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Background: Little is known about how use of chemotherapy has evolved in breast cancer patients. We therefore describe chemotherapy patterns for women with stage I-IIIA breast cancer in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study using data from KPNC (Kaiser Permanente Northern California) and KPWA (Kaiser Permanente Washington)., Findings: Among 33,670 women, aged 18 + y, diagnosed with primary stage I-IIIA breast cancer at KPNC and KPWA from 2006 to 2019, we explored patterns of intravenous chemotherapy use, defined here as receipt of intravenous cytotoxic drugs and/or anti-HER2 therapies. We evaluated trends in chemotherapy receipt, duration over which chemotherapy was received, and number of associated infusion visits. In secondary analyses, we stratified by receipt of anti-HER2 therapies (trastuzumab and/or pertuzumab), given their longer duration. 38.9% received chemotherapy intravenously, declining from 40.2% in 2006 to 35.6% in 2019 (p-trend < 0.001). Among 13,089 women receiving chemotherapy, neoadjuvant treatment increased (4.1-14.7%; p-trend < 0.001), as did receipt of anti-HER2 therapies (20.8-30.9%) (p-trend < 0.001). The average treatment duration increased (5.3 to 6.0 months; p-trend < 0.001), as did the number of infusion visits (10.8 to 12.5; p-trend < 0.001). For those receiving anti-HER2 therapies, treatment duration and average number of visits decreased; among those not receiving anti-HER2 therapies, number of visits increased, with no change in duration., Conclusions: While the prevalence of chemotherapy receipt has decreased over time, the use of neoadjuvant chemotherapy has increased, as has use of anti-HER2 therapies; duration and number of administration visits have also increased. Understanding these trends is useful to inform clinical and administrative planning., (© 2024. The Author(s).)

Purpose: There are conflicting reports on outcome trends following radical cystectomy (RC) for bladder cancer., Materials and Methods: Evolution of modern bladder cancer management and its impact on outcomes was analyzed using a longitudinal cohort of 3,347 patients who underwent RC at an academic center between 1971 and 2018. Outcomes included recurrence-free survival (RFS) and overall survival (OS). Associations were assessed using univariable and multivariable models., Results: In all, 70.9% of cases underwent open RC in the last decade, although trend for robot-assisted RC rose since 2009. While lymphadenectomy template remained consistent, nodal submission changed to anatomical packets in 2002 with increase in yield (p <0.001). Neoadjuvant chemotherapy (NAC) use increased with time with concomitant decrease in adjuvant chemotherapy; this was notable in the last decade (p <0.001) and coincided with improved pT0N0M0 rate (p=0.013). Median 5-year RFS and OS probabilities were 65% and 55%, respectively. Advanced stage, NAC, delay to RC, lymphovascular invasion and positive margins were associated with worse RFS (all, multivariable p <0.001). RFS remained stable over time (p=0.73) but OS improved (5-year probability, 1990-1999 51%, 2010-2018 62%; p=0.019). Among patients with extravesical and/or node-positive disease, those who received NAC had worse outcomes than those who directly underwent RC (p ≤0.001)., Conclusions: Despite perioperative and surgical advances, and improved pT0N0M0 rates, there has been no overall change in RFS trend following RC, although OS rates have improved. While patients who are downstaged with NAC derive great benefit, our real-world experience highlights the importance of preemptively identifying NAC nonresponders who may have worse post-RC outcomes.

We are witnessing a silent revolution in the treatment of early stage non-small cell lung cancer (NSCLC), with a series of practice-changing clinical trials enriching the therapeutic perspectives of lung cancer patients with potentially curable disease. The ADAURA study marked the advent of precision medicine and biomarker testing to the early stages setting. The IMPower-010 trial interrupted the negative trend of adjuvant lung cancer immunotherapy, paving the way to the application of immune-checkpoint inhibition in the resected disease. The ITACA trial definitively established no role for tailored adjuvant chemotherapy in NSCLC, while the Lung Art data questioned the efficacy of post-operative radiotherapy for pN2 resected disease. Growing evidence is supporting MRD as effective adjuvant prognostic biomarker to stratify disease's recurrence risk after radical interventions and select best candidates to the adjuvant strategies. This work summarizes the recent major breakthroughs in lung cancer adjuvant treatment, and provides a snapshot of the current real-world scenario, discussing the upcoming challenges and opportunities featuring the clinical management of early stage NSCLC patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Multifunctional nature of phytochemicals and their chemical diversity has attracted attention to develop leads originated from nature to fight COVID-19. Pharmacological activities of chelerythrine and its congeners have been studied and reported in the literature. This compound simultaneously has two key therapeutic effects for the treatment of COVID-19, antiviral and anti-inflammatory activities. Chelerythrine can prevent hyper-inflammatory immune response through regulating critical signaling pathways involved in SARS-CoV-2 infection, such as alteration in Nrf2, NF-κB, and p38 MAPK activities. In addition, chelerythrine has a strong protein kinase C-α/-β inhibitory activity suitable for cerebral vasospasm prevention and eryptosis reduction, as well as beneficial effects in suppressing pulmonary inflammation and fibrosis. In terms of antiviral activity, chelerythrine can fight with SARS-CoV-2 through various mechanisms, such as direct-acting mechanism, viral RNA-intercalation, and regulation of host-based antiviral targets. Although chelerythrine is toxic in vitro, the in vivo toxicity is significantly reduced due to its structural conversion to alkanolamine. Its multifunctional action makes chelerythrine a prominent compound for the treatment of COVID-19. Considering precautions related to the toxicity at higher doses, it is expected that this compound is useful in combination with proper antivirals to reduce the severity of COVID-19 symptoms.

Radical cystectomy is the primary treatment for muscle-invasive bladder cancer; however, approximately 50% of patients develop metastatic disease within 2 years of diagnosis, which results in dismal prognosis. Therefore, systemic treatment is important to improve the prognosis of muscle-invasive bladder cancer. Currently, several guidelines recommend cisplatin-based neoadjuvant chemotherapy before radical cystectomy, and adjuvant chemotherapy is recommended in patients who have not received neoadjuvant chemotherapy. Immune checkpoint inhibitors have recently become the standard treatment option for metastatic urothelial carcinoma. Owing to their clinical benefits, several immune checkpoint inhibitors, with or without other agents (including other immunotherapy, cytotoxic chemotherapy, and emerging agents such as antibody drug conjugates), are being extensively investigated in perioperative settings. Several studies for perioperative immunotherapy have shown that immune checkpoint inhibitors have promising efficacy with relatively low toxicity, and have explored the predictive molecular biomarkers. Herein, we review the current evidence and discuss the future perspectives of perioperative systemic treatment for muscle-invasive bladder cancer.

Introduction : Unfortunately, potentially curative surgical resection is possible in approximately the 25% of biliary tract cancer (BTC) patients at diagnosis, and even following radical surgery, relapse rates remain high. Thus, the role of adjuvant systemic treatment has been widely explored in this setting over the last decades, with the hope of lowering recurrence rates and improving outcomes of BTC patients. Areas covered : In this review, we provide an overview of available evidence regarding adjuvant systemic therapy in resected BTC, critically discussing the pros and cons of recently published clinical trials such as the BILCAP, the BCAT, and the PRODIGE-12/ACCORD-18 phase III studies. Expert opinion : Although the BILCAP trial has established adjuvant capecitabine for 6 months following radical resection as a novel standard of care, the role of adjuvant systemic chemotherapy is the object of debate and controversy in the BTC medical community. Although most of the international guidelines on BTC management have not yet been updated, the recently published ASCO guidelines support the use of capecitabine in this setting. Several phase I to III clinical trials are currently evaluating the role of novel therapeutic approaches in patients with resected BTC, and the results of these studies are highly awaited.

Treatment for HR+/HER2+ patients has been debated, as some tumors within this luminal HER2+ subtype behave like luminal A cancers, whereas others behave like non-luminal HER2+ breast cancers. Recent research and clinical trials have revealed that a combination of hormone and targeted anti-HER2 approaches without chemotherapy provides long-term disease control for at least some HR+/HER2+ patients. Novel anti-HER2 therapies, including neratinib and trastuzumab emtansine, and new agents that are effective in HR+ cancers, including the next generation of oral selective estrogen receptor downregulators/degraders and CDK4/6 inhibitors such as palbociclib, are now being evaluated in combination. This review discusses current trials and results from previous studies that will provide the basis for current recommendations on how to treat newly diagnosed patients with HR+/HER2+ disease.

Background: In 2004, the European Study Group for Pancreatic Cancer (ESPAC)-1 long-term data concluded that adjuvant chemotherapy provided a survival benefit for patients with pancreatic ductal adenocarcinoma (PDAC), whereas adjuvant chemoradiation was associated with worse overall survival. In this study, we investigated how long it took for US practice patterns to change following this trial., Methods: The National Cancer Database was used to identify patients with stage I-III PDAC who underwent R0 or R1 resection followed by adjuvant chemotherapy or chemoradiation between 1998 and 2015. A multivariate analysis was performed to determine predictors of receiving adjuvant chemoradiation in the post-ESPAC-1 era., Results: Between 1998 and 2015, adjuvant chemotherapy use increased from 2.9% to 51.6%, whereas adjuvant chemoradiation decreased from 49.5% to 22.9%. In 2010, adjuvant chemotherapy utilization surpassed that of chemoradiation. For patients diagnosed in the post-ESPAC-1 era, adjuvant chemotherapy (n = 7733) and chemoradiation (n = 6969) groups were compared. Patients who underwent adjuvant chemoradiation were younger, had private insurance, underwent surgery at nonacademic centers, and had more pathologically advanced cancers (all P < 0.01). After 2010, R1 resection was the strongest independent predictor of adjuvant chemoradiation use by multivariate analysis (OR 2.05, CI 1.8-2.3, P < 0.01)., Conclusions: Adjuvant chemotherapy use exceeded that of adjuvant chemoradiation 6 y after the final publication of ESPAC-1 in 2004, highlighting the challenges of disseminating and adopting clinical data. After 2010, R1 disease was the most significant predictor of receiving adjuvant chemoradiation. Prospective studies are underway to definitively address the role of adjuvant chemoradiation in PDAC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

5-Fluorouracil (5-FU) is the first-line chemotherapy drug for colorectal cancer but most of the patients get resistant to the drug on a longer course of treatment. After the successful use of immunotherapy in melanoma treatment, it was explored with enthusiasm in different types of solid cancers including colorectal cancer. Nivolumab and pembrolizumab (Programmed cell death-1 blocking antibodies) have shown efficacy in the mismatch repair deficient high microsatellite instability (dMMR-MSI-H) subtype of metastatic colorectal cancer (CRC) patients. Immunotherapy has shown long time remission in a subset of metastatic CRC patients. The molecular mechanism and emerging roles of immunotherapy in colorectal cancer are explored in this review article and future directions for the proper utilization of the development in immunobiology are suggested., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Main controversies in endometrial cancer treatment include the role of lymphadenectomy and optimal adjuvant treatment. We assessed clinical outcome in a population-based endometrial cancer cohort in relation to changes in treatment management over two decades., Methods: All consenting endometrial cancer patients receiving primary treatment at Haukeland University Hospital from 2001 to 2019 were included (n = 1308). Clinicopathological variables were evaluated for year-to-year changes. Clinical outcome before and after discontinuing adjuvant radiotherapy and individualizing extent of lymphadenectomy was analyzed., Results: The rate of lymphadenectomy was reduced from 78% in 2001-2012 to 53% in 2013-2019. The rate of patients with verified lymph node metastases was maintained (9% vs 8%, p = 0.58) and FIGO stage I patients who did not undergo lymphadenectomy had stable 3-year recurrence-free survival (88% vs 90%, p = 0.67). Adjuvant chemotherapy for completely resected FIGO stage III patients increased from 27% to 97% from 2001 to 2009 to 2010-2019, while adjuvant radiotherapy declined from 57% to 0% (p < 0.001). These patients had improved 5-year overall- and recurrence-free survival; 0.49 [95% CI: 0.37-0.65] in 2001-2009 compared to 0.61 [0.45-0.83] in 2010-2019, p = 0.04 and 0.51 [0.39-0.68] to 0.71 [0.60-0.85], p = 0.03, respectively. For stage I, II and IV, survival rates were unchanged., Conclusions: Our study demonstrates that preoperative stratification by imaging and histological assessments permits a reduction in lymphadenectomy to around 50%, and is achievable without an increase in recurrences at 3 years. In addition, our findings support that adjuvant chemotherapy alone performs equally to adjuvant radiotherapy with regard to survival, and is likely superior in advanced stage patients., Competing Interests: Declaration of competing interest There are no conflicts of interest to disclose., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Uterine carcinosarcoma (UCS) is a biphasic aggressive high-grade endometrial cancer in which the sarcoma element has de-differentiated from the carcinoma element. UCS is considered a rare tumor, but its incidence has gradually increased in recent years (annual percent change from 2000 to 2016 1.7%, 95% confidence interval 1.2-2.2) as has the proportion of UCS among endometrial cancer, exceeding 5% in recent years. UCS typically affects the elderly, but in recent decades patients became younger. Notably, a stage-shift has occurred in recent years with increasing nodal metastasis and decreasing distant metastasis. The concept of sarcoma dominance may be new in UCS, and a sarcomatous element >50% of the uterine tumor is associated with decreased survival. Multimodal treatment is the mainstay of UCS. Lymphadenectomy, chemotherapy, and brachytherapy have increased in the past few decades, but survival outcomes remain dismal: the median survival is less than two years, and the 5-year overall survival rate has not changed in decades (31.9% in 1975 to 33.8% in 2012). Carboplatin/paclitaxel adjuvant chemotherapy improves progression-free survival compared with ifosfamide/paclitaxel, particularly in stages III-IV disease (GOG-261 trial). Twenty-six clinical trials previously examined therapeutic effectiveness in recurrent/metastatic UCS. The median response rate and progression-free survival were 37.5% and 5.9 months, respectively, after first-line therapy, but after later therapies, the outcomes were far worse (5.5% and 1.8 months, respectively). One significant discovery was that epithelial-mesenchymal transition (EMT) plays a pivotal role in the pathogenesis of sarcomatous dedifferentiation in UCS and that heterologous sarcoma is associated with a higher EMT signature compared with homologous sarcoma. Furthermore, next-generation sequencing has revealed that UCS tumors are serous-like and that common somatic mutations include those in TP53, PIK3CA, FBXW7, PTEN, and ARID1A. This contemporary review highlights recent clinical and molecular updates in UCS. A possible therapeutic target of EMT in UCS is also discussed., Competing Interests: Declaration of Competing Interest Consultant, Quantgene (L.D.R.); honorarium, Chugai, textbook editorial expense, Springer, and investigator meeting attendance expense, VBL therapeutics (K.M.); research funding, MSD (S.M.); advisory board, Tesaro, GSK (M.K.); Consultant for Merck and Kiyatec, research funding from M-Trap, and shareholder for BioPath (A.K.S.)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To utilize a national dataset to compare outcomes and demonstrate trends in treatment for lymph node positive bladder cancer (N+ BC)., Methods: The National Cancer Database (2006-2014) was queried for cT2-4N1-3M0 N+ BC patients treated with radical cystectomy alone (RC), neoadjuvant chemotherapy (NAC), adjuvant chemotherapy (AC), chemoradiation (CRT), chemotherapy alone (CT), or no definitive treatment (NT). Survival by treatment was analyzed using Kaplan-Meier and multivariable Cox-proportional hazards regression. Pathologic down-staging was analyzed using univariable and multivariable logistic regression models. A univariable logistic regression model of treatment by year identified treatment trends., Results: Among 3241 patients (cN1, 46%; cN2, 44%; cN3 10%), the majority underwent combined chemotherapy and RC (NAC, 418; AC, 591; RC, 567; CRT, 392; CT, 1068; NT, 205). Overall survival did not differ between NAC and AC, but both had improved survival compared to RC. All other treatment groups had worse survival outcomes compared to NAC. Down-staging to pT0 (adjusted odds ratio = 26.39) and pN0 (adjusted odds ratio = 6.88) was higher for NAC than RC. Utilization of NAC has increased, AC and RC has declined, and CRT and NT is unchanged., Conclusion: Combined chemotherapy and RC demonstrates best survival outcomes for N+ BC, with complete pathologic response to pT0N0 after NAC associated with a 5-year overall survival rate of ∼85%. However, there is no significant difference between NAC and AC. CRT is associated with worse oncologic outcomes compared to RC with perioperative chemotherapy, but improved survival compared to RC or CT., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To characterize the presentation and management of spermatocytic seminoma (SS) compared to classic seminoma in adults utilizing a large cancer registry., Methods: Patients >18 years of age in the National Cancer Database from 2006 to 2016 who underwent orchiectomy for testicular tumors were identified. Demographics, oncologic characteristics, and treatment patterns were compared between patients with SS and classic seminoma., Results: Of 53,481 adults receiving orchiectomy, 29,208 were diagnosed with classic seminoma and 299 (1%) with SS. Compared to patients with classic seminoma, SS patients were older (57 vs 39 years) and more likely to be African-American (odds ratio (OR) 1.8) and insured by Medicare (OR 2.0; all P <.05). SS patients had larger tumors on presentation (3-6 cm: OR 1.8; >6 cm: OR 1.8), but were less likely to have ≥pT2 stage (OR 0.5), regional nodal involvement (Clinical Stage II: OR 0.3), or distant metastatic disease (Clinical Stage III: OR 0.1; all P <.01). For postorchiectomy management, 73.6% of SS patients underwent surveillance while 24.5% had active treatment (retroperitoneal lymph node dissection, chemotherapy, radiation, or a combination). When stratified by year, there was an increasing trend toward surveillance compared to active treatment., Conclusion: SS is a rare germ cell tumor that typically presents as a larger tumor in older patients. Although these tumors are less likely to be characterized by advanced disease compared to classic seminoma, many patients have undergone aggressive postorchiectomy treatment in the past. Importantly, treatment trends have shifted toward surveillance in recent years with adjuvant therapy limited primarily to higher stage tumors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Previous studies have noted increased utilization of perioperative chemotherapy over time. The goal of this study was to determine trends in perioperative chemotherapy use within a contemporary population., Materials and Methods: The National Cancer Database was queried for patients diagnosed with cT2-4N0M0 urothelial muscle invasive bladder cancer from 2011 to 2015 and underwent subsequent radical cystectomy. We retrospectively analyzed factors associated with perioperative chemotherapy and evaluated overall treatment trends in the use of neoadjuvant and adjuvant chemotherapy. Linear regression, logistic regression, Cox regression, and Kaplan-Meier analysis were performed., Results: In total, 7,101 patients met inclusion criteria for analysis. The use of perioperative chemotherapy increased from 46.4% in 2011 to 57.2% in 2015 (p=0.003). Neoadjuvant chemotherapy use increased from 22.9% to 32.3% (p=0.007) over the time period analyzed, while adjuvant chemotherapy use experienced no significant change (23.5% to 24.9%, p=0.182). Logistic regression demonstrated that increased age and Charlson Comorbidity Index were predictors of not receiving chemotherapy (p<0.05), while those with increasing T stage, income above $48,000, and insurance other than Medicaid or Medicare were more likely to receive perioperative chemotherapy (p<0.05). Kaplan-Meier analysis revealed patients receiving neoadjuvant chemotherapy had the best 5-year overall survival at 48.3% compared to adjuvant chemotherapy (42.6%) or no chemotherapy (37.8%) (p<0.001)., Conclusions: The increasing use of perioperative chemotherapy noted in prior studies has continued through 2015. Neoadjuvant chemotherapy appears to drive this increase while adjuvant chemotherapy utilization remains unchanged. Clinical and socioeconomic factors affect utilization of perioperative chemotherapy., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association, 2020.)

Objective: The Japan Society of Gynecologic Oncology published its first clinical guidelines for uterine cervical cancer in 2007 which has been revised twice in 2011 and 2017. The aim of this study was to investigate the influence of the first guideline publication on the therapeutic trend and patient outcome by analyzing uterine cervical cancer cases registered to the cancer registry organized by the Japan Society of Obstetrics and Gynecology., Methods: Data of uterine cervical cancer cases registered to the cancer registry from 2000 to 2012 were provided. Epidemiological and clinical trend were analyzed by the Chi-squared test with subsequent standardized residual analysis. Overall survival among the patients registered between 2004 and 2009 was analyzed using the Fine and Gray competing risk model., Results: 68,707 cases were registered during the study period. A trend analysis revealed that the guideline publication may have led to a decrease in neoadjuvant chemotherapy in parallel with an increase in radiation therapy mainly in stage II and III patients undergoing primary treatment. A survival analysis indicated that the introduction of the guideline may have improved overall survival among stage III uterine cervical cancer patients, even though a significant difference was not observed in all of the cases., Conclusions: This study demonstrated the potential influence of the guideline publication on the clinical trend and patient outcome. As this is the first assessment of the guideline for uterine cervical cancer in Japan, continuous evaluation is necessary to further comprehend the significance of this guideline., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to disclose regarding to this study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Remarkable progress has been made in treating pancreatic cancer over the past century, including refinement of our surgical techniques and improvements in adjuvant and neoadjuvant therapies. Despite these advances, the incidence of pancreatic cancer is rising globally, and it remains a deadly disease. In this review, we highlight the historical perspectives of pancreatic cancer treatment and outline the areas of future advancement that will assist progression towards better outcomes. Areas of future advancement include improving prevention strategies and early detection, refining our molecular understanding of pancreatic cancer, identifying more effective systemic therapies, and improving quality of life and surgical outcomes. Furthermore, systems need to be put in place to ensure all patients with pancreatic cancer receive high quality care and are given the appropriate options and sequence of therapy. This is best achieved through multidisciplinary care.

The surgical treatment of pancreatic cancer (PDAC) has seen sweeping changes during the past 5 decades. Up to the middle of the 20th century resection rates were below 5%, but the numbers of curative resections for PDAC are now continuously increasing due to improved neoadjuvant treatment concepts as well as progress in surgical techniques and perioperative management. During the same period, mortality rates after pancreatic surgery have decreased considerably and are now less than 5%. One of the most important cornerstones of reduced mortality has been the concentration of PDAC surgery in specialized centers. In addition, the management of postoperative complications has improved greatly as a result of optimized interdisciplinary teamwork. Adjuvant chemotherapy has become the reference treatment in resected PDAC, achieving significantly prolonged survival. Moreover, the concept of borderline resectable PDAC has emerged to characterize tumors with increased risk for tumor-positive resection margins or worse outcome. The best treatment strategy for borderline resectable PDAC is currently under debate, whereas neoadjuvant therapy has become established as a beneficial treatment option for patients with locally advanced PDAC, enabling conversion surgery in up to 60% of cases. This review article summarizes the principal changes in PDAC surgery during the past 50 years.

Purpose: The role and uptake of internal mammary nodal irradiation (IMNI) is variable. This study was designed to quantify the rates and determinants of IMNI at a tertiary cancer center., Methods: Consecutively treated breast cancer patients receiving adjuvant locoregional radiation therapy (RT) from January 1, 2012 to December 31, 2017 were sorted by IMNI receipt, disease risk and time period of RT delivery (2012-2015 vs 2016-2017). Differences between risk categories and groups were evaluated using χ 2 /Fisher's and Mann-Whitney test for categorical and continuous variables, respectively. Univariable and multivariable logistic regression analysis was done to determine factors associated with IMNI receipt., Results: A total of 1566 patients were eligible, with 376 in Group 1 (IMNI), and 1190 in Group 2 (no IMNI). The proportion of patients receiving IMNI increased significantly each year (p < 0.0001), and 83% of patients receiving IMNI had pT1-2/pN1 disease. On univariable analysis, younger age, lymphovascular invasion, medial/central quadrant, higher stage, PR negative, mastectomy, axillary dissection, receipt of chemotherapy and nodal positivity had higher odds of IMNI. On multivariable analysis, younger age (p =  < 0.001), medial/central quadrant (p = 0.0026), PR negative (p = 0.0011), mastectomy (p = 0.0055), increasing nodal positivity (p < 0.0001) and late cohort (p = 0.001) had increased likelihood of IMNI. The use of deep-inspiration breath hold was significantly higher in those receiving IMNI (45% vs 26%, p < 0.0001), and permitted achievement of acceptable mean heart and lung doses., Conclusions: There was a significant increase in IMNI utilization after 2015. Younger age, medial/central quadrant, PR-negative and node-positive disease predicted for receipt of IMNI. Modern RT techniques permit the safe delivery of IMNI.

Conjunctival melanoma is a rare tumor of the conjunctival epithelium with a heterogenous clinical presentation and a propensity for regional and distant metastatic spread. Guidelines for the treatment of local conjunctival melanoma are well-established, but there are no standard efficacious therapies for metastatic disease. Given that conjunctival melanoma is genetically similar to cutaneous melanoma and mucosal melanomas, targeted therapies effective in the treatment of these diseases, such as BRAF inhibitors and KIT inhibitors, may be effective in the treatment of patients with metastatic conjunctival melanoma. Other targeted small-molecule drugs in the drug development pipeline for the treatment of more prevalent melanomas could also be applicable to conjunctival melanoma. Furthermore, systemic immunotherapy treatments that are now a mainstay in the treatment of cutaneous melanoma, such as programmed cell death-1 and cytotoxic T lymphocyte-associated antigen-4 inhibitors, could also stand to benefit patients with metastatic conjunctival melanoma. Limited case reports provide clues about the effectiveness of both targeted small-molecule inhibitors and immunotherapy in patients with advanced local and metastatic conjunctival melanoma and give credence to the argument that conjunctival melanoma patients should be included in major trials studying new therapies in both cutaneous and mucosal melanomas where applicable.

BACKGROUND Despite recent advancements in surgical techniques, chemotherapy, and radiotherapy, the 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) remains an unsatisfactory ~8%. MATERIAL AND METHODS Data were extracted to identify patients with non-metastatic pancreatic adenocarcinoma diagnosed in the periods 1988-1996 and 2010-2014 in the Surveillance, Epidemiology, and End Results (SEER) database. The statistical analyses were performed with the log-rank test, Pearson's chi-square test, propensity score matching, and Cox regression model. RESULTS The hazard ratio (HR) of surgery was reduced from 0.454 to 0.302 in Cox regression modeling, and there was no overlapping about the 95% confidence intervals (CI) of surgery between the 2 periods. The HR values of radiotherapy, which were new prognostic factor for resectable PDAC in 2010-2014, were reduced in both the resectable and unresectable groups. The upgraded chemotherapy regimen reduced the HR values from 0.738 to 0.689 in all PADC patients, and from 0.656 to 0.588 in unresectable PDAC. The log-rank test results showed that advances in surgery significantly improved the median survival from 13 months to 32 months. Radiotherapeutic and chemotherapeutic advancements extended median survival by 12 months and 11 months, respectively, in resectable PDAC. The median survivals were extended by 3 months for both of radiotherapy and chemotherapy in unresectable PDAC. CONCLUSIONS The development of chemotherapy and radiotherapy has been slow, especially for unresectable PDAC. Although advances in surgery contributed significantly to improved survival for resectable PDAC, lack of early diagnostic tools, which lead to low resection rates, remain a barrier for all PDAC patients.

Treatment options for metastatic renal cell carcinoma (RCC) continue to expand. Three recent phase III trials, Checkmate 214, Keynote-426, and Javelin Renal 101, have led to FDA approval of three new regimens for patients with clear cell RCC: nivolumab plus ipilimumab, pembrolizumab plus axitinib, and avelumab plus axitinib, respectively. At the same time, the dearth of treatment options for non-clear cell RCC has changed very little. The role of cytoreductive nephrectomy has also come into question after the publication of the CARMENA and SURTIME trials. This review will examine recent changes in therapeutic options in clear cell RCC and non-clear RCC, and the role of surgery in the treatment of metastatic RCC.

Five-year survival rates for patients with early-stage non-small cell lung cancer have room for improvement. Adjuvant chemotherapy results in a small but significant increase in overall survival at 5 years. Efforts to improve outcomes by intensifying adjuvant treatment, utilizing cancer-specific vaccines or tyrosine kinase inhibitors in unselected patients, have been unsuccessful. In addition to research with immune checkpoint inhibitors that are addressed in a separate article, ongoing studies to personalize adjuvant therapy either by selecting only patients with evidence of minimal residual disease or targeting tumor driver mutations are promising., Competing Interests: Disclosure Dr H.A. Wakelee: honoraria from Novartis and AstraZeneca; advisory board participation (compensated): AstraZeneca and Xcovery; advisory board (NOT compensated): Merck, Takeda, and Genentech/Roche; research funding to institution: ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bayer, BMS, Celgene, Clovis Oncology, Exelixis, Genentech/Roche, Gilead, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, and Xcovery; and travel: AstraZeneca. Dr J.A. Hellyer has no relevant conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Our objective was to test whether the rates of perioperative chemotherapy (CHT) administration in patients with urothelial bladder cancer (UCUB) with prostatic stromal invasion (pT4a) changed over time. Moreover, we tested the effect of CHT on overall mortality (OM), as well as on cancer-specific mortality (CSM) in this patient population., Materials and Methods: Within the Surveillance, Epidemiology, and End Results database (2004-2016), we identified 1513 men with non-metastatic UCUB with prostatic stromal invasion who underwent radical cystectomy with lymph node dissection, with or without CHT administration. Estimated annual percentage change analyses, inverse probability of treatment-weighting (IPTW), Kaplan-Meier plots, Cox regression models, and landmark analyses were performed., Results: Overall, 732 (48.4%) patients with pT4a UCUB disease underwent radical cystectomy with perioperative CHT administration between 2004 and 2016. The CHT administration rate increased from 29.0% in 2004 to 64.8% in 2016 (P < .001). In IPTW-adjusted analyses, the 5-year overall survival was 47.7% versus 39.8%, and cancer-specific survival was 53.6 versus 50.1%, for with versus without CHT administration, respectively. After multivariable and IPTW-adjusted Cox regression models, administration of CHT independently predicted lower OM (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.52-0.73), as well as lower CSM (HR, 0.66; 95% CI, 0.55-0.80). even after 3-month landmark analyses (OM HR, 0.64; 95% CI 0.54-0.76; CSM HR, 0.70; 95% CI, 0.58-0.85)., Conclusions: The use of CHT in patients with pT4a UCUB increased from low to moderate in the most contemporary era. However, based on its impressive reduction in OM, as well as in CSM, further increases in CHT administration rates should be highly encouraged in this patient population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The objective of this study is to determine demographic, clinical, and pharmaceutical factors that are associated with longer endocrine therapy usage duration., Methods: South Carolina Central Cancer Registry incidence data linked with South Carolina Medicaid prescription claims and administrative data were used. The study included a sample ( N  = 1399) of female South Carolina Medicaid recipients with hormone receptor-positive breast cancer diagnosed between 2000 and 2012 who filled at least one ET prescription. A series of multiple regression models were built to explore the association of demographic, clinical, and pharmaceutical factors with the endocrine therapy usage duration., Results: Multiple linear regression analysis showed that none of the demographic or clinical factors tested were significantly associated with the endocrine therapy usage duration. However, the type of endocrine therapy taken as well as receipt of the prescriptions that could have been used to alleviate side-effects (adrenals, nonsteroidal anti-inflammatory agents, anti-inflammatory agents, and vitamins) were significantly associated., Conclusion: Our study highlights the potential value of concurrent prescriptions for improving the endocrine therapy usage duration, with an optimal intervention point before 14 months post ET initiation. This work informs further research needed to test pharmacologic interventions that may significantly increase the endocrine therapy duration as well as other nonpharmacologic strategies for side-effect management.

Background: In the randomized controlled trial (RCT) EORTC 62931, adjuvant chemotherapy failed to show improvement in relapse-free survival (RFS) or overall survival (OS) for patients with resected high-grade soft tissue sarcoma (STS). We evaluated whether the negative results of this 2012 RCT have influenced multidisciplinary treatment patterns for patients with high-grade STS undergoing resection at seven academic referral centers., Methods: The U.S. Sarcoma Collaborative database was queried to identify patients who underwent curative-intent resection of primary high-grade truncal or extremity STS from 2000 to 2016. Patients with recurrent tumors, metastatic disease, and those receiving neoadjuvant chemotherapy were excluded. Patients were divided by treatment era into early (2000-2011, pre-European Organisation for Research and Treatment of Cancer [EORTC] trial) and late (2012-2016, post-EORTC trial) cohorts for analysis. Rates of adjuvant chemotherapy and clinicopathologic variables were compared between the two cohorts. Univariate and multivariate regression analyses were used to determine factors associated with OS and RFS., Results: 949 patients who met inclusion criteria were identified, with 730 patients in the early cohort and 219 in the late cohort. Adjuvant chemotherapy rates were similar between the early and late cohorts (15.6% versus 14.6%; P = 0.73). Patients within the early and late cohorts demonstrated similar median OS (128 months versus median not reached, P = 0.84) and RFS (107 months versus median not reached, P = 0.94). Receipt of adjuvant chemotherapy was associated with larger tumor size (13.6 versus 8.9 cm, P < 0.001), younger age (53.3 versus 63.7 years, P < 0.001), and receipt of adjuvant radiation (P < 0.001). On multivariate regression analysis, risk factors associated with decreased OS were increasing American Society of Anesthesiologists class (P = 0.02), increasing tumor size (P < 0.001), and margin-positive resection (P = 0.01). Adjuvant chemotherapy was not associated with OS (P = 0.88). Risk factors associated with decreased RFS included increasing tumor size (P < 0.001) and margin-positive resection (P = 0.03); adjuvant chemotherapy was not associated with RFS (P = 0.23)., Conclusions: Rates of adjuvant chemotherapy for resected high-grade truncal or extremity STS have not decreased over time within the U.S. Sarcoma Collaborative, despite RCT data suggesting a lack of efficacy. In this retrospective multi-institutional analysis, adjuvant chemotherapy was not associated with RFS or OS on multivariate analysis, consistent with the results from EORTC 62931. Rates of adjuvant chemotherapy for high-grade STS were low in both cohorts but may be influenced more by selection bias based on clinicopathologic variables such as tumor size, margin status, and patient age than by prospective, randomized data., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The standard treatment for locally advanced gastric cancer differs across the world. In western countries, perioperative chemotherapy or postoperative adjuvant chemoradiotherapy are the preferred treatment options, whereas in Asia, D2 gastrectomy followed by postoperative adjuvant chemotherapy is standard. In Japan, adjuvant chemotherapy with S-1 is the standard treatment for pStage II gastric cancer, whereas adjuvant chemotherapy with a doublet regimen is preferred for pStage III gastric cancer. The efficacy of preoperative neoadjuvant chemotherapy using S-1 plus cisplatin, has been investigated in selected patients with expected poor survival outcomes. To expand the indications for neoadjuvant chemotherapy, a clinical trial investigating the efficacy of preoperative S-1 plus oxaliplatin in patients with cStage III (cT3-4N1-3) gastric cancer (JCOG1509) is ongoing in Japan. The addition of immune checkpoint inhibitors to cytotoxic chemotherapy also seems promising and is being investigated in international randomized clinical trials. Although we have to await the final results of these studies, preoperative neoadjuvant chemotherapy is a promising treatment strategy and likely to become standard treatment for locally advanced gastric cancer in Japan.

Background: The management of proximal esophageal cancer differs from that of tumors located in the mid and lower part of the esophagus due to the close vicinity of vital structures. Non-surgical treatment options like radiotherapy and definitive chemoradiation (CRT) have been implemented. The trends in (non-)surgical treatment and its impact on overall survival (OS) in patients with proximal esophageal cancer are unclear, related to its rare disease status. To optimize treatment strategies and counseling of patients with proximal esophageal cancer, it is therefore essential to gain more insight through real-life studies., Aim: To establish trends in treatment and OS in patients with proximal esophageal cancer., Methods: In this population-based study, patients with proximal esophageal cancer diagnosed between 1989 and 2014 were identified in the Netherlands Cancer Registry. The proximal esophagus consists of the cervical esophagus and the upper thoracic section, extending to 24 cm from the incisors. Trends in radiotherapy, chemotherapy, and surgery, and OS were assessed. Analyses were stratified by presence of distant metastasis. Multivariable Cox proportional hazards regression analyses was performed to assess the effect of period of diagnosis on OS, adjusted for patient, tumor, and treatment characteristics., Results: In total, 2783 patients were included. Over the study period, the use of radiotherapy, resection, and CRT in non-metastatic disease changed from 53%, 23%, and 1% in 1989-1994 to 21%, 9%, and 49% in 2010-2014, respectively. In metastatic disease, the use of chemotherapy and radiotherapy increased over time. Median OS of the total population increased from 7.3 mo [95% confidence interval (CI): 6.4-8.1] in 1989-1994 to 9.5 mo (95%CI: 8.1-10.8) in 2010-2014 (logrank P < 0.001). In non-metastatic disease, 5-year OS rates improved from 5% (95%CI: 3%-7%) in 1989-1994 to 13% (95%CI: 9%-17%) in 2010-2014 (logrank P < 0.001). Multivariable regression analysis demonstrated a significant treatment effect over time on survival. In metastatic disease, median OS was 3.8 mo (95%CI: 2.5-5.1) in 1989-1994, and 5.1 mo (95%CI: 4.3-5.9) in 2010-2014 (logrank P = 0.26)., Conclusion: OS significantly improved in non-metastatic proximal esophageal cancer, likely to be associated with an increased use of CRT. Patterns in metastatic disease did not change significantly over time., Competing Interests: Conflict-of-interest statement: de Vos-Geelen J has received non-financial support from BTG, and Servier, and has served as a consultant for Shire and has received institutional research funding from Servier. van Laarhoven HWM has served as a consultant for BMS, Celgene, Lilly, Nordic, and Servier and has received unrestricted research funding from Bayer, BMS, Celgene, Lilly, Merck Serono, MSD, Nordic, Philips, Roche, and Servier, all outside the submitted work. Slingerland M has served as a consultant for BMS and Lilly. Tjan-Heijnen VCG has received honoraria/travel grants from Roche, Novartis, Pfizer, Lilly, and Accord Healthcare, and has received institutional research funding from AstraZeneca, Roche, Pfizer, Novartis, Eisai, and Lilly. All remaining authors have declared no conflicts of interest., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

Numerous rheumatologic autoimmune diseases, among which rheumatoid arthritis, are chronic inflammatory diseases capable of inducing multiple cumulative articular and extra-articular damage, if not properly treated. Nevertheless, benign conditions may, similarly, exhibit arthritis as their major clinical finding, but with short-term duration instead, and evolve to spontaneous resolution in a few days to weeks, without permanent articular damage. Such distinction- self-limited arthritis with no need of immunosuppressive treatment or chronic arthritis at early stages? -represents one of the greatest challenges in clinical practice, once many metabolic, endocrine, neoplastic, granulomatous, infectious diseases and other autoimmune conditions may mimic rheumatoid arthritis. Indeed, the diagnosis of rheumatoid arthritis at early stages is a crucial step to a more effective mitigation of the disease-related damage. As a prototype of chronic inflammatory autoimmune disease, rheumatoid arthritis has been linked to oxidative stress, a condition in which the pool of reactive oxygen species increases over time, either by their augmented production, the reduction in antioxidant defenses, or the combination of both, ultimately implying compromise in the redox signaling. The exact mechanisms through which oxidative stress may contribute to the initiation and perpetuation of local (in the articular milieu) and systemic inflammation in rheumatoid arthritis, particularly at early stages, still remain to be determined. Furthermore, the role of antioxidants as therapeutic adjuvants in the control of disease activity seems to be overlooked, as a little number of short studies addressing this issue is currently found. Thus, the present review focuses on the binomial rheumatoid arthritis-oxidative stress , bringing insights into their pathophysiological relationships, as well as the implications of potential diagnostic oxidative stress biomarkers and therapeutic interventions directed to the oxidative status in patients with rheumatoid arthritis., Competing Interests: The authors declare that no conflicts of interest exist., (Copyright © 2019 Lucas José Sá da Fonseca et al.)

Surgical excision is the treatment of choice for early stage melanoma, and this strategy is initially curative for the vast majority of patients. However, only approximately 40-60% of high-risk patients who undergo surgery alone will be disease-free at 5 years. These patients will ultimately experience loco-regional relapse or relapse at distant sites. The main aim of adjuvant therapies is to reduce the recurrence rate of radically operated patients at high risk and to potentially improve survival. Recent practice changing results with immune checkpoint inhibitors and targeted therapies have been published in stage III/IV melanoma patients, after surgical complete resection, and have dramatically improved the landscape of adjuvant therapy. Interferon-α, ipilimumab, and more recently anti-programmed cell death protein-1 antibodies and BRAF inhibitors plus MEK inhibitors have been approved in the adjuvant setting by the US Food and Drug Administration; similarly, the same drugs are approved by the European Medicines Agency with the exception of ipilimumab. A completely new scenario is emerging in the neoadjuvant setting as well: in locally advanced or metastatic disease, patients may partially respond to neoadjuvant therapy and become virtually resectable with systemic control of disease. This review summarizes the current state of the field and describes new strategies tracing the history of adjuvant therapy in melanoma, with a view on future projects.

Background: Historical data demonstrated similar survival outcomes in patients with stage I nonseminoma germ-cell tumor of the testis (NSGCTT) subjected to either surveillance or active treatment (AT) after orchiectomy. However, data with long-term follow-up are unavailable. We tested contemporary treatment rates and their effect on cancer-specific mortality (CSM) and other-cause mortality (OCM) relative to surveillance, as well as after stratification between chemotherapy (CHT) versus retroperitoneal lymph node dissection (RPLND)., Patients and Methods: We identified patients with stage I NSGCTT with initial orchiectomy within the Surveillance, Epidemiology, and End Results (SEER) database (1988-2015). Subsequent surveillance versus CHT versus RPLND use rates were reported. Cumulative incidence plots and multivariable competing-risks regression (CRR) models were used after propensity score (PS) matching. These tests first compared surveillance versus AT (CHT vs. RPLND) and subsequently CHT versus RPLND., Results: Of 5034 patients with stage I NSGCTT, 61.2%, 24.9%, and 13.9%, respectively, underwent surveillance, CHT, and RPLND. Between 1988 and 2015, surveillance (estimated annual percentage change [EAPC]: +1.1%, P < .001) and CHT (EAPC: +2.3%, P < .001) rates increased. RPLND rates decreased (EAPC: -5.7%; P < .001). After PS matching, CRR models failed to identify AT as an independent predictor of lower mortality relative to surveillance. However, after PS matching, CRR models identified RPLND as an independent predictor of lower CSM (hazard ratio, 0.26; P = .002) relative to CHT. No difference in OCM rates was recorded (hazard ratio, 1.25; P = .2)., Conclusion: Surveillance and CHT use rates increased while RPLND decreased in the last two decades. Virtually the same outcomes were recorded between surveillance and AT. However, within AT, RPLND was associated with lower CSM than CHT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Glioblastoma (GB) is the most aggressive primary brain tumor, historically resistant to treatment, and with overall fatal outcome., Recent Findings: Recently, several molecular subgroups and rare genetic alterations have been described in GB. In this review article, we will describe the current clinical management of patients with GB in the United States, discuss selected next-generation molecular-targeted therapies in GB, and present ongoing clinical trials for patients with GB. This review is intended for clinical and preclinical researchers who conduct work on GB and would like to understand more about the current standard of treatment of GB patients, historical perspectives, current challenges, and ongoing and upcoming clinical trials., Conclusions: GB is an extremely complex disease, and despite recent progress and advanced therapeutic strategies, the overall patient's prognosis remains dismal. Innovative strategies and integrative ways of approach to disease are urgently needed., (© 2019 Wiley Periodicals, Inc.)

Background: Many new antitumor drugs to treat soft tissue sarcoma (STS) were approved in the 2010's, and the need for the management of STS patients by medical oncologists has been increasing. Clinical data about the patterns of treatment of STS patients by medical oncologists in Japan are lacking., Methods: We retrospectively reviewed the clinical records of STS patients who consulted the Department of Medical Oncology at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research between August 2012 and March 2017. The STS patients who received any systemic chemotherapy at the Department of Medical Oncology were enrolled in the analyses. We evaluated the details of the systemic chemotherapies used: treatment regimens, drugs, and treatment settings. We focused on the treatment lines and the prognoses of salvage chemotherapy administered for recurrent and/or metastatic STS patients., Results: Among the 273 patients who consulted the Department of Medical Oncology, 185 patients (68%) received some systemic chemotherapy; 20 patients received chemotherapy as definitive and/or in a perioperative setting, and 171 patients in a salvage setting. The median overall survival of the 171 recurrent and/or metastatic STS patients who received salvage chemotherapy was 14.1 months (95%CI: 10.4-17.8), and the median number of salvage chemotherapy treatment lines throughout their follow-up periods was two lines (range 1-9)., Conclusion: About two-thirds of the STS patients who consulted a medical oncologist underwent chemotherapy. In the recurrent and/or metastatic settings, newly approved drugs such as pazopanib were frequently used, and the prognoses of the STS patients treated by medical oncologists were similar to those reported in recent global clinical trials. For the better management of patients with STS, medical oncologists should contribute to the management as multidisciplinary team members., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Introduction and Objectives: The treatment of locally advanced carcinomas of the hypopharynx may include surgery or several combinations of radiotherapy and chemotherapy as organ preservation strategies. The objective of the present study is to analyze the results of locally advanced hypopharyngeal carcinoma patients treated in a single centre over a 30-year period., Methods: Retrospective chart review of 278 patients with T3-T4 hypopharyngeal carcinomas treated between 1985 and 2015 at a tertiary institution., Results: As much as 15.5% of the patients received only palliative treatment. Surgery, usually followed by radiotherapy or chemoradiotherapy was offered to 38.1% of the patients, and radiotherapy or chemoradiotherapy alone was offered to the remaining 46.6% of the patients. Cause-specific survival at 5 years was 39.7% (95% CI 33.7-45.7) for the whole sample. Surgery achieved better local control of the disease, but these figures did not translate into an increase of cause-specific survival for T3 tumours. Five-year survival free of laryngeal dysfunction for patients who received conservative treatment was 36.4%. In a multivariate analysis, only T4 local extension, N2-3 category, and posterior hypopharyngeal wall location related significantly with cause-specific survival., Conclusions: There were no significant differences in cause-specific survival related to treatment modality for T3 carcinomas. On the other hand, surgery achieved a significant increase in cause-specific survival for T4 hypopharyngeal carcinomas., (Copyright © 2018 Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: The role of primary tumor resection (PTR) for asymptomatic stage IV colon cancer with unresectable metastases remains unclear. Increasingly there has been a trend away from resection. The aim of this study was to examine trends in the treatment of stage IV colon cancers, impact of different treatments on long-term mortality, and factors associated with receipt of postoperative chemotherapy., Methods: The 2006-2012 National Cancer Data Base was queried for stage IV colon cancer patients. Treatments were grouped into PTR and chemotherapy, PTR only, chemotherapy only, and no treatment. A descriptive analysis was performed examining patient and hospital characteristics associated with different treatments. A Cox regression analysis was used to assess the adjusted effect of different treatments on long-term survival. A multivariable logistic regression was used to examine factors associated with postoperative chemotherapy., Results: Of 31,310 patients, who met inclusion criteria, 22% of the patients underwent PTR and chemotherapy, 37.5% received chemotherapy only, 11.9% underwent PTR, and 28.6% received no treatment. Patients who received no treatment had the highest hazard of death at 1, 3, and 5 y, followed by PTR only, and chemotherapy only compared with PTR combined with chemotherapy. Patients who were older and had more comorbidities were less likely to receive postoperative chemotherapy., Conclusions: Primary tumor resection in conjunction with postoperative chemotherapy among stage IV colon cancer patients with unresectable metastases was associated with a long-term survival benefit compared with other treatment options. Efforts should be made to increase the use of postoperative chemotherapy where feasible., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Contemporary guidelines recommend cystectomy with neoadjuvant or adjuvant cisplatin-based chemotherapy given with curative intent for patients with resectable muscle-invasive bladder cancer (MIBC). However, rates and appropriateness of perioperative chemotherapy utilization remain unclear. We therefore sought to characterize use of perioperative chemotherapy in older radical cystectomy MIBC patients and examine factors associated with use., Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified patients with MIBC diagnosed between 2004 and 2013 and treated with radical cystectomy. We classified patients into 3 treatment groups: cystectomy alone, neoadjuvant, or adjuvant chemotherapy. Chemotherapy was classified by regimen. We then fit a multinomial multivariable logistic regression model to assess association between patient factors with the receipt of each treatment., Results: We identified 3,826 eligible patients. The majority (484; 65%) received cystectomy alone. Neoadjuvant (676; 18% overall, 69% cisplatin-based), and adjuvant chemotherapy (666, 17% overall, 55% cisplatin-based) were used in similar proportions of cystectomy patients. Over the study period, the odds of receiving adjuvant chemotherapy decreased by 7.5%, whereas neoadjuvant therapy increased by 27.5% (both P < 0.001). There was an increase in use of cisplatin-based regimens in the neoadjuvant setting (35 to 72%, P < 0.001), but not the adjuvant setting. Female gender, lower comorbidity, married status, and lower stage disease were associated with greater odds of receiving neoadjuvant chemotherapy (all P < 0.05)., Conclusion: From 2004 to 2013 use of neoadjuvant chemotherapy for MIBC increased while use of adjuvant chemotherapy decreased. Future studies examining barriers to appropriate chemotherapy use, and the comparative effectiveness of neoadjuvant versus adjuvant chemotherapy are warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Locally advanced muscle-invasive bladder cancer (MIBC) patients who are candidates for radical cystectomy (RC) should receive perioperative chemotherapy (CHT). However, the adherence to CHT guidelines is low. Thus, we tested contemporary CHT use rates and associated cancer-specific mortality (CSM) and overall mortality (OM) rates., Materials and Methods: Within the SEER database (2004-2015), we identified pT3N0/+ MIBC patients, who underwent RC, with or without perioperative CHT. Estimated annual percentage changes (EAPCs) analyses were used. After inverse probability of treatment weighting (IPTW), Kaplan-Meier (KM) analyses and Cox regression models (CRMs) tested the association of CHT on survival in the overall population (n = 3817), as well as after stratification according to stage, gender and age. Landmark analyses tested for immortal time bias., Results: Overall, 44.3% of patients received CHT. Between 2004 and 2015, CHT administration rates increased from 32.1% to 55.6% (EAPC: +6.0%; p < 0.001). In CRMs, CHT was associated with lower CSM (HR 0.73, CI 0.65-0.81) and OM (HR 0.69, CI 0.62-0.76). In sensitivity analyses, CHT was also associated with lower CSM and OM in N0 patients (CSM: HR 0.76, 95% CI 0.65-0.88; OM: HR 0.69, 95% CI 0.60-0.79) and in N+ patients (CSM: HR 0.69, 95% CI 0.59-0.80; OM: HR 0.67, 95% CI 0.58-0.77), as well as according to gender and age. Landmark analyses confirmed the above results., Conclusions: Perioperative CHT was associated with better survival and its rate of use increased in locally-advanced MIBC RC patients. The latter confirm one large observational study and several small prospective studies., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Population-based data on borderline ovarian tumors (BOTs) are scarce and information regarding recent trends in incidence, treatment and survival is lacking. The purpose of this study was to analyze these trends in the Netherlands and to assess the risk of developing a subsequent invasive ovarian tumor. Material and methods: All consecutive patients diagnosed with BOTs between 1993 and 2016 ( n  = 7113) were identified from the Netherlands Cancer Registry (NCR). Annual age-adjusted incidence rates were calculated. Relative survival (RS) analyses and multivariable analyses estimating excess mortality were conducted. Patients with a subsequent invasive ovarian tumor were identified by the NCR. Results: Age-adjusted incidence increased from 2.1/100,000 person-years in 1993 to 4.2/100,000 in 2011, after 2011 the incidence declined. The proportion of bilateral tumors decreased over time from 16% in 1993-1998 to 11% in 2005-2010 and remained stable onwards. Survival improved over time (excess mortality ratio adjusted 2011-2016 versus 1993-1998: 0.25; 95%CI: 0.13-0.47). Five-year RS increased from 91% in 1993-1998 to 98% in 2011-2016 and 10-year RS from 88% in 1993-1998 to 96% in 2005-2010. Fewer patients were treated with chemotherapy (4.4% in 1993-1998 versus 0.7% in 2011-2016). During a median follow-up time of 8 years, 0.9% developed a subsequent invasive ovarian carcinoma. Conclusions: The incidence of BOTs increased over time from 1993 until 2010 but declined since 2011. This decline may be partly due to changes in the classification of gynecological tumors, as serous BOTs are now more often diagnosed as low grade serous ovarian cancers. Survival is high and has improved since 1993. The risk of a subsequent invasive ovarian carcinoma seems low.

Background: It is not known whether perioperative chemotherapy, compared with adjuvant chemotherapy alone, improves disease-free survival (DFS) in patients with upfront resectable colorectal liver metastases (CLM). The aim of this study was to estimate the impact of neoadjuvant 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) on DFS in patients with upfront resectable CLM., Methods: Consecutive patients who presented with up to five resectable CLM at two Japanese and two French centres in 2008-2015 were included in the study. Both French institutions favoured perioperative FOLFOX, whereas the two Japanese groups systematically preferred upfront surgery plus adjuvant chemotherapy. Inverse probability of treatment weighting (IPTW) and Cox regression multivariable models were used to adjust for confounding. The primary outcome was DFS., Results: Some 300 patients were included: 151 received perioperative chemotherapy and 149 had upfront surgery plus adjuvant chemotherapy. The weighted 3-year DFS rate was 33·5 per cent after perioperative chemotherapy compared with 27·1 per cent after upfront surgery plus adjuvant chemotherapy (hazard ratio (HR) 0·85, 95 per cent c.i. 0·62 to 1·16; P  = 0·318). For the subgroup of 165 patients who received adjuvant FOLFOX successfully (for at least 3 months), the adjusted effect of neoadjuvant chemotherapy was not significant (HR 1·19, 0·74 to 1·90; P  = 0·476). No significant effect of neoadjuvant chemotherapy was observed in multivariable regression analysis., Conclusion: Compared with adjuvant chemotherapy, perioperative FOLFOX does not improve DFS in patients with resectable CLM, provided adjuvant chemotherapy is given successfully., (© 2019 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Background: Multimodality therapy (MMT) is recommended for patients with resectable gastric cancer, but no single approach has been established as standard. Little is presently known about current national practice patterns and sequencing of MMT., Methods: Retrospective cohort study of patients with gastric cancer aged 18 to 80 y in the National Cancer Database (2006-2014) with ≥T2 and/or node-positive disease (i.e., stage Ib to III) treated with MMT. Clinical nodal staging accuracy was ascertained among those treated with upfront surgery by comparing clinical and pathologic nodal staging. Multivariable Cox regression was used to evaluate the association between overall risk of death and MMT approach (i.e., radiation used versus not and treatment sequence)., Results: Among 5817 patients, 16.1% received perioperative MMT, 50.6% preoperative only, and 33.3% postoperative only. The sensitivity, specificity, positive predictive value, and negative predictive values of clinical nodal staging were 68.4%, 88.8%, 91.1%, and 62.7%, respectively. Current clinical nodal staging modalities understage 37.3% of clinically node-negative patients. Over time, radiation utilization decreased (74.3% in 2006 versus 53.9% in 2014; trend test, P < 0.001), perioperative MMT increased (8.9% versus 22.2%%; trend test, P < 0.001), and postoperative MMT decreased (43.1% versus 21.0%; trend test, P < 0.001). Neither type of MMT nor treatment sequence is associated with risk of death., Conclusions: One-third of patients with gastric cancer who are candidates to receive MMT are treated with upfront surgery. Given the high false negative rate of clinical nodal staging and high noncompletion rate of postoperative treatment, efforts should be directed at improving and optimizing preoperative therapy utilization., (Published by Elsevier Inc.)

Lynch syndrome is one of the most common hereditary cancer predisposition syndromes and is associated with increased risks of colorectal and endometrial cancer, as well as multiple other cancer types. While the mechanism of mismatch repair deficiency and microsatellite instability and its role in Lynch-associated carcinogenesis has been known for some time, there have been significant advances recently in diagnostic testing and the understanding of the molecular pathogenesis of Lynch tumors. There is also an increased awareness that the clinical phenotype and cancer risk varies by specific mismatch repair mutation, which in turn has implications on surveillance strategies for patients. Even the treatment of Lynch-associated cancers has changed with the addition of immunotherapy for advanced disease. This progress report aims to review some of the many advances in epidemiology, molecular pathogenesis, diagnosis, clinical phenotype, cancer surveillance, treatment, and chemo- and immune-prevention strategies in the Lynch syndrome field over the past 5 years.

Objective: We evaluated patterns of surgical care and their association with overall survival among a contemporary cohort of women with stage IV breast cancer., Background: Surgical resection of the primary tumor remains controversial among women with stage IV breast cancer., Methods: Women diagnosed with clinical stage IV breast cancer from 2003 to 2012 were identified from the American College of Surgeons National Cancer Database. Those with intact primary tumors who were alive 12 months after diagnosis were categorized by treatment sequence: (1) surgery before systemic therapy, (2) systemic therapy before surgery, and (3) systemic therapy alone. Multivariate logistic regression was used to estimate the association of treatment sequence with surgery type. Overall survival was estimated using multivariate Cox proportional hazards models., Results: Among 24,015 women, 56.2% (13,505) underwent systemic therapy alone and 43.8% (10,510) underwent surgical resection. Rates of surgery decreased slightly over time (43.1% in 2003 to 41.9% in 2011). Treatment with systemic therapy before surgery was associated with larger tumor size (median 4.5 vs 3.1 cm, P < 0.001) and receipt of mastectomy (81.4% vs 52.2%, P < 0.001) when compared to those who underwent surgery first. Receipt of surgery, whether before or after systemic therapy (Hazard Ratio, 0.68; 95% confidence interval, 0.62-0.73; Hazard Ratio, 0.56; 95% confidence interval, 0.52-0.61; P < 0.001), was independently associated with improved adjusted overall survival when compared to systemic therapy alone., Conclusions: Surgical resection of the primary tumor occurs in almost half of women with stage IV breast cancer alive 1 year after diagnosis, and is increasingly occurring after systemic therapy. Coordinated multidisciplinary care remains highly relevant in the setting of metastatic breast cancer, where surgical decisions should be made on an individual basis and may affect survival in select women.

Purpose of Review: This article will provide an opinion on adjuvant treatment of stage I-III endometrial cancer based on existing and evolving evidence., Recent Findings: For early-stage (I and II) intermediate risk endometrial cancer, vaginal brachytherapy reduces the risk of locoregional relapse. Recent studies have investigated the use of chemotherapy in early stage, high-risk patient population, but did not demonstrate a survival benefit. As such, chemotherapy is only recommended for selected patients at high risk for distant recurrence. On the other hand, for stage III disease, chemotherapy has a well established role. A landmark trial recently reported confirmed that chemoradiation improves recurrence-free survival compared with radiation alone in stage III endometrial cancer. However, in another randomized phase III trial, chemoradiotherapy was not superior to chemotherapy alone in this group, raising questions as to whether addition of radiation is necessary. Therefore, improved risk stratification using molecular markers in addition to traditional pathological criteria is critically needed to better predict the risk of local and systemic recurrence and to assist therapy decision-making., Summary: Endometrial cancer care is evolving and recent pivotal trials highlight the significance of chemotherapy to the treatment of stage III endometrial cancer and not to the approach for stage I and II cancer. The role of radiation therapy for stage III disease is raised into question.

Drug development in oncology usually establishes efficacy in metastatic disease before advancing a therapy to the adjuvant or neoadjuvant settings. Unfortunately, too often use in adjuvant or neoadjuvant settings fails to improve overall survival. Reasons for the modest benefits include the fact that in many cases surgery cures a majority of patients making it difficult to demonstrate gains. We begin by looking at the history of adjuvant and neoadjuvant therapies and the principles guiding their development. We summarize accepted adjuvant and neoadjuvant therapies in several cancers and tabulate their outcomes. Then, extending our work on the growth and regression rate constants of tumors and the fraction of cells killed we demonstrate that therapies developed in the metastatic setting primarily delay tumor growth rather than kill more cells and argue this is a likely explanation for poor outcomes in adjuvant or neoadjuvant settings. We suggest a rational approach for enhancing success., (Copyright © 2019. Published by Elsevier Inc.)