Timing Of Systemic Therapy Research Articles

PP01.94 Timing of Systemic Therapy does not Impact Overall Survival for Non-small-cell Lung Cancer with Brain Oligometastases

PP01.94 Timing of Systemic Therapy does not Impact Overall Survival for Non-small-cell Lung Cancer with Brain Oligometastases

Bladder malignancy as a cause of spontaneous bladder rupture: A systematic review.

To characterise cases of spontaneous rupture of the urinary bladder in the context of bladder cancer. A systematic review was performed to characterise cases of spontaneous bladder rupture in patients with bladder cancer. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) system was utilised, with databases being searched for relevant cases. Patient characteristics were extracted, including age, sex, presenting signs and symptoms, management modalities, tumour histology and mortality. Thirty cases were included. Seventeen (57%) were male, and the median age of presentation was 59. Abdominal pain and peritonism were the most common presenting symptoms, in 80% and 60% of patients, respectively. Most patients (n = 16, 53%) had urothelial cell carcinoma. Nine patients (30%) died during their initial hospitalisation. Spontaneous bladder perforation in the context of bladder cancer is a rare cause of acute abdomen. The diagnosis is associated withhigh mortality, highlighting the aggressive nature of the malignancies that cause spontaneous bladder rupture. This raises important questions about the role of emergency cystectomy, the timing of systemic therapy and the appropriate involvement of palliative care.

ASO Author Reflections: Timing of Systemic Therapy and Postoperative Morbidity in Resectable Pancreatic Ductal Adenocarcinoma and Distal Cholangiocarcinoma.

ASO Author Reflections: Timing of Systemic Therapy and Postoperative Morbidity in Resectable Pancreatic Ductal Adenocarcinoma and Distal Cholangiocarcinoma.

Clinical Factors Associated with Radionecrosis Following Stereotactic Radiosurgery in the Era of Modern Systemic Therapy

<h3>Purpose/Objective(s)</h3> Stereotactic radiosurgery (SRS) is commonly utilized in the treatment of brain metastases; however, radiation necrosis (RN) is a dose-limiting toxicity. Systemic therapy has greatly improved in recent years with the advent of immunotherapy and targeted therapy leading to increased overall survival. Here, we examined the impact of clinical factors on development of RN after SRS for brain metastasis in the era of modern systemic therapy. <h3>Materials/Methods</h3> We retrospectively reviewed patients treated with Linac-based SRS at a single institution from 2015-2020. Overall survival was calculated using the Kaplan-Meier method. Univariable (UVA) and multivariable (MVA) analysis was performed using Cox proportional hazards modeling. Covariates included age, sex, race, ethnicity, ECOG, primary cancer site, neurologic deficits at diagnosis, seizures, number/size of tumors, benign vs. malignant disease, prior systemic therapy, post-op vs. intact SRS, whole brain radiotherapy before or after SRS, edema at diagnosis, receipt and timing of immunotherapy/targeted therapy. Concurrent therapy was defined as within 30 days of SRS. <h3>Results</h3> 412 patients treated with SRS to 950 lesions were identified at a median follow-up of 8 months. Median age was 63 (interquartile range [IQR] 54-70) with 90% ECOG 0-1. At presentation, 53% had neurologic deficits and 7.6% had seizures. 82% were treated for malignant disease. 30% received post-op SRS. Prior to SRS, treatment included 1-9 lines of systemic therapy (58%), immunotherapy (24%), and WBRT (7.4%). SRS was given for 1-5 lesions in 91% of patients. Median tumor diameter was 2.0 cm (IQR 1.2-2.8). Median OS was 35 months (95% confidence interval [CI] 21-50); 1- and 2-year OS were 68% (95% CI 75-84) and 54% (95% CI 63-73). 17% developed radiographic RN with a median time to RN of 10 months (95% CI 9-13). Of 68 patients who developed RN, those with clinical symptoms (65%) were successfully treated with steroids (65%), laser interstitial thermal therapy (47%), bevacizumab (10%), and craniotomy (21%). On UVA, factors predictive of time to RN included post-op SRS (HR 1.84, 95% CI 1.12-3.00, p=0.015), number of treated lesions (HR 1.11, 95% CI 1.03-1.21, p=0.011), size of largest lesion (HR 1.46, 95% CI 1.17-1.81, p=0.001), malignant tumor (HR 4.17, 95% CI 1.49-11.11, p=0.006), prior systemic therapy (HR 1.7, 95% CI 1.1-2.86, p=0.046), and vasogenic edema at diagnosis (HR 1.97, 95% CI 1.19-3.26, p=0.008). On MVA, for every 1 cm increase in diameter of the largest lesion, the likelihood of developing RN was increased 1.45-fold (95% CI 1.12-1.88, p=0.005). Timing of systemic therapy did not impact RN rate. <h3>Conclusion</h3> Our data demonstrate that RN occurs in ∼17% of patients at a median of 10 months following SRS and can be successfully managed with medical and surgical therapies. The strongest predictor of RN was the size of the treated tumor. Our findings highlight the need for continued clinical surveillance as improved systemic therapy leads to increased long-term survival.

Long-term follow-upexperience with adjuvant therapy after irreversible electroporation of locally advanced pancreatic cancer.

Irreversible electroporation (IRE) expands the surgical options for patients with unresectable pancreatic cancer. This study evaluated for differences in survival stratified by type of IRE and receipt of adjuvant chemotherapy. Patients with locally advanced pancreatic cancer treated by IRE (2012-2020) were retrospectively included. Overall survival (OS) and recurrence-free survival (RFS) were compared by type of IRE (in situ for local tumor control or IRE of potentially positive margins with resection) and by receipt of adjuvant chemotherapy. Thirty-nine patients had IRE in situ, 61 had IRE for margin extension, and 19 received adjuvant chemotherapy. Most (97.00%) underwent induction chemotherapy. OS was 28.71 months (interquartile range [IQR] 19.17, 51.19) from diagnosis, with no difference by IRE type (hazard ratio [HR] 1.05 for margin extension [p = 0.85]) or adjuvant chemotherapy (HR 1.14 [p = 0.639]). RFS was 8.51 months (IQR 4.95, 20.17) with no difference by IRE type (HR 0.90 for margin extension [p = 0.694]) or adjuvant chemotherapy (HR 0.90 [p = 0.711]). These findings suggest that adjuvant therapy may have limited benefit for patients treated with induction chemotherapy followed by local control with IRE for unresectable pancreatic cancer. Further study of the duration and timing of systemic therapy is warranted to maximize benefit and limit toxicity.

National guideline concordance and outcomes for pathologic N2 disease in non-small cell lung cancer.

BackgroundReal-world treatment practices for positive mediastinal nodal disease in non-small cell lung cancer (NSCLC) continues to vary despite guidelines. We aim to assess national trends in the treatment of pathologic-N2 disease, and evaluate the association with clinical nodal staging and timing of systemic therapy.MethodsThe National Cancer Database was queried for patients with NSCLC who underwent lobectomy and had pathologic-N2 disease from 2010–2017. National Comprehensive Cancer Network (NCCN) guideline concordance was evaluated. cN2 patients were analyzed based on timing of systemic therapy and response. Multivariable logistic regression evaluated outcomes by type of systemic therapy. Survival analysis utilized Cox proportional hazards regression and Kaplan-Meier methods.Results10,225 patients met inclusion criteria. Fifty-four percent of patients were understaged prior to surgery as either cN0 or cN1. Of clinically staged N2 patients, 56% received NCCN recommended neoadjuvant therapy. Annual guideline concordance increased until 2016 to a max of 62.9%. Neoadjuvant and adjuvant systemic therapy showed an overall survival benefit compared with no systemic therapy (HR 0.54 & 0.57), but no difference when compared against each other. Complete response after neoadjuvant therapy was associated with improved survival (5-year OS 56.1%, P<0.001), while partial response, no-response, and adjuvant therapy were similar. All systemic treatment strategies improved survival compared with no systemic therapy (5-year OS 24.5%).ConclusionsGuideline concordance for treatment of cN2 disease has been increasing, but still not followed in over 1/3 of patients. Responsiveness to neoadjuvant therapy appears to be a predictor of survival, and may become a prognostic adjunct for determining which patients would benefit from additional systemic therapy.

Radiotherapy in oligometastatic prostate cancer—a pattern of care survey among members of the German Society for Radiation Oncology (DEGRO)

PurposeDue to improved imaging, oligometastatic prostate cancer (OMPC) is diagnosed more frequently. Growing evidence shows that patients with a limited number of metastases benefit from primary-directed radiotherapy (PDT) as well as from metastasis-directed radiotherapy (MDT). This survey investigates the current treatment practice for OMPC among German-speaking radiation oncologists.MethodsMembers of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie [DEGRO]) were surveyed regarding their current treatment practice via an anonymous online questionnaire sent by email. The survey included six general items and 14 specific items regarding treatment characteristics. Questionnaires with at least 50% of questions completed were considered for further analysis.ResultsA total of 204 responses were received (15% response rate), 167 were considered for further analysis. Most respondents stated to be specialized in treating prostate cancer patients and to treat 10–30 patients with OMPC per annum; 97% considered PSMA-PET/CT necessary to define oligometastatic disease. Opinions differed regarding the use of systemic therapies: 63% of the respondents aimed to defer systemic therapy using radiotherapy in OMPC, whereas 37% considered systemic therapy necessary. In the setting of synchronous OMPC, 97% recommended PDT with or without a combination of MDT and/or systemic therapy. For metachronous nodal or bone oligometastatic recurrence, 98 and 99%, respectively, would opt for MDT. The majority would combine MDT with systemic therapy in patients with metachronous oligorecurrence. Respondents recommended normofractionation, hypofractionation, and SBRT for lymph node metastases in 49, 27, and 24%, respectively. No consensus existed regarding the field size for MDT of lymph node metastases. Most respondents preferred > 5 fractions for treatment of bone metastases.ConclusionLocal radiotherapy for PDT and MDT is routinely used among respondents of this survey, representing 12% of all German-speaking radiation oncologists. The timing of systemic therapy, fractionation schedules, and field sizes are handled differently and remain an area of active investigation.

Benefits of Trimodality Therapy Compared with Systemic Therapy Alone in Male Patients with Stage IV Breast Cancer

Male breast cancer (MBC) represents <1% of all breast cancer (BC) diagnoses. Recent publications in female stage IV BC have shown that surgical intervention has a survival benefit. This study aims to determine the impact of surgical intervention in men with stage IV BC and known estrogen (ER) and progesterone receptor (PR) status. The National Cancer Database was used to identify 539 stage IV MBC patients with known ER/PR status from 2004 to 2017. Chi-square tests examined subgroup differences between the treatment modalities received. Overall survival (OS) was assessed using the Kaplan-Meier method. Multivariate Cox proportional hazard models examined factors associated with survival. The Kaplan-Meier estimation showed that ER-positive (ER+) and PR-positive (PR+) patients who received surgery, systemic therapy, and radiation (Trimodality) or systemic therapy and surgery (ST+Surg) had improved survival compared with systemic therapy alone (ST) [ER+, p<0.003; PR+, p<0.033]. For ER+ patients, the 5-year OS rates by treatment were: Trimodality, 40%; ST+Surg, 27%; and ST, 20%. For PR+ patients, the 5-year OS rates were: Trimodality, 39%; ST+Surg, 24%; and ST, 20%. The Cox proportional hazard model revealed a survival advantage in patients who received Trimodality compared with ST (hazard ratio 0.622; p<0.002). The timing of systemic therapy in relation to surgery was not found to be significant. Trimodality therapy has a survival benefit in stage IV MBC patients with known ER+ status than in male patients who receive systemic therapy alone.

Effect of type and timing of systemic therapy on risk of radiation necrosis in patients with HER2+ breast cancer brain metastases.

e14002 Background: It is estimated that 30% of patients with metastatic human epidermal growth factor receptor 2-positive (HER2+) breast cancer will develop brain metastases. Current standard of care options for HER2+ breast cancer brain metastasis (BCBrM) includes radiation therapy (stereotactic radiosurgery [SRS] or whole brain radiation), brain permeable systemic therapies, and in select cases, neurosurgical resection. A multimodal approach combining these different treatment modalities has improved the overall survival and functional outcomes of patients with BCBrM. Some HER2-directed systemic therapies, however, may increase the risk of radiation necrosis (RN), a longer-term consequence of SRS. This study explores the impact of timing and type of systemic therapies on the development of RN in patients treated with SRS for HER2+ BCBrM. Methods: This was a single-institution, retrospective study including patients ≥18 years of age with HER2+ BCBrM who received SRS between 2013 and 2018 at Duke University with at least 12-month post-SRS follow-up. Presence of RN was determined at one-year post-SRS. Demographics, radiotherapy parameters (total dose, fractions, clinical target volume [CTV], gross tumor volume [GTV], conformity index [CI], volume receiving 12 gray [V12Gy]), and timing (during [within 4 weeks of SRS] vs. not during SRS) and type of systemic therapy (HER2-directed therapy, mitosis inhibitors, DNA synthesis inhibitors, others) were evaluated. Results: Among 46 patients with HER2+ BCBrM who received SRS, 28 (60.9%) developed RN and 18 (39.1%) did not. Age at time of SRS did not differ between those who developed RN and those who did not (mean 53.3 vs 50.4 years, respectively). There was a higher percentage of African Americans in the RN group (28.6% vs 11.1%, p = 0.3). There were no significant differences between the measured radiotherapy parameters—including dose, fraction, CTV, GTV, CI, V12Gy—between the two groups (all p &gt; 0.05). Receipt of any type of systemic therapy during SRS did not differ between patients who did or did not develop RN (60.7% vs 55.6%, p = 0.97). However, patients who developed RN more commonly received more than one line of HER2-directed therapy independent of SRS timing compared to those who did not develop RN (75.0% vs 44.4%, p = 0.08). In fact, a significantly higher proportion of those who developed RN received more than one line of HER2-directed therapy during SRS compared to those did not develop RN (35.7% vs 5.6%, p&lt;0.05). Conclusions: Patients with HER2 BCBrM who receive multiple lines of HER2-directed therapy during SRS for BCBrM may be at higher risk of RN. This data supports a practice of holding HER2-directed therapy during SRS if medically acceptable. Further investigation of next generation HER2-directed therapies in a larger cohort of patients should be investigated to help guide best practice to minimize RN.

ES03.04 Timing of Systemic Therapy in OMD

ES03.04 Timing of Systemic Therapy in OMD

Quantitative Volumetric Tumor Response And Toxicity Outcomes In Patients Treated With Combination Stereotactic Radiosurgery (SRS) And Immunotherapy For Melanoma Brain Metastases

Stereotactic radiosurgery (SRS) confers excellent local control for melanoma brain metastases (MBM). Factors impacting the rate of volumetric regression in the follow-up period, including the nature and timing of systemic therapy, are poorly understood. This study examines the impact of systemic therapy on MRI volumetric tumor response over time of melanoma brain metastases following SRS. A retrospective analysis was performed of patients who received single-fraction Cobalt-based SRS for MBM from January 2016 to June 2019. Predictive factors relating to SRS dose, volume and systemic therapy treatment factors such type (CTLA-4, PD-1 and/or BRAF/MEK inhibitors) and timing were collected. Treatment volume of each lesion was delineated on a T1-weighted Gadolinium contrast enhanced MRI at baseline and follow-up. Cubic spline interpolation was used to impute missing data across time intervals. The primary outcome was relative volumetric change in T1-contrast enhancement at 3, 6, 9, 12- and 15-months relative to baseline. A repeated measures ANOVA was used to assess for differences in mean volumetric change between intervals. A linear mixed multivariate regression analysis was performed to assess the relationship between explanatory variables and volumetric change with a two-tailed significance of α = 0.05. 101 patients with 425 MBM were treated with SRS. Median follow-up was 29.2 months (IQR 19.7-39.8). Median dose, baseline volume and lesion diameter were 20Gy (IQR 18-20), 0.24cc (IQR 0.06-1.02) and 7.7mm (IQR 4.8-12.4). 53% of patients were BRAF mutant. 65% had failed BRAF inhibitors at time of SRS. 34% of patients received BRAF inhibitors concurrently (± 48 hours). 77% of patients received concurrent CTLA-4/PD-1 immunotherapy (2 weeks prior-4 weeks post-SRS). Median interpolated lesion size at 3, 6, 9, 12 and 15-month was 73.6%, 55.4%, 49.7%, 54.2% and 42.5% of baseline respectively. There was a statistically significant decrease in lesion size in the 0-3 and 3-6 month interval (p<0.001). Lesion regression stabilized after 6-months. 89.7% of treated lesions had durable local control on MRI at last follow-up. Patients receiving concurrent immunotherapy had a significantly greater regression in tumor volume at 3-months (37% superior [95% CI 6-68.1%, p = 0.02] and 6-months (48% superior [95% CI 7.4-89.5%, p = 0.02] compared to those commencing >4 weeks post SRS however lesion regression velocity was comparable by 9- and 12-months. A 1mm increase in maximal lesion diameter was associated with a 1.5% (95% CI 0.04-2.9, p = 0.04) and 2% (95% CI 0.4-3.7%, p = 0.016) greater reduction in volume at 3- and 6-months. 5% of patients experienced symptomatic radionecrosis (RN). 19% had non-RT grade 3 or higher toxicity. This study demonstrates a significantly greater volumetric regression with concurrent immunotherapy and SRS in MBM in the initial 6 months post SRS. Combined modality treatment offers excellent local control with low RN specific toxicity.

Short-term adjuvant versus neoadjuvant hormone therapy in localized prostate cancer: A pooled individual patient analysis of two phase III trials.

5584 Background: The timing of systemic therapy in relation to radiotherapy (RT) is important in most malignancies. In contrast, androgen deprivation therapy (ADT) has largely been investigated in relation to its duration rather than its sequencing with RT. Herein, we conduct the first combined individual patient analysis of two phase III randomized trials to determine the optimal timing of ADT with RT in localized prostate cancer (PCa). Methods: Individual patient data was obtained from the Malone et al trial (JCO 2019), which randomized patients to receive neoadjuvant/concurrent or concurrent/adjuvant ADT for 6 months with prostate only RT. This was combined with the prostate only RT arms of RTOG 9413 that randomized patients to 4 months of neoadjuvant/concurrent or adjuvant ADT. The neoadjuvant/concurrent arms of both trials were combined into the “neoadjuvant” group, and the concurrent/adjuvant (Malone) and adjuvant arm (RTOG 9413) were combined in the “adjuvant” group. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Cumulative incidence of distant metastasis (DM), PCa-specific mortality (PCSM) and biochemical failure (BF) were calculated using the Fine-Gray method with non-PCa deaths as competing events. Late genitourinary (GU) and gastrointestinal (GI) toxicity are also reported. Results: The median follow-up was 14.9 years (yrs) and 1065 patients were included (n=531 neoadjuvant, 534 adjuvant). Groups were well balanced for all baseline characteristics. Adjuvant ADT was superior to neoadjuvant ADT in terms of BF (15yr: 33% vs 43%, HR: 1.37 (95%CI: 1.12-1.68), p=0.002), DM (15yr: 12% vs 18%, HR: 1.40 (95%CI: 1.00-1.95), p=0.04), and PFS (15yr: 36% vs 29%, HR: 1.25 (95%CI: 1.07-1.47), p=0.01). Adjuvant ADT yielded lower PCSM (15yr: 15% vs 20%, HR: 1.29 (95%CI: 0.95-1.75), p=0.10), but did not reach statistical significance. This approached statistical significance in high risk PCa (HR 1.39 (95%CI 1.00-1.93), p=0.053). OS was not significantly different between arms (15yr: 39% vs 34%, HR: 1.11 (95%CI: 0.95-1.30), p=0.20). There was no significant difference in either late grade ≥3 GI (p=0.21) or GU (p=0.98) toxicity. Conclusions: We demonstrate for the first time that sequencing of ADT with RT significantly impacts long-term oncologic outcomes in localized PCa, favoring an adjuvant rather than neoadjuvant approach, without increasing late toxicity. This data has important implications to ongoing and future clinical trial design. Clinical trial information: NCT00769548 .

MLTI-12. TIMING OF SYSTEMIC THERAPY ADMINISTRATION RELATIVE TO STEREOTACTIC RADIOSURGERY AND DEVELOPMENT OF RADIATION NECROSIS IN PATIENTS WITH BRAIN METASTASES

PURPOSE: The mainstay of oncologic therapy for patients with brain metastases involves brain-directed radiation, increasingly given via stereotactic radiosurgery (SRS), and systemic therapy for extracranial disease control. We sought to investigate the association between the timing of systemic therapy and SRS administration on development of radiation necrosis among patients with brain metastases. METHODS: We retrospectively identified 429 patients treated at Brigham and Women’s Hospital/Dana-Farber Cancer Institute with SRS for newly-diagnosed brain metastases between 2001–2015. Systemic therapy was tiered into 4 categories: chemotherapy, immunotherapy, hormonal therapy, and targeted therapy. All images were manually reviewed by two radiation oncologists specializing in brain tumors to assess the presence versus absence of radiographic necrosis. Patients with radiographic necrosis who harbored associated neurologic symptoms or were managed with steroids/bevacizumab/resection were considered to have symptomatic radiation necrosis. Data were analyzed using univariable Cox regression in SAS v9.4. The median follow-up in surviving patients was 1.79 years. RESULTS: In total, 252/429 and 361/429 patients received systemic therapy pre and/or post SRS, respectively. Patients receiving systemic therapy ≤5 days before SRS displayed higher rates of radiographic (HR 2.48, 95% CI 1.06–5.81, p=.04) and symptomatic (HR 3.74, 95% CI 1.08–12.98, p=.04) necrosis; a similar association was seen in patients receiving systemic therapy ≤5 days after SRS (HR 1.72, 95% CI 0.84–3.53, p=.14 and HR 4.42, 95% CI 1.75–11.14, p=.002, respectively). Trends towards increased necrosis risk were noted when comparing systemic therapy administration 1–5 days versus 6–10 days before/after SRS. The above 4 associations were significant when restricting the cohort to patients receiving targeted systemic therapy (HR-range 3.57–21.49, p-range 0.01–0.04). CONCLUSIONS: Our results suggest that a reasonable delay between SRS and systemic therapy administration may reduce rates of radiation necrosis, even among patients receiving targeted therapies. Validation in an independent data set would lend further support to this concept.

Effect of MAF amplification on treatment outcomes with adjuvant zoledronic acid in early breast cancer: a secondary analysis of the international, open-label, randomised, controlled, phase 3 AZURE (BIG 01/04) trial

Adjuvant use of bisphosphonates can reduce the incidence of bone metastases in early breast cancer. Recurrence and survival seem to be improved only in postmenopausal patients, but the underlying mechanisms remain unclear. We investigated whether MAF amplification (a biomarker for bone metastasis) in primary tumours could predict the treatment outcomes of adjuvant zoledronic acid. The study population included patients enrolled in the international, open-label, randomised, controlled, phase 3 AZURE trial at eligible UK sites who had stage II or III breast cancer and who gave consent for use of their primary tumour samples. Patients were randomly assigned (1:1) to receive standard adjuvant systemic therapy alone (control group) or with zoledronic acid every 3-4 weeks for six doses, then every 3-6 months until the end of 5 years. Minimisation took into account the number of involved axillary lymph nodes, clinical tumour stage, oestrogen-receptor status, type and timing of systemic therapy, menopausal status, statin use, and treating centre. The primary endpoint was disease-free survival; the secondary endpoint, invasive-disease-free survival, was the primary disease endpoint for the analysis in this report. MAF amplification was assessed by fluorescence in-situ hybridisation of two cores of breast tumour tissue in a microarray, done in a central laboratory by technicians unaware of treatment assignment. We used multivariate analyses to assess disease outcomes by intention to treat. We also assessed interactions between MAF-positive status and menopausal status on efficacy of zoledronic acid. The AZURE trial is registered with the International Standard Randomised Controlled Trial Registry, number ISRCTN79831382. 1739 AZURE patients contributed primary tumour samples, of whom 865 (50%) had two assessable cores (445 in the control groups and 420 in the zoledronic acid group). 184 (21%) tumours were MAF positive (85 in the control groups and 99 in the zoledronic acid group) and the remaining tumours were MAF negative. At a median follow-up of 84·6 months (IQR 72·0-95·8), MAF status was not prognostic for invasive-disease-free survival in the control group (MAF-positive vs MAF-negative: hazard ratio [HR] 0·92, 95% CI 0·59-1·41), but was in the zoledronic acid group (0·52, 0·36-0·75). In patients with MAF-negative tumours, zoledronic acid was associated with higher invasive-disease-free survival than was control treatment (HR 0·74, 95% CI 0·56-0·98), but not in patients who had MAF-positive tumours. Additionally, among 121 patients not postmenopausal at randomisation with MAF-positive tumours, zoledronic acid was associated with lower invasive-disease-free survival (HR 2·47, 95% CI 1·23-4·97) and overall survival (2·27, 95% CI 1·04-4·93) than control treatment. MAF status can predict likelihood of benefit from adjuvant zoledronic acid and merits further investigation as a potential companion diagnostic. Novartis Global and Inbiomotion.

Cancer in pregnancy: safety and efficacy of systemic therapies.

Cancer in pregnancy has become increasingly frequent. It has become clear that for specific cancers under well defined circumstances, oncological treatment in pregnancy can be well tolerated and feasible for both mother and fetus. Continued critical assessment of the available literature and registration of cancer in pregnancy cases and outcomes for mother and child are necessary to work toward implementing optimal cancer treatment during pregnancy. Physiologic changes in pregnancy may alter distribution and efficacy of systemic therapy. Data on systemic therapy including, chemotherapy, hormonal therapy, and targeted therapy during pregnancy are available but incomplete. Outcomes of fetuses exposed to chemotherapy in utero are generally reassuring, but new targeted therapies are mostly discouraged in pregnancy. Cancer treatment during pregnancy is possible, depending on type and timing of systemic therapy and treatment modality. Available data are reassuring with a modest increase in complications such as growth restriction and preterm birth. The effect of new targeted therapies is often still unclear and therefore discouraged.

Systematic Review: Perioperative Systemic Therapy for Metastatic Renal Cell Carcinoma.

Background: Approximately 16% of patients with renal cell carcinomas (RCC) present with stage IV disease at time of diagnosis. Treatment options for metastatic clear cell RCC, the most common histologic subtype, have proliferated over the past decade and include a combination of surgery and systemic therapy. The selection of systemic agent and best timing of systemic therapy in relation to nephrectomy is an area of active research.Objective: To evaluate the evidence for perioperative systemic therapy, including presurgical and postsurgical, for metastatic RCC.Methods: A systematic literature search using PubMed and MEDLINE databases was performed in January 2017 for articles related to perioperative systemic therapy in metastatic RCC using key word search terms. The authors screened the search results and identified selected publications by predetermined inclusion criteria and consensus. Expert opinion was obtained to assess for publications missed by search.Results: Early phase clinical trials of antiangiogenic tyrosine kinase inhibitors prior to cytoreductive nephrectomy in select patients show that these systemic agents are safe and effective in the presurgical setting. There are no randomized data evaluating pre- or post-surgical systemic therapy in metastatic RCC.Conclusions: Retrospective and early-phase prospective studies on the use and timing of systemic therapy in relation to cytoreductive nephrectomy in metastatic RCC show that standard of care antiangiogenic agents are safe and effective in the perioperative setting, though randomized data are still lacking. Pre-surgical immune checkpoint therapy for metastatic RCC has strong biologic rationale and holds promise. Sequential tumor sampling in neoadjuvant and presurgical trials is necessary to determine biomarkers of response and resistance.

Impact of cytoreductive nephretomy on timing of systemic therapy in metastatic kidney cancer.

503 Background: High rates of disease control with systemic therapy (ST) in the post-cytokine era for metastatic renal cell carcinoma (mRCC) cause apprehension that cytoreductive nephrectomy (CN) may delay effective therapy. We therefore evaluated factors associated with early mortality and time to ST after CN. We hypothesized markers of poor performance status and morbid CN would be associated with postoperative mortality and therapeutic delays. Methods: The National Cancer Database was screened for adult mRCC cases having CN followed by ST, years 2006-2013. We classified a delay in systemic therapy as interval &gt; 45 days (median time to ST in the cohort). Multivariable logistic regression was performed, identifying factors associated with perioperative mortality and delays to initiation of ST. Results: Of 10,913 patients with initial CN (45% of mRCC), 30- and 90-day mortality were 3% and 11%, respectively. 6,362 later received ST (87% targeted therapy, 13% immunotherapy), median start was 45 days post-operatively (IQR 9-72), with 73% receiving ST within 30 days of CN. Multivariable factors associated with 30-day mortality included, older age, (OR 2.3, 95% CI 1.5-3.5 for those &gt;75 [referent &lt; 55 years]), Charlson index &gt;0 (OR 1.3, 95% CI 1.0-1.6), lack of insurance (OR 1.9, 95% CI 1.2-2.8 [referent private payer]), node-positive disease (OR 1.4 95% CI 1.1-1.7), length of stay &gt; 90th percentile (&gt; 10 days, OR 3.2, 95% CI 2.0-5.3), larger tumor size (T4 lesion OR 1.7, 95% CI 1.2-2.5 [referent T1]). Delayed ST was associated with travel burden &gt; 50 miles (OR 1.2, 95% CI 1.0-1.4), concurrent metastasectomy (OR 1.3, 95% CI 1.2-1.5), and length of stay &gt; 90th percentile (OR 1.5, 95% CI 1.1-2.3). Conclusions: These data suggest that markers of frailty, more progressive disease, and surgical morbidity may contribute to surgical-related deaths or hinder patients receiving potentially disease-controlling therapy when treated with initial CN in mRCC. Going forward, existing surgical prognostic models could incorporate risks of surgical-related mortality and delay to ST when considering CN.

Effect of Systemic Therapies on Outcomes following Vertebroplasty among Patients with Multiple Myeloma.

The role of vertebroplasty in patients with myeloma remains relatively undefined. Accordingly, we sought to better define the efficacy of vertebroplasty for myeloma-associated fractures and determine the effect of procedure timing relative to the initiation of systemic therapy on outcomes and complication rates. Clinical, laboratory, and medication data were retrieved for 172 patients with multiple myeloma treated with vertebroplasty since October 2000. Quantitative outcome data (Roland-Morris Disability Questionnaire [scale, 0-24] and the Numeric Rating Scale [0-10] for pain at rest and with activity) were collected immediately pre- and postoperatively and at 1 week, 1 month, 6 months, and 1 year following vertebroplasty. Patients with ≥50% improvement on the Numeric Rating Scale and ≥40% improvement on the Roland-Morris Disability Questionnaire were classified as "responders." Peri- and postoperative complications were also collected. Significant median improvement in the Roland-Morris Disability and rest and activity Numeric Rating Scale scores (15, 2, and 6 points, respectively; P < .0001) persisted at 1 year without significant change from the immediate postoperative scores (P > .36). Patients on systemic therapy at the time of vertebroplasty were more likely to achieve "responder status," compared with patients not on systemic therapy, for the Numeric Rating Scale pain at rest score (P < .01) and the Roland-Morris Disability Questionnaire score (P < .003), with no difference in complication rates (χ2 = 0.17, P = .68). Vertebroplasty is an effective therapy for patients with myeloma with symptomatic compression fractures. Favorable outcomes are more likely to be achieved when spinal augmentation is performed after systemic therapy is initiated. Complication rates were not affected by the timing of systemic therapy.

Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases?

OBJECT Radiation necrosis (RN), or its imaging equivalent, treatment-related imaging changes (TRIC), is an inflammatory reaction to high-dose radiation in the brain. The authors sought to investigate the hypothesis that immunotherapy increases the risk of developing RN/TRIC after stereotactic Gamma Knife (GK) radiosurgery for brain metastases. METHODS A total of 180 patients who underwent GK surgery for brain metastases between 2006 and 2012 were studied. The systemic therapy they received was classified as cytotoxic chemotherapy (CT), targeted therapy (TT), or immunotherapy (IT). The timing of systemic therapy in relation to GK treatment was also recorded. Logistic regression was used to calculate the odds of developing RN according to type of systemic therapy received. RESULTS The median follow-up time was 11.7 months. Of 180 patients, 39 (21.7%) developed RN/TRIC. RN/TRIC rates were 37.5% (12 of 32) in patients who received IT alone, 16.9% (14 of 83) in those who received CT only, and 25.0% (5 of 20) in those who received TT only. Median overall survival was significantly longer in patients who developed RN/TRIC (23.7 vs 9.9 months, respectively). The RN/TRIC rate was increased significantly in patients who received IT alone (OR 2.40 [95% CI 1.06-5.44]; p = 0.03), whereas receipt of any CT was associated with a lower risk of RN/TRIC (OR 0.38 [95% CI 0.18-0.78]; p = 0.01). The timing of development of RN/TRIC was not different between patients who received IT and those who received CT. CONCLUSIONS Patients who receive IT alone may have an increased rate of RN/TRIC compared with those who receive CT or TT alone after stereotactic radiosurgery, whereas receiving any CT may in fact be protective against RN/TRIC. As the use of immunotherapies increases, the rate of RN/TRIC may be expected to increase compared with rates in the chemotherapy era.

Surgical management of metastatic renal cell carcinoma in the era of targeted therapies

Cytoreductive nephrectomy (CN) has been considered standard management for patients with metastatic renal cell carcinoma (mRCC) for over a decade. This practice, based on evidence from the immunotherapy era, has now come into question with the dramatic shift in management of mRCC patients due to the development and approval of several targeted molecular therapies (TMT). A comprehensive English language literature review was performed using MEDLINE/PubMed to identify articles and guidelines pertinent to CN in mRCC. Retrospective studies have demonstrated improved survival for patients who underwent CN compared to those that did not; however, these studies suffer from heavy selection bias. Furthermore, the optimal timing of TMT, before or after surgery is not known. Pre-surgical TMT has the advantage of early treatment of metastases, downsizing of the primary, and may be an effective 'litmus test' for the selection of patients for CN based on response to TMT. The results of two ongoing phase III trials (CARMENA and SURTIME) will address much of the controversy on the role of CN and the timing of systemic therapy in the TMT era. In this review, we aim to present the evidence that lead to adoption of CN in the era of immunotherapies as well as the available data about the oncologic benefit of CN in patients with mRCC who receive TMT as their primary systemic therapy. There seems to be an important role for CN in the era of TMT, mostly in patients with favorable risk and where a high percentage of tumor burden can be removed by cytoreductive surgery.