Breast cancer immunotherapy: Current and novel approaches.

The crucial role of the immune system in the progression/regression of breast cancer (BC) should always be taken into account. Various immunotherapy approaches have been investigated for BC, including tumor-targeting antibodies (bispecific antibodies), adoptive T cell therapy, vaccines, and immune checkpoint blockade such as anti-PD-1. In addition, a combination of conventional chemotherapy and immunotherapy approaches contributes to improving patients' overall survival rates. Although encouraging outcomes have been reported in most clinical trials of immunotherapy, some obstacles should still be resolved in this regard. Recently, personalized immunotherapy has been proposed as a potential complementary medicine with immunotherapy and chemotherapy for overcoming BC. Accordingly, this review discusses the brief association of these methods and future directions in BC immunotherapy.

Use of treatment pathway improves neoadjuvant chemotherapy use in muscle-invasive bladder cancer.

PURPOSE: To assess the trends of neoadjuvant chemotherapy (NAC) use since its introduction in our practice pathway in patients with cT2 + bladder cancer over a 20-year period. METHODS: This is a retrospective review of patients with cT2 + bladder cancer who underwent RC between 01/01/1998 and 01/01/2018 that aimed to evaluate the trends of NAC use and associated after implementation of a multidisciplinary treatment pathway. Cohorts were stratified into eras: pre-NAC (1998-2007) to NAC eras (2008-2018). Univariate analysis was conducted using Chi-squared test and Kaplan-Meier estimates were used to evaluate survival. RESULTS: In 904 total patients who underwent RC, there were 493 with cT2 + UCC disease. The rate of NAC peaked at 84.2% in the most recent year of analysis in all patients and was 100% in cT2 + patients eligible for NAC. There was an increased rate of complete response (downstage to pT0) from 8.7% to 15.8% (p = 0.018) between the two eras. Unadjusted survival analysis revealed improved overall survival (OS) between eras with 5-year OS 53.2% vs. 42.7% and 10-year OS 42.7% vs. 26.4% in the NAC vs. pre-NAC cohorts, respectively (p = 0.016). CONCLUSIONS: In this review of 20 years of experience, we report a dramatic rise in the use of NAC after adoption of a multidisciplinary pathway that is associated with expected survival benefits.

Changes in the multidisciplinary management of rectal cancer from 2009 to 2015 and associated improvements in short-term outcomes.

AIM: Significant recent changes in management of locally advanced rectal cancer (LARC) include preoperative staging, use of extended neoadjuvant therapies and minimally invasive surgery (MIS). This study was aimed at characterizing these changes and associated short-term outcomes. METHOD: We retrospectively analysed treatment and outcome data from patients with T3/4 or N+ LARC ≤ 15 cm from the anal verge who were evaluated at a comprehensive cancer centre in 2009-2015. RESULTS: In total, 798 patients were identified and grouped into five cohorts based on treatment year: 2009-2010, 2011, 2012, 2013 and 2014-2015. Temporal changes included increased reliance on MRI staging, from 57% in 2009-2010 to 98% in 2014-2015 (P < 0.001); increased use of total neoadjuvant therapy, from 17% to 76% (P < 0.001); and increased use of MIS, from 33% to 70% (P < 0.001). Concurrently, median hospital stay decreased (from 7 to 5 days; P < 0.001), as did the rates of Grade III-V complications (from 13% to 7%; P < 0.05), surgical site infections (from 24% to 8%; P < 0.001), anastomotic leak (from 11% to 3%; P < 0.05) and positive circumferential resection margin (from 9% to 4%; P < 0.05). TNM downstaging increased from 62% to 74% (P = 0.002). CONCLUSION: Shifts toward MRI-based staging, total neoadjuvant therapy and MIS occurred between 2009 and 2015. Over the same period, treatment responses improved, and lengths of stay and the incidence of complications decreased.

Treatment of malignant pleural mesothelioma with chemotherapy preceding versus after surgical resection.

OBJECTIVES: There are 2 main treatment paradigms recognized by the National Comprehensive Cancer Network for resectable malignant pleural mesothelioma (MPM): induction chemotherapy followed by resection (IC/R), and up-front resection with postoperative chemotherapy (R/PC). These paradigms are being compared in an accruing randomized phase II trial. In the absence of such completed trials, in this study we evaluated overall survival (OS) and postoperative outcomes of IC/R and R/PC. METHODS: The National Cancer Database was queried for newly diagnosed epithelioid/biphasic MPM. Metastatic, node-positive, and/or cT4 disease was excluded, along with nondefinitive surgery and lack of chemotherapy. Multivariable logistic regression ascertained factors independently associated with induction chemotherapy delivery. Kaplan-Meier analysis was used to evaluate OS between cohorts; multivariable Cox proportional hazards modeling was used to assess factors associated with OS. Survival was also evaluated between propensity-matched populations. Last, postoperative outcomes were assessed between groups. RESULTS: Overall, 361 patients (182 IC/R, 179 R/PC) were analyzed. Temporal trends revealed that IC/R is decreasing over time. Survival of the IC/R cohort was similar to that of R/PC patients (20.9 vs 21.7 months; P = .500); this persisted after propensity matching (20.8 vs 22.0 months; P = .270). However, patients who underwent IC/R experienced longer postoperative hospitalization (median 7 days vs 6 days; P = .001) and higher 30-day mortality (3.3% vs 0%; P = .020). CONCLUSIONS: To our knowledge, this is the only comparative investigation of the 2 major management paradigms of operable MPM. IC/R regimens are decreasing over time in the United States. Although associated with survival similar to R/PC, IC/R might be associated with worse postoperative outcomes. Careful induction chemotherapy patient selection is thus highly recommended.

National guidelines may reduce socioeconomic disparities in treatment selection for esophageal cancer.

The 2011 National Comprehensive Cancer Network guidelines first incorporated the results of the landmark CROSS trial, establishing induction therapy (chemotherapy ± radiation) and surgery as the treatment standard for locoregional esophageal cancer in the United States. The effect of guideline publication on socioeconomic status (SES) inequalities in cancer treatment selection remains unknown. Patients diagnosed with Stage II/III esophageal cancer between 2004 and 2013 who underwent curative treatment with definitive chemoradiation or multimodality treatment (induction and surgery) were identified from the Surveillance, Epidemiology and End Results (SEER)-Medicare registry. Clinicopathologic characteristics were compared between the two therapies. Multivariable regression analysis was used to adjust for known factors associated with treatment selection. An interaction term with respect to guideline publication and SES was included Of the 2,148 patients included, 1,478 (68.8%) received definitive chemoradiation and 670 (31.2%) induction and surgery. Guideline publication was associated with a 16.1% increase in patients receiving induction and surgery in the low SES group (21.4% preguideline publication vs. 37.5% after). In comparison, a 4.5% increase occurred during the same period in the high SES status group (31.8% vs. 36.3%). After adjusting for factors associated with treatment selection, guideline publication was associated with a 78% increase in likelihood of receiving induction and surgery among lower SES patients (odds ratio 1.78; 95% confidence interval (CI): 1.05,3.03). Following the new guideline publication, patients living in low SES areas were more likely to receive optimal treatment. Increased dissemination of guidelines may lead to increased adherence to evidence-based treatment standards.

A look at the progress of treating pancreatic cancer over the past 20 years.

INTRODUCTION: Pancreatic cancer is known to be the deadliest of all common cancers. Despite all efforts in pancreatic cancer treatment, the five-year survival rates at diagnosis over the past 20 years have only increased from 5% to 8%. Assuming that pancreatic cancer is going to become the second most frequent cause of cancer related death in the next 20 years, we are all encouraged to treat patients in clinical trials to gain improvements in this devastating disease. Areas covered: This review will provide a summary of pancreatic cancer treatment over the last 20 years, starting with the pivotal study in 1997 which showed the superiority of gemcitabine over 5-FU in advanced pancreatic cancer and is marked as the beginning of a new era in pancreatic cancer treatment. This review will also focus on improvements in different areas of treatment, including pancreatic surgery, adjuvant treatment, neoadjuvant therapy and palliative therapy. Expert commentary: The treatment of pancreatic cancer has changed substantially in the last 20 years compared to almost no improvements in the decades before. This provides hope that more effective treatment options will become available in the near future. Particularly, new concepts such as neoadjuvant therapy in resectable and borderline-resectable tumors may potentially shift treatment strategies.

Emerging therapeutic targets in esophageal adenocarcinoma.

The incidence of gastro-esophageal disease and associated rate of esophageal adenocarcinoma (EAC) is rising at an exponential rate in the United States. However, research targeting EAC is lagging behind, and much research is needed in the field to identify ways to diagnose EAC early as well as to improve the rate of pathologic complete response (pCR) to systemic therapies. Esophagectomy with subsequent reconstruction is known to be a morbid procedure that significantly impacts a patient's quality of life. If indeed the pCR rate of patients can be improved and those patients destined to be pCR can be identified ahead of time, they may be able to avoid this life-altering procedure. While cancer-specific biological pathways have been thoroughly investigated in other solid malignancies, much remains unexplored in EAC. In this review, we will highlight some of the latest research in the field in regards with EAC, along with new therapeutic targets that are currently being explored. After reviewing conventional treatment and current changes in medical therapy for EAC, we will focus on unchartered grounds such as cancer stem cells, genetics and epigenetics, immunotherapy, and chemoradio-resistant pathways as we simultaneously propose some investigational possibilities that could be applicable to EAC.

Neoadjuvant chemotherapy and primary debulking surgery utilization for advanced-stage ovarian cancer at a comprehensive cancer center.

OBJECTIVE: The aim of this study was to evaluate the use of neoadjuvant chemotherapy (NACT) and primary debulking surgery (PDS) before and after results from a randomized trial were published and showed non-inferiority between NACT and PDS in the management of advanced-stage ovarian carcinoma. METHODS: We evaluated consecutive patients with advanced-stage ovarian cancer treated at our institution from 1/1/08-5/1/13, which encompassed 32 months before and 32 months after the randomized trial results were published. We included all newly diagnosed patients with high-grade histology and stage III/IV disease. Associations between the use of NACT and clinical variables over time were evaluated. RESULTS: Our study included 586 patients. Median age was 62 years (range, 30-90); 406 patients (69%) had stage III disease, and 570 (97%) had disease of serous histology. Twenty-six percent (154/586) were treated with NACT and 74% (432/586) with PDS. NACT use increased significantly from 22% (56/256) before 2010 (at which point the results of the randomized trial were published) to 30% (98/330) after 2010 (p=0.037). Although patients who underwent PDS were more likely to experience grade 3/4 surgical complications than those who underwent NACT, those selected for PDS had a median OS of 71.7 months (CI, 59.8-not reached) compared with 42.9 months (CI 37.1-56.3) for those selected for NACT. CONCLUSIONS: In this single-institution analysis, the best survival outcomes were observed in patients who were deemed eligible for PDS followed by platinum-based chemotherapy. Selection criteria for NACT require further definition and should take institutional surgical strategy into account.

[Chemotherapy for early breast cancer: practices in 2010]. / Chimiothérapie des cancers du sein non métastatiques: état des lieux en 2010.

The management of breast cancer has changed at both surgery levels, with the development of sentinel node, and at the medical level with the use of new therapies. Breast cancer is a heterogeneous disease and each patient should be offered an adapted treatment in an effort to reduce the risk of relapse and death, with the minimal toxicities. The micrometastatic disease appears early in the history of the tumor and chemotherapy aims to eradicate it. In this review, we describe the state of practice regarding adjuvant and neoadjuvant chemotherapy for early breast cancer.

The Kadota Fund International Forum 2004--clinical group consensus.

The results from experimental studies indicate that hyperthermia is both an effective complementary treatment to, and a strong sensitiser of, radiotherapy and many cytotoxic drugs. Since the first international hyperthermia conference in 1975, Washington DC, techniques to increase tumour temperature have been developed and tested clinically. Hyperthermia can be applied by several methods: local hyperthermia by external or internal energy sources, perfusion hyperthermia of organs, limbs, or body cavities, and whole body hyperthermia. The clinical value of hyperthermia in combination with other treatment modalities has been shown by randomised trials. Significant improvement in clinical outcome has been demonstrated for tumours of the head and neck, breast, brain, bladder, cervix, rectum, lung, oesophagus, for melanoma and sarcoma. The addition of hyperthermia resulted in remarkably higher (complete) response rates, accompanied by improved local tumour control rates, better palliative effects, and/or better overall survival rates. Toxicity from hyperthermia cannot always be avoided, but is usually of limited clinical relevance. In spite of these good clinical results, hyperthermia has received little attention. Problems with acceptance concern the limited availability of equipment, the lack of awareness concerning clinical results, and the lack of financial resources. In this paper the most relevant literature describing the clinical effects of hyperthermia is reviewed and discussed, and means to overcome the lack of awareness and use of this modality is described.

Current treatments and future perspectives in colorectal and gastric cancer.

Given the high rate of distant spread, effective systemic therapy is key to improving survival in patients with colorectal cancer (CRC). The past 40 years have seen progress. The addition of folinic acid (FA) to 5-fluorouracil (5-FU), the use of infusional rather than bolus 5-FU, and the combination of new active agents such as irinotecan and oxaliplatin with 5-FU/FA have each led to an increase in activity. In trials of current combination regimens first-line, response rates (RRs) in excess of 50% and median survival durations longer than 16 months are seen. A recent controlled trial suggests that overall time to progression is maximized and toxicity minimized when an irinotecan/5-FU/FA combination is used first-line, followed by an oxaliplatin/ 5-FU/FA combination on progression. In the adjuvant setting, 5-FU/FA is the standard of care in stage III disease but of uncertain value in stage II patients. The role of new agents such as irinotecan in adjuvant regimens is being assessed. Use of highly active chemotherapy in patients with unresectable disease (particularly liver metastases) achieves responses that allow a subset of patients to proceed to potentially curative surgery. The emergence of novel agents targeted at processes such as tumor angiogenesis will complement cytotoxic chemotherapy, while improved understanding of tumor biology should enable agents to be selected according to the likely sensitivity of the disease in a particular patient. In gastric cancer also, surgery remains the only potentially curative treatment. The extent of dissection required is debated, as is the potential benefit of adjuvant chemoradiotherapy (indeed the degree of resection may interact with the effect of adjuvant treatment). In untreated metastatic gastric cancer, median survival is 3-4 months. This can be increased to around 10 months using chemotherapy. Quality of life is also enhanced. There is no clearly defined standard of care. However, some form of cisplatin/5-FU combination can serve as a reference regimen. As single agents, both irinotecan and docetaxel achieve RRs of around 20% in metastatic CRC. In combination with cisplatin and/or 5-FU a very high and promising RR is achieved. The promise of these agents in combination with 5-FU and 5-FU plus cisplatin is currently being tested in phase III trials.

Combined modality therapy of rectal cancers.

Rectal cancer accounts for about 10% of new cancer cases each year. It strikes men and women at nearly the same rate, generally in the range of 50-80 years of age, with rising incidence with age. Despite simple screening procedures rectal cancer is often advanced when discovered. Current trends in the management of cancer have focused on organ preservation and improved quality of life without compromising the overall survival. During the last decade substantial progress has been made in treatment modalities: new and improved radiation techniques (conformal radiotherapy, altered fractionation, brachytherapy), chemotherapy (protracted infusion, use of radiosensitizers) and development of surgical procedures-enabling safer postoperative irradiation. In patients with advanced/unresectable disease aggressive combined chemoradiation can be added prior to surgery to downstage the tumour and increase the proportion treated with anal-rectal-sparing procedures. Preoperative chemoradiation therapy regimens are as safe and tolerable as the standard postoperative treatment. In this presentation indications for preoperative radiochemotherapy will be discussed in detail, together with treatment-related side effects, prognostic parameters, tumour response and outcome. Different irradiation settings and chemotherapy schedules are described. In patients with primary resectable disease (mainly Dukes C) several prospective randomised trials have shown less local recurrence with postoperative combined modality therapy.