=0.16). ConclusionIn this trial replacing the last 2 FEC100 cycles of 6FEC100 regimen by 4 Taxol does not lead to a discernable DFS or OS advantage. The lack of a significant difference between the randomised treatment arms may however be due to a lack of power of this trial to detect small, yet clinically worthwhile, treatment benefits.

Abstract P5-10-05: A Phase III Adjuvant Randomized Trial of 6 Cycles of 5-Fluorouracil - Epirubicine-Cyclophosphamide (FEC100) Versus 4 FEC 100 Followed by 4 Taxol (FEC-T) in Node Positive Breast Cancer Patients (Trial B2000)

Abstract The risk of relapse after local therapy remains unacceptable for the majority of patients with early stage breast cancer. Adjuvant chemotherapy has been shown to prolong both disease-free survival (DFS) and overall survival. Several large phase III trials addressing the benefit of adding a taxane to conventional anthracycline-based regimen in early breast cancer showed a significant improves DFS in node-positive breast cancer patients. Taxane-based regimen seems to be more toxic in terms of myelosuppression. There seem to be fewer cardiac events after the taxane-based regimen attributable to the lower anthracycline cumulative dose. Therefore, the optimal adjuvant treatment in node positive breast cancer is still debated and several attempts are made to identify the patients, who will benefit most of taxane. The primary end point of this phase III randomized trial was to compare chemotherapy with 6 cycles of FEC100 versus 4 cycles of FEC100 followed by 4 cycles of Taxol, in patients with non-metastatic breast cancer with lymph node invasion (N+), in terms of DFS assessed by Kaplan-Meier analysis. The secondary end-points were overall survival (OS), local recurrence free interval, metastases free interval and tolerance. Material and Methods Between 10.3.2000 and 31.12.2002, 837 patients with invasive non-metastatic N+ breast cancer were randomized between (arm A) epirubicine 100 mg/m2 plus 5FU 500 mg/m2 plus cyclophosphamide 500 mg/m2 every 3 weeks (w) (FEC) for 6 cycles (417 patients) or (arm B) FEC every 3 w for 4 cycles then taxol 175 mg/m2 every 3 w for 4 cycles (FEC-T) (420 patients). Hormone-receptor-positive patients received either tamoxifen or anti-aromatize depending of their menopausal status, for 5 years after chemotherapy. Results The patients’ characteristics were well balanced between the 2 arms. The mean number of N+ was 4.5. Seventy-three % of the patients had oestrogen receptor positive (RO+) and 62 % progesterone receptor positive (RP+). The hazard ratio for DFS was 0.986 (95% confidence limits 0.773 — 1.257, P = 0.91). Five-year DFS rates were 78.5% with FEC and 78.4% with FEC-T. Nine-year DFS rates were 62.9% with FEC and 62.5% with FEC-T. The hazard ratio for OS was 0.848 (95% confidence limits 0.622 — 1.155, P = 0.29). The 5-y-OS was 86.1 % with FEC and 88.6 % with FEC-T) and the 9-y-OS was 73.9 % and 77 % respectively. The incidence of grade 3 to 4 neutropenia, infection, and nausea were higher with FEC without reaching significativity, neurotoxicity and hypersensitivity reactions were more frequent with FEC-T. There was no statistical difference in cardiac toxicity and febrile neutropenia between the 2 arms. Conclusion The final results of this trial suggest that adding taxol (every 3 weeks regimen) to an anthracycline-based regimen in patients with non-metastatic breast cancer with lymph node invasion (N+), confers little advantage in terms of DFS and OS. However, the present trial was powered to detect a 30% reduction in the risk of recurrence or death. A meta-analysis of all similar trials is needed to rule out smaller differences that could still be clinically worthwhile. This trial was supported by BMS Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-05.