Therapy-free Interval Research Articles

Stereotactic radiotherapy for managing ovarian cancer oligoprogression under poly (ADP-ribose) polymerase inhibitors (PARPi)

ObjectivePoly (ADP-ribose) polymerase inhibitors (PARPi) have become a new standard of care for the maintenance treatment of advanced epithelial ovarian cancer. This study aims to evaluate the efficacy and safety...

Digital transition in rural emergency medicine: Impact of job satisfaction and workload on communication and technology acceptance.

Tele-emergency physicians (TEPs) take an increasingly important role in the need-oriented provision of emergency patient care. To improve emergency medicine in rural areas, we set up the project 'Rural|Rescue', which uses TEPs to restructure professional rescue services using information and communication technologies (ICTs) in order to reduce the therapy-free interval. Successful implementation of ICTs relies on user acceptance and knowledge sharing behavior. We conducted a factorial design with active knowledge transfer and technology acceptance as a function of work satisfaction (high vs. low), workload (high vs. low) and point in time (prior to vs. after digitalization). Data were collected via machine readable questionnaires issued to 755 persons (411 pre, 344 post), of which 304 or 40.3% of these persons responded (194 pre, 115 post). Technology acceptance was higher after the implementation of TEP for nurses but not for other professions, and it was higher when the workload was high. Regarding active communication and knowledge sharing, employees with low work satisfaction are more likely to share their digital knowledge as compared to employees with high work satisfaction. This is an effect of previous knowledge concerning digitalization: After implementing the new technology, work satisfaction increased for the more experienced employees, but not for the less experienced ones. Our research illustrates that employees' workload has an impact on the intention of using digital applications. The higher the workload, the more people are willing to use TEPs. Regarding active knowledge sharing, we see that employees with low work satisfaction are more likely to share their digital knowledge compared to employees with high work satisfaction. This might be attributed to the Dunning-Kruger effect. Highly knowledgeable employees initially feel uncertain about the change, which translates into temporarily lower work satisfaction. They feel the urge to fill even small knowledge gaps, which in return leads to higher work satisfaction. Those responsible need to acknowledge that digital change affects their employees' workflow and work satisfaction. During such times, employees need time and support to gather information and knowledge in order to cope with digitally changed tasks.

Stereotactic body radiotherapy to defer systemic therapy in patients with oligorecurrent disease

BackgroundPatients who develop oligorecurrent disease may be treated with metastasis-directed stereotactic body radiotherapy (SBRT) to defer the start of systemic therapy and delay its potential side effects. We report oncological outcomes and patterns of failure in patients with oligorecurrent disease treated with SBRT and determine which factors impact the interval to initiation of systemic therapy. Material/MethodsThis retrospective study included patients with oligorecurrent disease (≤5 lesions) from any solid organ malignancy, treated with SBRT to all metastases and no systemic therapy for a minimum one month after SBRT between 01/2014 and 12/2019. The Kaplan-Meier method was used to analyze overall survival (OS) and progression-free survival (PFS), and the cumulative incidence of initiation of systemic therapy was analyzed assuming death without systemic therapy as a competing risk. Univariable and multivariable analyses are used to assess predictors of the systemic therapy-free interval. ResultsAmong 545 patients treated with SBRT for oligometastatic disease, 142 patients were treated with SBRT only for oligorecurrent disease. The most common primary tumors were lung and gastrointestinal cancer in 47 (33.1 %) and 28 (19.7 %) patients, respectively. After a median follow-up of 25 months, the median PFS and OS was 6.1 months and 48.9 months, respectively. Distant metastases were the most common first failure, and oligometastatic distant failure occured in 86 patients (60.6 %). New metastases were treated with repeat SBRT in 48 patients (33.8 %). The 1- and 2-year cumulative incidence of initiation of systemic therapy was 24.6 % and 36.8 %, respectively. In multivariable analysis, the number of previous lines of systemic therapy and the cumulative volume of metastases were significantly associated with the interval to initiation of systemic therapy. ConclusionSelected patients with oligorecurrence achieved favorable OS and low cumulative incidence of initiation of systemic therapy. Prospective studies are warranted to determine how the deferral of systemic therapy impacts OS compared with immediate systemic therapy in combination with SBRT.

PERCEPTION: Phase II investigational study of pembrolizumab combination with chemotherapy in platinum-sensitive recurrent low-grade serous ovarian cancer— A NOGGO trial.

TPS5613 Background: Low-grade serous ovarian cancer (LGSOC) represents a minority within the group of invasive epithelial ovarian malignancies. Recent analyses showed a very limited responsiveness to chemotherapy in LGSOC. Since bevacizumab many years ago, none other agents have been approved in LGSOC. There is a high demand of new therapy combinations with modern substances to improve the response rate and prognosis in this group of patients. Immune check-point inhibitors provide a new possibility which showed to be effective in different malignant diseases as well as in selected ovarian cancer patients. In this study, the standard chemotherapy is going to be combined with pembrolizumab in recurrent LGSOC cases with therapy free interval (TFI) over 6 months after last platinum-based chemotherapy. To the authors knowledge no comparable studies have been performed or planned. If our trial should show pembrolizumab effectivity in LGSOC, it would be a signal and impulse for future clinical studies in this rare disease. Methods: PERCEPTION/NOGGO-ov44 (NCT04575961) clinical trial is a multi-center, single-arm phase 2 study to evaluate pembrolizumab therapy concomitant to platinum-based chemotherapy (carboplatin plus pegylated liposomal doxorubicin, carboplatin plus gemcitabine or carboplatin monotherapy) and as maintenance in recurrent low-grade serous ovarian cancer cases. LGSOC patients with progression or recurrence at least six months after most previous platinum-containing therapy and in good general performance (ECOG 0 or 1) are eligible to participate in this clinical trial. The primary objective is the 12 months progression free survival (PFS) rate. Secondary end-points include overall survival, response rate (RR), PFS and RR according to Ki67 expression levels, time to first subsequent therapy (TFST) and its response, safety and quality of life. The trial is planned according to Simon’s two-stage design with total sample size up to 33 patients. The null hypothesis is PFS-rate after 12 months of 20%. In the first phase 18 patients will be enrolled and if at least 5 patients show PFS after 12 months the study is going to be continued with an additional 15 patients. The trial is claimed successful, if at least 11 patients show PFS after 12 months. Assuming a true PFS-rate of 40%, this trial has 5% type I error rate and 80% power. Clinical trial information: NCT04575961.

Chemotherapeutic Regimens and Chemotherapy-Free Intervals Influence the Survival of Patients with Recurrent Advanced Epithelial Ovarian Carcinoma: A Retrospective Population-Based Study.

We aimed to evaluate factors influencing the outcomes of patients with platinum-sensitive recurrent epithelial ovarian carcinoma (EOC). Patients with advanced-stage EOC, who received debulking surgery and adjuvant chemotherapy for recurrence, were obtained from the National Health Insurance Research database of Taiwan between 2000 and 2013. A total of 1038 patients with recurrent advanced-stage EOC were recruited. The platinum + paclitaxel (PT) group had the best five-year overall survival (OS) compared with the other three groups (p < 0.001). The hazard ratios (HRs) of five-year OS for the platinum + liposomal doxorubicin (PD), topotecan (TOP), and pegylated liposomal doxorubicin (PLD) groups were 1.21 (p = 0.07), 1.35 (p = 0.016), and 1.80 (p < 0.001), respectively, compared with the PT group. The PT group also had lower hazard ratios of five-year OS for patients with platinum therapy-free interval (TFIp) between 6 and 12 months compared with the other three groups (p < 0.0001). However, the HRs of five-year OS did not differ between the PT and PD groups in patients with TFIp >12 months. Patients with TFIp >12 months had lower HRs of five-year OS compared with those with TFIp of 6–12 months, regardless of whether they were treated with platinum-based (p = 0.001) or non-platinum-based (p = 0.003) regimens. Chemotherapeutic regimens and TFIp influenced the outcomes of patients with recurrent EOC. For patients with TFIp of 6–12 months, the PT regimen is the first choice based on their best overall survival result. For patients with TFIp >12 months, either platinum-based or non-platinum regimens could be used because of their similar excellent overall survival.

Tumor Growth Rate Estimates Are Independently Predictive of Therapy Response and Survival in Recurrent High-Grade Serous Ovarian Cancer Patients.

Simple SummaryWhile latest evidence suggests that some patients with recurrent high-grade serous ovarian cancer may profit from reinduction with platinum-based chemotherapy regimens, the selection of patients who are likely to respond remains difficult. The present study therefore aimed to adapt a mathematical model, which used frequently available laboratory values to estimate growth rates of recurring tumors as an objectifiable surrogate of both therapy response and patient survival. After clinical validation, the model may help to personalize treatment strategies and thereby increase survival of affected patients.This study aimed to assess the predictive value of tumor growth rate estimates based on serial cancer antigen-125 (CA-125) levels on therapy response and survival of patients with recurrent high-grade serous ovarian cancer (HGSOC). In total, 301 consecutive patients with advanced HGSOC (exploratory cohort: n = 155, treated at the Medical University of Vienna; external validation cohort: n = 146, from the Ovarian Cancer Therapy–Innovative Models Prolong Survival (OCTIPS) consortium) were enrolled. Tumor growth estimates were obtained using a validated two-phase equation model involving serial CA-125 levels, and their predictive value with respect to treatment response to the next chemotherapy and the prognostic value with respect to disease-specific survival and overall survival were assessed. Tumor growth estimates were an independent predictor for response to second-line chemotherapy and an independent prognostic factor for second-line chemotherapy use in both univariate and multivariable analyses, outperforming both the predictive (second line: p = 0.003, HR 5.19 [1.73–15.58] vs. p = 0.453, HR 1.95 [0.34–11.17]) and prognostic values (second line: p = 0.042, HR 1.53 [1.02–2.31] vs. p = 0.331, HR 1.39 [0.71–2.27]) of a therapy-free interval (TFI) < 6 months. Tumor growth estimates were a predictive factor for response to third- and fourth-line chemotherapy and a prognostic factor for third- and fourth-line chemotherapy use in the univariate analysis. The CA-125-derived tumor growth rate estimate may be a quantifiable and easily assessable surrogate to TFI in treatment decision making for patients with recurrent HGSOC.

Recurrence, survival, and therapy-free interval after irreversible electroporation for pancreatic adenocarcinoma

Presenter: Wooil Kwon MD, PhD | Columbia University Background: Locally advanced pancreatic cancer (LAPC) is particularly challenging to treat. Systemic therapy may prolong survival but cannot offer a cure. Patients do not qualify for resection according to international guidelines, but accumulating experience from high volume centers in the modern era of chemotherapy suggest survival benefit in select patients undergoing resection. Recent efforts have focused on expanding surgical options. Irreversible electroporation (IRE) can be used to primarily control tumors in situ or to extend resection margins. This study provides valuable insight on survival, recurrence, and complications from a center that has integrated IRE into its treatment protocols. Methods: Data were collected for patients with T4 pancreatic ductal adenocarcinoma treated with IRE at a single tertiary center from 2012-2020. Those undergoing second IRE or IRE for other diagnoses were excluded. Primary end points included patterns of adjuvant and palliative therapy, overall survival (OS), recurrence free survival (RFS) and Clavien-Dindo complications. Therapy-free interval was defined as time from last neoadjuvant chemotherapy or radiation to the initiation of adjuvant or palliative therapy for recurrence. OS and RFS were evaluated by Kaplan Meier analysis and compared via log-rank test. Potential predictive factors were evaluated by Cox proportional hazard regression. Results: Of 110 patients, 46 underwent in situ IRE and 64 for margin extension. Eight (7.27%) were treated for recurrent pancreatic adenocarcinoma. Patients were similar in baseline characteristics, tumor location, and receipt of neoadjuvant chemotherapy. Median overall tumor size of 3.4 (2.8-4.0) on preoperative imaging was not different between IRE approach (p= 0.2810), Median OS from diagnosis (28.18 months, IQR 15.94-51.91) was similar for in situ vs. resection with margin extension (30.03 vs. 24.59 months, p=0.3298). There was no difference in local/distant RFS (respectively 7.26 vs. 10.59 months, p=0.7543). Both groups were similar with regard to Grades 3-5 90-day complications (28.3% vs. 25.0%, p=0.7018). Univariate Cox regression found no individual predictors of survival or recurrence to be significant. Adjuvant chemotherapy was given to 25.53% of patients who survived beyond 90 days. Thirty-two (34.04%) were not initially treated with adjuvant therapy, but later received treatment for recurrence. This group benefitted from a median therapy-free interval of 12.08 months (9.14-27.59) from last neoadjuvant chemotherapy or radiation, while maintaining similar overall survival (21.09 months vs. 20.96 months for planned adjuvant therapy, p=0.454). Conclusion: Many patients in this series would not have been candidates for traditional surgical resection. Compared to historical controls and studies of systemic therapy alone, this study demonstrates the favorable survival outcomes of IRE. By demonstrating a median one year treatment-free interval from neoadjuvant chemotherapy or radiation, this study highlights the potential for IRE to improve quality of life by limiting the inconveniences and toxicities of systemic therapy and raises questions about the role of adjuvant therapy after maximal neoadjuvant therapy for these selected patients.

Too good for CARMENA: criteria associated with long systemic therapy free intervals post cytoreductive nephrectomy for metastatic clear cell renal cell carcinoma

Purpose The prospective CARMENA trial surprisingly suggested that patients with upfront metastatic clear-cell renal cell carcinoma (m-ccRCC) would not benefit from cytoreductive nephrectomy (CN). We aimed to identify the m-ccRCC patient subpopulation who would benefit from the continued use of CN. Methods We performed a retrospective cohort study on upfront m-ccRCC patients and identified three subgroups: patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) only without CN (TKI ONLY), patients undergoing CN immediately followed within 6 months by VEGFR-TKIs (CN > TKI) and patients undergoing CN followed by a considerable therapy-free interval of at least 6 months (CN > AS). Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare outcomes and investigate predictive factors. Results We included 119 patients. Overall survival was 17, 13 and 56 months for the CN > TKI, TKI only and CN > AS subgroups, respectively (p < 0.0001). Oligometastatic disease (HR = 0.33, 95% CI = 0.21–0.54, p < 0.0001), lung as only metastatic site (HR = 0.48, 95% CI = 0.31–0.76, p = 0.001) and having ≤ 2 evaluable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (HR = 0.56, 95% CI = 0.32–0.98, p = 0.04) were predictive for systemic therapy free survival after diagnosis. Conclusions The CARMENA results only apply for m-ccRCC patients in immediate need for systemic therapy, but not for patients in whom a period of AS can be expected after CN. Patients in whom systemic therapy most likely can be deferred and who are likely to benefit from CN have oligometastatic disease, only present in the lung and few (≤2) evaluable IMDC criteria.

Retrospective Multicenter Analysis of the Outcome of a Re-Induction with Immune Checkpoint Inhibitors in Advanced Merkel Cell Carcinoma

Significant progress has been made in the treatment of advanced Merkel cell carcinoma (MCC) by establishing immune checkpoint inhibitors (ICI). Tumor progression, durable response, or adverse events may lead to ICI discontinuation in MCC patients. If in these patients tumor progression occurs, the question remains if re-induction with ICI achieves renewed tumor response. This retrospective multicenter study evaluated patients in with re-induction of anti-PD-1/anti-PD-L1 therapy for advanced MCC. Clinical data were extracted at treatment initiation, tumor response, treatment cessation, and subsequent tumor response to re-induction. Eight patients from seven centers (mean age 67.8 years) were included. The median duration of initial therapy with anti-PD-1/anti-PD-L1 was 9.6 months (2–21 months). Two patients achieved complete response (CR), four patients partial response (PR), one patient stable disease (SD), while in one patient progressive disease (PD) occurred as best overall response (BOR) to ICI. Reason for discontinuation of ICI was PD in three patients and severe adverse events in five patients. Following a median anti-PD-1/anti-PD-L1 therapy-free interval of 9.5 months (3–18 months), re-induction with ICI therapy was initiated. Five of eight patients (62.5%) achieved an objective response upon re-induction, while in three patients, no response could be observed. Notably, adverse events, which had led to the discontinuation of the first ICI treatment line, were not observed upon re-induction. The initial response to immune checkpoint inhibitors seems to be an important marker for successful re-induction. Interestingly, adverse events leading to treatment discontinuation were not observed during re-induction.

Oncological Outcomes of Metastasis-Directed Therapy in Oligorecurrent Prostate Cancer Patients Following Radical Prostatectomy.

Several retrospective and a few prospective studies have shown that metastasis-directed therapy (MDT) could delay clinical progression and postpone the initiation of systemic treatment in oligorecurrent prostate cancer (PCa) patients. However, these endpoints are strongly influenced by variables such as concomitant use of androgen deprivation therapy (ADT) and follow-up imaging protocols. The aim of this manuscript was to assess palliative ADT- and metastatic castration-resistant prostate cancer (mCRPC)-free survival as long-term oncological outcomes in oligorecurrent PCa treated by MDT. We retrospectively identified consecutive post-prostatectomy oligorecurrent PCa patients treated by MDT (salvage lymphadenectomy, radiotherapy, or metastasectomy) at our tertiary referral center. Patients were eligible for inclusion if they developed recurrence following radical prostatectomy, had ≤5 metastatic lesions on imaging and had a serum testosterone >50 ng/dL or a testosterone suppression therapy-free interval of >2 years prior to the first MDT as an assumption of recovered serum testosterone (if no testosterone measurement available). Patients with castration-resistant or synchronous oligometastatic PCa at the time of first MDT were excluded. Repeated MDTs were allowed, as well as a period of concomitant ADT. Kaplan–Meier analyses were performed to assess palliative ADT-free and mCRPC-free survival. We identified 191 eligible patients who underwent MDT. Median follow-up from first MDT until last follow-up or death was 45 months (IQR 27–70; mean 51 months). Estimated median palliative-ADT free survival was 66 months (95% CI 58–164) and estimated median mCRPC-free survival was not reached (mean 117 months, 95% CI 103–132). In total, 314 MDTs were performed and 25 patients (13%) received ≥3 MDTs. This study demonstrated that (repeated) MDT is feasible and holds promise in terms of palliative ADT-free and mCRPC-free survival for patients with oligorecurrent PCa. However, these findings should be confirmed in prospective randomized controlled trials.

Progress of MM/CML treatment and medical economics

Cost-effectiveness of the sequential application of tyrosine kinase inhibitors (TKIs) is an important issue in chronic myelogenous leukemia (CML). Similarly, although overall survival (OS) has tremendously improved, the treatment of multiple myeloma (MM), including 12 new drugs, typically costs more than $100,000 per year. This price should not be judged in isolation but rather evaluated in the context of clinical benefit, which can be assessed by cost-effectiveness analyses such as the total cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. Physicians change drugs several times to prolong individual patient survival over the course of their therapy, which means there are variations in treatment choices and treatment sequence. To achieve a clinical response by each treatment is very important, and the overall response rate and OS are key pieces of information to assess this. The additional treatment goal is sustained minimal residual disease (MRD) negativity. In Japan, medical costs for MM are mostly covered by public health insurance. Modifications in treatment patterns for CML and MM drugs and medical costs for patients are important issues; how to cure the disease or prolong the therapy-free interval with lower costs is an urgent requirement. Total medical costs have remained stable since 2010, but there are important issues to consider in the use of generic drugs, Phase 2 approval of new drugs, and decreasing costs of other care, particularly for hospitalization that includes treatment costs other than that of CML and MM drugs. We must aim for treatment-free remission and a clinical cure in the future. We can stop treatment with a 2-year sustained molecular response (MR)4.5 in CML and MRD negative (<10-5) in MM with full informed consent and careful watch by the BCR-ABL international scale and next-generation flow.

Evaluation of a Rural Emergency Medical Service Project in Germany: Protocol for a Multimethod and Multiperspective Longitudinal Analysis.

BackgroundGerman emergency medical services are a 2-tiered system with paramedic-staffed ambulances as the primary response, supported by prehospital emergency doctors for life-threatening conditions. As in all European health care systems, German medical practitioners are in short supply, whereas the demand for timely emergency medical care is constantly growing. In rural areas, this has led to critical delays in the provision of emergency medical care. In particular, in cases of cardiac arrest, time is of the essence because, with each passing minute, the chance of survival with good neurological outcome decreases.ObjectiveThe project has 4 main objectives: (1) reduce the therapy-free interval through widespread reinforcement of resuscitation skills and motivating the public to provide help (ie, bystander cardiopulmonary resuscitation), (2) provide faster professional first aid in addition to rescue services through alerting trained first aiders by mobile phone, (3) make more emergency physicians available more quickly through introducing the tele-emergency physician system, and (4) enhance emergency care through improving the cooperation between statutory health insurance on-call medical services (German: Kassenärztlicher Bereitschaftsdienst) and emergency medical services.MethodsWe will evaluate project implementation in a tripartite prospective and intervention study. First, in medical evaluation, we will assess the influences of various project measures on quality of care using multiple methods. Second, the economic evaluation will mainly focus on the valuation of inputs and outcomes of the different measures while considering various relevant indicators. Third, as part of the work and organizational analysis, we will assess important work- and occupational-related parameters, as well as network and regional indexes.ResultsWe started the project in 2017 and will complete enrollment in 2020. We finished the preanalysis phase in September 2018.ConclusionsOverall, implementation of the project will entail realigning emergency medicine in rural areas and enhancing the quality of medical emergency care in the long term. We expect the project to lead to a measurable increase in medical laypersons’ individual motivation to provide resuscitation, to strengthen resuscitation skills, and to result in medical laypersons providing first aid much more frequently. Furthermore, we intend the project to decrease the therapy-free interval in cases of cardiac arrest by dispatching first aiders via mobile phones. Previous projects in urban regions have shown that the tele-emergency physician system can provide a higher availability and quality of emergency call-outs in regular health care. We expect a closer interrelation of emergency practices of statutory health insurance physicians with the rescue service to lead to better coordination of rescue and on-call services.International Registered Report Identifier (IRRID)DERR1-10.2196/14358

Ki67 expression as a predictor of chemotherapy outcome in low-grade serous ovarian cancer

ObjectiveLow-grade serous ovarian cancers characterize a unique clinical pattern and lower chemotherapy responsiveness. The expression level of Ki67 is associated with differences in prognosis; however, this has not yet been...

Analysis of prognostic factors and therapeutic patterns of recurrent stage Ⅰb-Ⅱa cervical squamous carcinoma treated with radical hysterectomy

Objective: To analyze the prognosis and appropriate treatment modalities of the patients with recurrence of early stage (Ⅰb-Ⅱa) cervical squamous cancer primarily treated with radical hysterectomy. Methods: This retrospective study included patients with International Federation of Gynecology and Obstetrics (FIGO) stage Ⅰb and Ⅱa recurrent cervical squamous cancer who underwent radical hysterectomy primarily from January 2007 to July 2015. Kaplan-Meier method and Cox regression analysis were performed to analyze related prognostic factors of overall survival and progression-free survival, which included age, postoperative therapy, the site of recurrence, therapy-free interval (TFI) and treatment modality. The patients who were treated with palliative chemotherapy after recurrence were selected as a subgroup. The responses of palliative chemotherapy were evaluated and analyzed among different factors, included TFI, the site of recurrence and chemotherapy regime. Results: Of the 2 071 patients, 116 relapsed Ⅰb-Ⅱa cervical squamous cancer were included in the study with the average age of (45.6±7.2) years old. 3-year progression-free survival rate and 3-year overall survival rate after recurrence were 30.2% and 42.2%, respectively. Univariate analysis implied that postoperative radiotherapy, recurrence site, TFI and treatment modality were associated with progression-free survival (P<0.05), while postoperative radiotherapy, TFI and treatment modality with overall survival (P<0.05). Multivariate analysis showed that TFI and treatment modality were independent prognostic factors for progression-free survival (P<0.05), while postoperative radiotherapy at initial treatment, TFI and treatment modality were independent prognostic variables for overall survival (P<0.05). In the analysis of treatment modality, 3-year progression-free survival rate and 3-year overall survival rate of 47 patients who were treated with definitive local therapy were significantly higher than that of 69 patients who were treated with palliative chemotherapy (P<0.01). In the subgroup analysis of palliative chemotherapy, 15 patients achieved complete response (21.7%) and 16 displayed partial response (23.2%). The overall response rate (ORR) was 44.9%. TFI (P<0.01) and chemotherapy regime (P<0.05) were significant factors associated with ORR. The ORR of TFI ≥12 months was significantly higher than that of TFI <12 months. Besides, the ORR of paclitaxel plus platinum chemotherapy was prominently higher than that of other regimens, while there was no significant difference between the ORR of paclitaxel plus cisplatin and other platinum (P=0.408). Conclusions: For recurrent stageⅠb-Ⅱa cervical squamous carcinoma treated with radical hysterectomy, use of definitive local therapy for suitable patients is advised to achieve better prognosis. In terms of palliative chemotherapy, longer TFI may mean better ORR and the combination of paclitaxel plus platinum is preferred.

Association of Ki67 expression levels and therapy outcome in low-grade serous ovarian cancer.

5577 Background: Low-grade serous ovarian cancers (LGSOC) characterize different clinical pattern and lower chemotherapy responsiveness. The expression level of Ki67 is associated with prognosis differences in this patient group. However, Ki67 has not been evaluated as prognostic marker and a predictor of therapy outcome until now. Methods: Patients with LGSOC and Ki67 expression results were identified in institutional database. Receiver-operator characteristics (ROC) curve analysis was performed to find cut off values of Ki67% to discriminate patients with residual tumor mass after surgery from maximal debulked patients, and platinum sensitive patients from platinum resistant patients. Odd ratios (OR) and 95% confidence intervals (95% CI) were calculated using univariate and multivariate logistic regression analysis. Two-sided tests p &lt; 0.05 and are considered statistically significant at a 95% confidence interval. The statistical analysis was performed with the IBM SPSS Statistics 25.0. Results: A total of 68 patients with LGSOC were included. All patients underwent surgery and 15 (22.1%) patients had residual mass ( &gt; 0 mm) after cytoreduction. Sixty-one (89.7%) patients received platinum based first-line chemotherapy. Forty-three patients revealed a recurrence ≥6 months and eleven &lt; 6 months. Patients with Ki67 &lt; 3.6% had significantly higher therapy-free interval (TFI≥6 months), (OR = 13.9, 95%CI 1.62-118.40, p = 0.016). In the multivariate analysis of TFI over 6 months including CA 125, age at diagnosis, peritoneal carcinomatosis and ascites ( &gt; 500ml) Ki67 &lt; 3.6% remained significant (OR = 17.6, 95%CI 1.56-197.52, p = 0.020). Moreover, Ki67% &gt; 3.6% were associated with higher risk of residual mass after surgery (OR = 6.75, 95%CI 1.39-32.87, p = 0.018). Conclusions: It is the first study showing association between Ki67% expression and duration of TFI to platinum-based chemotherapy as well as outcome of the surgery in LGSOC. Further prospective trials should be planned to develop predictive models in this patients.

Place of death and chemotherapy use at the end of life in colorectal cancer.

e23006 Background: Over the last decades, new drugs and multidisciplinary treatment increased the therapeutic options for palliative treatment of colorectal cancer (CRC). It is unclear, whether these options led to a more aggressive therapy at the end of life. Methods: For this retrospective cohort trial, we identified all stage IV CRC patients who received their complete therapy at an university hospital in Germany and investigated the use of palliative chemotherapy at the end of life (EOL) and the place of death (POD). Results: Between 01/2002 and 12/2012, 245 patients were treated with palliative chemotherapy for stage IV CRC and were evaluable for duration of palliative chemotherapy and place of death. 21% of the patients received chemotherapy within the last 30 days and 9% within 14 days before death. Overall survival of patients with chemotherapy use within the last 30 days of life was significantly shorter compared to patients without chemotherapy in the last month of life (12 vs. 20 months, p = 0.02), duration of palliative chemotherapy was non-significantly shorter (11 vs. 15 months, p = 0.29). Chemotherapy use was significantly more frequent used within 30 days before death from 2009-2012 (24%) compared to 2002-2005 (17%), p = 0.001. 58% of patients died in their residence (at home or in a nursing home), 27% on a general hospital ward (GHW)/ intensive care unit (ICU) and 15% on a palliative care unit (PCU) or hospice. Patients ≥70 years died significantly more often in their residence (70% vs. 53%; p = 0.013). From 2002-2005 to 2010-2012, less patients died in a GHW or ICU of acute care hospitals (39% vs. 16%; p = 0.007). Patients with a distance of ≤45 minutes to our institution more often died at home and in a PCU, Patients with a short therapy-free interval before death more often died in a hospital, (with chemotherapy in the last 30 days: 38%, with chemotherapy in the last 14 days: 45%). Conclusions: Although chemotherapy use at the EOL increased over the decade, more patients were able to die at home. Older patients and patients living in an urban centre more often died at home indicating that conditions for home care have improved independent of the duration of chemotherapy. However, patients with chemotherapy use at the EOL more often die in hospital.

Chemotherapy-associated Liver Injury prior Surgery of Hepatic Colorectal Metastases – Comparison of Functional and Histopathological Damage

Background: Chemotherapy prior liver resection of colorectal liver metastases (CLM) implies the risk of chemotherapy-associated liver injury (CALI) leading to increased postoperative morbidity and mortality. Methods: Retrospective analysis of patients with CLM prior resection. Preoperative assessment of liver function by LiMAx test. Histologic staging of resected tumor-free liver tissue. Analysis of 12-month history of chemotherapy prior surgery including the regime, the number of cycles and the therapy-free interval. Results: A total of 204 patients were analyzed. The majority (n=127; 62 %) had received previous chemotherapy. Impaired LiMAx results were determined in 49% of patients after chemotherapy. The extent of LiMAx impairment was dependent on number of oxaliplatin cycles, therapy-free interval and obesity in multivariate analysis. Patients with impaired LiMAx showed regeneration during chemotherapy cessation. Chemotherapy increased the incidence of steatosis (>33%; 29 vs. 17%) as well as of mild fibrosis (62 vs. 45%). The LiMAx was markedly decreased in steatosis (335 vs. 375 μg/kg/h, P=0.024), steatohepatitis (292 vs. 372 μg/kg/h, P=0.003), and severe fibrosis (318 vs. 395 μg/kg/h, P=0.001). While the degree of steatosis was associated with a short therapy-free interval, the degree of fibrosis was increased by the number of cycles. Conclusion: The LiMAx test enables preoperative assessment of CALI. Acute injury with steatohepatitis deteriorates LiMAx more severely than chronic injury with fibrosis.

Stereotactic body radiotherapy for oligometastatic soft tissue sarcoma.

Stereotactic body radiotherapy (SBRT) is emerging as a novel treatment option in metastatic soft tissue sarcoma (STS). The aim of our study was to evaluate the effectiveness of exclusive SBRT on disease control and survival in oligometastatic (≤ 3 synchronous lesions) STS. In total, 16 consecutive patients, accounting for 26 metastases (including 21 lung and 5 lymph node or soft tissue metastases), were treated at our institution with SBRT. Patient- and treatment-related characteristics were collected. Local control (LC), overall survival (OS), distant metastases-free survival (DMFS), and time to initiation of chemotherapy or best supportive care (corrected disease-free survival, cDFS) were assessed. Four-year OS was 54% and median OS was 69months [95% confidence interval (CI) 20-118months]. LC of 26 lesions at 4years was 78%. Median DMFS and cDFS were 17 (95% CI 5-30months) and 28months (95% CI 5-52months), respectively. Disease-free interval < 24months from primary tumor treatment to first metastasis was the only predictor of reduced LC, cDFS, and OS (p = 0.022, 0.023, and 0.028, respectively). No acute or chronic grade ≥ 3 toxicity was observed. Median follow-up was 36months (IQR 18-71months). In patients with oligometastatic STS, SBRT yields satisfying local control with minimal toxicity. Median OS was 69months. Repeated SBRT may be considered to extend disease-free and systemic therapy-free interval. Increased time from primary tumor to first metastasis identifies patients with potentially greater benefit from SBRT.

Therapy-free interval has prognostic value in patients with recurrent cervical cancer treated with chemotherapy following definitive concurrent chemoradiotherapy.

Patients with cervical cancer recurrence after concurrent chemoradiotherapy (CCRT) who are not candidates for surgical resection or salvage radiotherapy have a dismal prognosis. The predictive factors for the effects of chemotherapy and prognostic factors in these patients were analyzed. We collected data for patients with recurrent cervical cancer who were primarily treated with CCRT between 2000 and 2013. Among them, 57 patients treated with only systemic chemotherapy were analyzed for the overall survival (OS), the overall response rate (ORR), and prognostic factors. The median age was 47years. Inside the irradiated field recurrence occurred in 24, outside in 20 and both in 13 patients. Time to recurrence after the CCRT (i.e., therapy-free interval; TFI) were <6months in 11, 6-12months in 15, ≥12months in 23 patients, and persistent disease in 8 patients. The median OS was 18months and ORR was 15.7%. Those with a longer TFI showed a tendency for better ORR (p=0.051) and those receiving a taxane-containing regimen showed significantly higher ORR (p=0.0232). Multivariate analysis revealed a significant correlation between the median OS and TFI (HR=4.688, 95% CI=2.178-11.10, p<0.0001) and chemotherapy response (HR=20.08, 95% CI=3.936-368.4, p<0.0001). Furthermore, even in patients with stable disease, the median OS increased corresponding to the length of the TFI (p<0.0001). TFI has predictive value for response to chemotherapy and prognosis of patients with recurrent cervical cancer after definitive CCRT.

LiMAx Test Improves Diagnosis of Chemotherapy-Associated Liver Injury Before Resection of Colorectal Liver Metastases.

Chemotherapy of colorectal liver metastases (CLMs) prior to liver resection implies the risk of chemotherapy-associated liver injury, leading to increased postoperative morbidity and mortality OBJECTIVE: The aim of this study was to evaluate the LiMAx (liver maximum capacity) test for diagnosis of chemotherapy-associated liver injury. This was a retrospective analysis of patients with CLMs, prior to liver resection. We performed preoperative assessment of liver function using biochemical parameters and the LiMAx test. The individual history of chemotherapy within 12 months, including regimen, number of cycles, and therapy-free interval were collected, and histopathological evaluation of tumor-free liver tissue was performed in resected patients. A total of 204 patients were included, of whom 127 (62%) had received previous chemotherapy. The LiMAx test was worse after chemotherapy (340±95 vs. 391±82 µg/kg/h; p<0.001). Impaired LiMAx results (<315µg/kg/h) were determined in 49% of patients after chemotherapy, and no effects of chemotherapy, liver steatosis or fibrosis on biochemical parameters were observed. LiMAx impairment was dependent on the number of oxaliplatin cycles, the therapy-free interval, and obesity in multivariate analysis. In addition, the LiMAx test was worse in patients with relevant steatosis, fibrosis and steatohepatitis. Patients with an impaired LiMAx showed sufficient regeneration during chemotherapy cessation when surgery was postponed (272±57-348±72 µg/kg/h; p=0.003). The LiMAx test enables non-invasive preoperative diagnosis of chemotherapy-associated liver injury. Preoperative performance of the LiMAx test can augment surgical strategy and timing of surgery after previous chemotherapy, thus avoiding increased postoperative morbidity.