Benefit Of Systemic Therapy Research Articles

Benefit of systemic therapy in MINDACT patients with small, ER-positive, HER2-negative breast cancers

Small, hormone receptor-positive (HR+), HER2-negative (HER2-), lymph node-negative breast cancers are associated with relatively low rates of disease recurrence and have therefore been underrepresented in clinical trials assessing the effects of systemic therapy. Consequently, it remains uncertain if this patient population derives benefit from these treatments. For this exploratory analysis, we selected MINDACT (NCT00433589) patients with a HR+, HER2-, T1ab (≤1 cm) tumor and negative lymph nodes. Patients with discordant clinical risk and MammaPrint genomic risk classification were randmomized to receive chemotherapy based on either the clinical or the genomic risk assessment. Endocrine therapy treatment was based on local guidelines. 715/6693 (10.7%) MINDACT patients had HR+, HER2-, T1abN0 breast cancer and were included in this analysis. All were clinically low-risk, 124/715 (17.3%) were genomic high-risk. For genomic high-risk tumors, 8-year distant metastasis-free survival (DMFS) was 92.9% (95% CI 86.2–96.4%) compared to 95.0% (95% CI 92.8–96.6%) for genomic low-risk tumors. For genomic high-risk tumors treated with or without chemotherapy, 8-year DMFS was 89.2% (95% CI 73.6–95.8%) and 94.1% (95% CI 82.9–98.1%), respectively. For genomic low-risk tumors, the 8-year DMFS and disease-free survival (DFS) were 96.1% (95% CI 93.4–97.6%) and 89.3% (95% CI 85.5–92.2%) when treated with endocrine therapy and 92.9% (95% CI 87.9–95.9%) and 79.4% (95% CI 72.5–84.8%) without. In conclusion, although the number of randomized patients is small, patients with small, genomic high-risk breast cancer did not seem to derive benefit from chemotherapy. Endocrine therapy was associated with improved outcomes even in genomic low-risk breast cancers.

Phase 3 randomized study for evaluation of physician choice Rx versus best supportive care as second-line or beyond therapy in head and neck cancer with poor performance status.

LBA6019 Background: Relapsed-recurrent head and neck squamous cell carcinoma (HNSCC) cancers have limited treatment options in the second line and beyond setting. Many of these patients have poor performance status (PS) and are subject to best supportive care (BSC). There is a lack of any level 1 evidence about the benefit of systemic therapy in HNSCC with poor PS. Methods: This was a randomized phase 3 superiority open-label multicentric study. Adult patients (age>=18 years) with relapsed-recurrent HNSCC, qualified to receive 2nd line or beyond systemic palliative therapy and had ECOG PS 2-3 were eligible. Such patients underwent central stratified random assignment 2:1 to either physician choice therapy either triple metronomic chemotherapy (tablet erlotinib 150 mg [fixed-dose] OD, capsule celecoxib 200 mg [fixed-dose] BD, and oral weekly methotrexate 9 mg/m2 orally or intravenous docetaxel [75 mg/m2 3 weekly]) or BSC. The chemotherapy was continued either till the progression of the disease or till the development of intolerable side effects. The primary endpoint was 6 month-overall survival (OS). The OS in the 2 arms was estimated using the Kaplan-Meier method and by log-rank test. A p-value of 0.05 was considered significant. Sample size: The 6-month OS assumed based on our previous data was 20%, we had assumed that it would increase to 50% in the intervention arm with a type 1 error of 5%, type 2 error of 20%, 2:1 allocation (1- BSC and 2- intervention) and 10% lost to follow up rate. The sample size required was 66. The events required for analysis were 47. Results: The study recruited 66 patients between 1st September 2022 to 27th December 2022 with 44 patients in physician choice therapy (PCT) and 22 in the BSC arm. The data was censored for analysis on 1st March 2024. The median age was 50 years (Range 25-75) with a predominantly male population (n=53;85%). The ECOG PS was PS 2 in 56 (84.8%) and PS 3 in 10 (15.2%) patients. The predominant site of primary was the oral cavity with 52 patients (78.8%). The previous number of systemic lines of therapy received were 1 in 41 (62.1%), 2 in 22 (33.3%), and >2 in 3 (4.5%) patients. Except for 2, all patients had a platinum refractory status (64;97%). The PCT was triple metronomic chemotherapy in 41 patients (93.2%; n=44) and docetaxel in 3 patients (6.8%; n=44). The 6-month OS was 9.09% (95% CI 1.56-25.1) in the BSC versus 53.8% (95% CI 37.9-67.2) in the PCT arm (P<0.0001). The median overall survival in PCT was 223.0 days (95% CI 129-283) versus 77.5 days (95%CI 58 -110) in the BSC arm. The corresponding hazard ratio was 0.333 (95%CI 0.187-0.593; P<0.0001). The data regarding adverse events will be presented at the conference. Conclusions: In this first-ever randomized study on poor PS HNSCC patients, warranting second-line and beyond therapy, the administration of systemic therapy led to a substantial improvement in OS. Clinical trial information: CTRI/2022/08/044733 .

REPLACE: A phase III, randomized, open-label trial to evaluate the safety and efficacy of regorafenib and pembrolizumab versus locoregional therapy (LRT) with transarterial chemoembolization (TACE) or transarterial radioembolization (TARE), for the first-line treatment of intermediate-stage hepatocellular carcinoma (HCC) with beyond up-to-7 criteria.

TPS4200 Background: Intermediate-stage HCC represents a heterogeneous population, posing unique challenges for therapeutic management. With the advent of effective systemic therapies for unresectable HCC, the treatment landscape for intermediate-stage extends beyond LRT, particularly in patients with high tumor burden. The growing evidence about the benefit of systemic therapy in intermediate-stage HCC led to the inclusion in some recent guidelines of systemic therapy as the first choice of treatment in TACE-unsuitable patients with intermediate-stage HCC. Despite these recommendations, no randomized clinical trial has been published comparing LRT with TACE/TARE versus systemic therapy in patients with intermediate-stage HCC and high tumor burden. Methods: REPLACE is a phase III, multicenter, randomized, open-label trial that will compare the efficacy and safety of LRT with TACE/TARE versus systemic therapy, for the first-line treatment of intermediate-stage HCC with beyond up-to-7 criteria. Eligible participants will be randomized 1:1 to receive regorafenib (90 mg orally q.d. on days 1 to 21 of a 4-week cycle), and pembrolizumab (400 mg i.v. on day 1 of a 6-week cycle) or LRT with TACE or TARE, and will be stratified according to geographic region (Asia vs. non-Asia), ECOG Performance Status (0 vs 1) and Albumin-Bilirubin (ALBI) grade (1 vs 2). Patients must have intermediate-stage HCC with beyond up-to-seven criteria (Up-to-7 criteria = largest tumor diameter (cm) + number of tumors ≤7), measurable disease per RECIST 1.1, disease not amenable to curative treatment but amenable to LRT with TACE or TARE, no prior systemic or LRT for HCC, except for successful resection and/or ablation completed ≥ 6 months prior to randomization. Patients will be treated until progressive disease, unacceptable toxicity, or other treatment discontinuation criteria is met. The primary endpoint is progression free survival (PFS), assessed locally by the Investigator using mRECIST for HCC. Secondary endpoints include PFS assessed locally by the Investigator using RECIST 1.1; PFS centrally assessed using mRECIST and RECIST 1.1; overall survival; overall response rate according to RECIST v.1.1 and mRECIST based on the Investigator’s and central assessment; time to unTACEable progression; duration of response; safety and tolerability of the trial treatments, and patient reported outcomes for health-related quality of life. The estimated enrollment is 496 patients from approximately 14 countries. Recruitment started in October 2023 and is currently ongoing. Clinical trial information: NCT04777851 .

Improved uptake and survival with systemic treatments for metastatic non-small cell lung cancer: younger versus older adults

BackgroundOver the past decade, there has been increasing availability of novel therapeutics with improved tolerability and efficacy for advanced non-small cell lung cancer (NSCLC). The study goals were: to compare the uptake of systemic therapy (ST) before and after the availability of targeted tyrosine kinase inhibitors (TKI) and immunotherapy and to examine the changes in overall survival (OS) over time between younger and older adults with advanced NSCLC.MethodsAll patients with advanced NSCLC referred to British Columbia (BC) Cancer in 2009, 2011, 2015 and 2017 were included. One-year time points were based on molecular testing implementation and funded drug availability: baseline (2009), epidermal growth factor receptor TKI (2011), anaplastic lymphoma kinase TKI (2015) and Programed Death-1 (PD-1) inhibitors (2017). Age groups were <70years and ≥70years. Baseline demographics, simplified comorbidity scores (SCS), disease characteristics, and ST details were collected retrospectively. Variables were compared using X2, Fisher’s exact tests and logistic-regression analysis. OS was calculated using the Kaplan-Meier method and compared using the log-rank test.Results3325 patients were identified. Baseline characteristics were compared between ages < 70 years and ≥ 70 years for each time cohort with significant differences noted in baseline Eastern Cooperative Oncology Group (ECOG) performance status and SCS. The rate of ST delivery trended upwards over time with age <70 years: 2009 44%, 2011 53%, 2015 50% and 2017 52% and age ≥70 years: 22%, 25%, 28% and 29% respectively. Predictors for decreased use of ST for age <70 years: ECOG ≥2, SCS ≥9, year 2011, and smoking history; and age ≥70 years: ECOG ≥2, years 2011 and 2015, and smoking history. The median OS of patients who received ST improved from 2009 to 2017: age <70 years 9.1 m vs. 15.5 m and age ≥70 years 11.4 m vs. 15.0 m.ConclusionsThere was an increased uptake of ST for both age groups with the introduction of novel therapeutics. Although a smaller proportion of older adults received ST, those who received treatment had comparable OS to their young counterpart. The benefit of ST in both age groups was seen across the different types of treatments. With careful assessment and selection of appropriate candidates, older adults with advanced NSCLC appear to benefit from ST.

Novel Radiomic Measurements of Tumor-Associated Vasculature Morphology on Clinical Imaging as a Biomarker of Treatment Response in Multiple Cancers.

The tumor-associated vasculature (TAV) differs from healthy blood vessels by its convolutedness, leakiness, and chaotic architecture, and these attributes facilitate the creation of a treatment-resistant tumor microenvironment. Measurable differences in these attributes might also help stratify patients by likely benefit of systemic therapy (e.g., chemotherapy). In this work, we present a new category of computational image-based biomarkers called quantitative tumor-associated vasculature (QuanTAV) features, and demonstrate their ability to predict response and survival across multiple cancer types, imaging modalities, and treatment regimens involving chemotherapy. We isolated tumor vasculature and extracted mathematical measurements of twistedness and organization from routine pretreatment radiology (CT or contrast-enhanced MRI) of a total of 558 patients, who received one of four first-line chemotherapy-based therapeutic intervention strategies for breast (n = 371) or non-small cell lung cancer (NSCLC, n = 187). Across four chemotherapy-based treatment strategies, classifiers of QuanTAV measurements significantly (P < 0.05) predicted response in held out testing cohorts alone (AUC = 0.63-0.71) and increased AUC by 0.06-0.12 when added to models of significant clinical variables alone. Similarly, we derived QuanTAV risk scores that were prognostic of recurrence-free survival in treatment cohorts who received surgery following chemotherapy for breast cancer [P = 0.0022; HR = 1.25; 95% confidence interval (CI), 1.08-1.44; concordance index (C-index) = 0.66] and chemoradiation for NSCLC (P = 0.039; HR = 1.28; 95% CI, 1.01-1.62; C-index = 0.66). From vessel-based risk scores, we further derived categorical QuanTAV high/low risk groups that were independently prognostic among all treatment groups, including patients with NSCLC who received chemotherapy only (P = 0.034; HR = 2.29; 95% CI, 1.07-4.94; C-index = 0.62). QuanTAV response and risk scores were independent of clinicopathologic risk factors and matched or exceeded models of clinical variables including posttreatment response. Across these domains, we observed an association of vascular morphology on CT and MRI-as captured by metrics of vessel curvature, torsion, and organizational heterogeneity-and treatment outcome. Our findings suggest the potential of shape and structure of the TAV in developing prognostic and predictive biomarkers for multiple cancers and different treatment strategies.

Systemic therapy in patients with metastatic Xp11.2 translocation renal cell carcinoma.

341 Background: Xp11.2 translocation renal cell carcinoma (RCC) is a unique RCC subtype with high malignant potential and poor prognosis, its natural course and response to systemic therapy are not fully understood. We analyzed the clinic features of this distinct entity and the benefit of systemic therapy in these patients. Methods: Between May 2006 and December 2019, 1113 consecutive patients diagnosed with RCC from Peking university cancer hospital (Beijing, China) were reviewed, data of the clinical characteristics and outcome of patients with metastatic Xp11.2 RCC were retrospectively collected. Tumor response to systemic therapy was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) distributions. Results: Metastatic Xp11.2 tRCC was found in 45 patients. The median PFS and median OS was 7.4 months (4.5 - 8.8) and 17.9 months (12.4 - 24.4), respectively. First-line treatment mainly included sunitinib (n = 14), sorafenib (n = 15), axitinib (n = 6), and pazopanib (n = 5), and the median PFS of these regimens were 7.4 months, 5.4 months, 9.4 months, 8.9 months, respectively. Two patients who received Vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR-TKI) plus immune checkpoint inhibitor (ICI) as first line therapy had a PFS of more than 16.6 months and more than 25.6 months, respectively. Twenty-four patients received subsequent therapies, which included VEGFR-TKI/ICI, axitinib and mTOR inhibitor, the median PFS for these regimens was 8.5, 7.2 and 2.0 months, respectively. Patients with serous cavity effusion or IMDC poor risk groups had significantly shorter median PFS and median OS. Conclusions: Metastatic Xp11.2 tRCC is an aggressive disease. VEGFR-TKI agents appeared to demonstrate some efficacy, VEGFR-TKI/ICI combination might be a useful tool for the treatment of metastatic Xp11.2 tRCC.

Assessment of Predictive Biomarkers in Breast Cancer: Challenges and Updates.

The management of patients with breast cancer (BC) relies on the assessment of a defined set of well-established prognostic and predictive markers. Despite overlap, prognostic markers are used to assess the risk of recurrence and the likely benefit of systemic therapy, whereas predictive markers are used to determine the type of systemic therapy to be offered to an individual patient. In this review, we provide an update and present some challenges in the assessment of the main BC-specific molecular predictive markers, namely hormone receptors (oestrogen receptor [ER] and progesterone receptor [PR]), human epidermal growth factor receptor 2 (HER2), and KI67. As the main platform for assessing these markers in BC is immunohistochemistry (IHC), we address the cut-off values used to define positivity, the ER-low subgroup, the existence and significance of the ER-/PR+ phenotype, the use of PR in routine practice, and the role of hormone receptors in ductal carcinoma in situ. We discuss the newly introduced HER2-low class of BC and the clinical/biological difference between different HER2 groups (e.g., HER2 IHC score 3+ BCs vs. those with a HER2 IHC score 2+ with HER2 gene amplification). The review concludes with an update on the applications of KI67 assessment in BC and observations on the role of immune checkpoint identification in BC.

Overall survival benefits of advances in NSCLC systemic treatments: Younger versus older adults.

93 Background: Historically, there has been limited systemic therapy options for older adults with cancer attributed to underlying frailty, co-morbidities, poor functional status, and limited social supports. In the past decade, treatment for advanced NSCLC has changed with increasing availability of novel therapeutics associated with improved tolerability and efficacy, such as targeted therapy and immunotherapy. The study goal is to compare the difference in overall survival (OS) between younger adults and older adults with the introduction of novel therapeutic options. Methods: All patients with stage IV NSCLC referred to BC Cancer in 2009, 2011, 2015 and 2017 were included in the study. One-year time points were chosen based on molecular testing implementation and provincial formulary listing: baseline (2009), EGFR testing (2011), ALK testing (2015) and immunotherapy listing (2017). Age was categorized as younger (&lt; 70 years) and older (≥70 years) adults. Baseline demographics, simplified comorbidity score (SCS ≥9 associated with poor prognosis), disease characteristics, and systemic therapy details (agent, duration, line of therapy) were collected retrospectively. Univariate analysis using X2 and Fisher’s exact tests were used to compare age groups. OS was calculated using the Kaplan-Meier method and compared using the log-rank test. Results: 3325 patients with stage IV NSCLC were identified. Baseline characteristics for patients &lt; 70 y; female 51%, non-squamous 62%, ECOG ≥2 50%, SCS ≥9 29% vs patients ≥70 y; female 49%, non-squamous 57%, ECOG ≥2 61%, SCS ≥9 58%. In the four time cohorts 2009/2011/2015/2017, systemic treatment was delivered to &lt; 70 y 44/53/51/52 % vs ≥70 y 23/25/28/30 %. Median OS with BSC for &lt; 70 y 3.1/2.8/2.8/2.5 m vs ≥70 y 3.8/3.3/3.4/3.1 m (p = 0.10). Median OS with systemic treatment for &lt; 70 y 9.0/10.9/13.9/15.5 m (p &lt; 0.001) vs ≥70 y 11.4/11.7/13.9/14.9 m (p &lt; 0.001). Median OS by type of treatment BSC/chemotherapy only/targeted therapy/immunotherapy; &lt; 70 y 2.8/8.9/21.4/20.2 m vs ≥70 y 3.1/10.1/21.5/20.1 m (p &lt; 0.001). Conclusions: In this real-world retrospective review of patients with advanced NSCLC, there was an increased uptake of systemic therapy for both age groups with the introduction of novel therapeutics. Although there was a smaller proportion of older adults who received systemic therapy, those who received treatment had comparable OS to their young counterpart. The benefit of systemic therapy in both age groups was seen across the different types of treatments. This suggests with careful assessment and selection of appropriate candidates, older adults with advanced NSCLC should receive equitable access to systemic therapy.

Clinicopathologic features of Xp11.2 translocation renal cell carcinoma and its response to target therapy.

e16559 Background: Xp11.2 translocation renal cell carcinoma (RCC) is a unique RCC subtype with high malignant potential and poor prognosis, its natural course and response to systemic therapy are not fully understood. We analyzed the clinic features of this distinct entity and the benefit of systemic therapy in these patients. Methods: Between May 2006 and December 2019, 1113 consecutive patients diagnosed with RCC from Peking university cancer hospital (Beijing, China) were reviewed, data of the clinical characteristics and outcome of patients with metastatic Xp11.2 RCC were retrospectively collected. Tumor response to systemic therapy was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) distributions. Results: Metastatic Xp11.2 translocation RCC was found in 41 cases. The median PFS and Median OS was 6.3 months (4.4 - 8.8) and 17.3 months (12.4 - 21.8) for the whole cohort, respectively. First-line treatment mainly included sunitinib (n = 12), sorafenib (n = 13), axitinib (n = 6), and pazopanib (n = 4), and the median PFS of these regimens was 5.4 months, 5.1 months, 9.4 months, 8.3 months, respectively. Twenty-three patients received subsequent therapies, the median PFS and the median OS was 4.3 months and 12 months for the second-line therapy(n = 21), 4.3 months and 14.1 months for the third-line therapy(n = 11), 2.4 months and 9.6 months for the fourth-line therapy(n = 6). Conclusions: Metastatic Xp11.2 translocation RCC is an aggressive disease. Vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR-TKI) agents appeared to demonstrate some efficacy, the combination of VEGFR-TKI and immune checkpoint inhibitor (ICI) might be a useful tool for the treatment of metastatic Xp11.2 translocation RCC.

Non-pegylated Liposomal Doxorubicin as Palliative Chemotherapy in pre-Treated Advanced Pancreatic Cancer: A Retrospective Analysis of Twenty-Eight Patients.

Background: Pancreatic cancer carries a devastating prognosis and is the fourth leading cause for cancer-related death in the United States and most European countries. Although one-third of patients receive a palliative third line therapy, the benefit of systemic therapy beyond second-line remains unclear. A plethora of clinical trials investigating novel drugs have failed over the past years. Due to the lack of established treatment regimens beyond second line, we offered nonpegylated liposomal doxorubicin, well known in other tumor entities, to pretreated pancreatic cancer patients requesting systemic therapy. Material and Methods: In this retrospective analysis, 28 patients with pancreatic carcinoma treated with nonpegylated liposomal doxorubicin (Myocet®) between 2012 and 2018 at our department were included. Results: For the majority of patients (n = 18, 64%), nonpeglyted liposomal doxorubicin was offered as a third-line therapy. Five patients received it as second line, four patients as fourth line, and one patient as fifth line of therapy. Half of the patients received at least a therapy cycle. The objective response rate to treatment was 7.1%. One patient had a period of radiologically confirmed stable disease with stable tumor markers. Another patient experienced partial remission. Conclusion: According to our findings the benefit of nonpegylated liposomal doxorubicin in pancreatic cancer beyond second line is limited.

Do all patients with recurrent ovarian cancer need systemic therapy?

The scientific organizing committee of the 12th International Symposium on Advanced Ovarian Cancer: Optimal Therapy. Update proposed the question regarding whether all patients with recurrent ovarian cancer (ROC) need systemic therapy. This article has addressed this question and focused on the clinical scenarios in which the benefits of systemic therapy in patients with ROC are limited, including the frail elderly and patients with multiple medical comorbidities, as well as a subset of patients with platinum-resistant ovarian cancer who have a particularly poor prognosis with a short survival. The challenges of identifying and selecting which patients are unlikely to benefit from systemic therapy were addressed. The benefit of systemic therapy also can be questioned in specific histological subtypes of ROC such as low-grade serous cancers as well as clear cell and mucinous cancers in view of low response rates. Finally, the contentious question regarding the timing of chemotherapy in asymptomatic patients with CA 125 disease progression after response to first-line chemotherapy was addressed and an argument made challenging the current treatment paradigm. Clearly, not all patients with ROC need or should be offered systemic therapy, and ultimately the recommendations need to be based on evidence and communicated in a clear and sensitive manner to patients and their families.

A Method to Summarize Toxicity in Cancer Randomized Clinical Trials.

Purpose: Despite development of clinical "value frameworks" by national and international groups, there remains no generally accepted method to summarize toxicity in cancer clinical trials. We explored ways to simplify toxicity data of an arm of a cancer clinical trial to a single value, termed a "weighted toxicity score" (WTS).Experimental Design: We compiled 58 randomized clinical trials of FDA-approved kinase-directed inhibitors. We generated 5 models, each of which assigned different weights for each observed grade 1 to 4 toxicities. For each model, we calculated WTS values as different weighted averages of the sum of the toxicities. We correlated each WTS with the dose reduction rate in each trial, using the dose reduction rate as a clinically relevant surrogate of treatment that is too toxic. The WTS method yielding the strongest correlation with frequency of dose reduction was declared the best model.Results: Nineteen of 58 trials were placebo controlled and had complete data. Of the 5 models examined, differences in dose reduction rates correlated best with differences in WTS using a model with a clinician-weighted scale for toxicities (model M5). The WTS difference thus serves as a surrogate for a desired dose reduction rate difference and could be used to adjust dose/schedule as patients are accrued to a clinical trial.Conclusions: The WTS distills a tabular listing of toxicities of a treatment into a single value, and provides a simple method that can be incorporated into value frameworks, or used to guide discussion of the risks and benefits of systemic therapy. Clin Cancer Res; 24(20); 4968-75. ©2018 AACR See related commentary by Vaishampayan, p. 4918.

Utility of Adjuvant Chemotherapy After Neoadjuvant Chemoradiation and Esophagectomy for Esophageal Cancer.

To determine whether adjuvant chemotherapy (AC) after neoadjuvant chemoradiation and esophagectomy is associated with improved overall survival for patients with locally advanced esophageal cancer, and to evaluate how pathologic disease response to neoadjuvant treatment impacts this effect. Neoadjuvant chemoradiation is currently the preferred management approach for locoregional esophageal cancer. Although there is interest in the use of AC, the benefit of systemic therapy after neoadjuvant chemoradiation and esophagectomy is unclear. Retrospective cohort study of patients with esophageal cancer treated with neoadjuvant chemoradiation and esophagectomy in the National Cancer Data Base (2006-2012). Among 3592 patients with esophageal cancer (84.7% adenocarcinoma, 15.2% squamous cell carcinoma), 335 (9.3%) were treated with AC. AC was not associated with a significantly lower risk of death among patients with no residual disease (ypT0N0) or residual non-nodal disease (ypT+N0). Among patients with residual nodal disease (ypTanyN+), AC was associated with a 30% lower risk of death in the overall cohort [hazard ratio (HR) 0.70, (0.57-0.85)] and among those with adenocarcinoma [HR 0.69 (0.57-0.85)]. Using a 90-day postoperative landmark, findings were similar. Among patients with postoperative length of stay ≤10 days and no unplanned readmission, AC was associated with approximately 40% lower risk of death among patients with residual nodal disease [overall cohort, HR 0.63 (0.48-0.84); adenocarcinoma, HR 0.66 (0.49-0.88)]. AC after neoadjuvant chemoradiation and esophagectomy is associated with improved survival in patients with residual nodal disease. Our findings suggest AC may provide additional benefit for esophageal cancer patients, and merits further investigation.

Establishment of a New Approach to Defining Essential Medicines for Cancer: Implications of the 2014-2015 UICC Review of the WHO Model List

Abstract 4 Background: In 2013, there were more than 8 million deaths attributed to cancer, and nearly 15 million new cancer cases worldwide. The majority of this burden falls on countries that are often already triply burdened by infectious diseases, under-resourced systems, and inadequate numbers of health professionals. Access to medicines is a critical component of addressing gaps in cancer care outcomes, and has been prioritized by the United Nations in the post-2015 development agenda. Since 1977, the World Health Organization (WHO) has published a Model List of Essential Medicines bi-annually as a tool for policy-makers and procurement agencies. Approach: In January 2014, the WHO invited the Union for International Cancer Control (UICC) to convene a task team to review the cancer therapies on the WHO's Model List. UICC, and leadership from Dana-Farber Cancer Institute identified 27 diseases for consideration. Approximately 100 oncology experts from around the world participated. Disease-based documents were produced by at least 3 experts each, resulting in recommended treatment regimens which defined the medicines proposed for addition to the EML. This process was driven by the guiding principle of the magnitude of benefit of systemic therapies – for which the focus was on first-line options – and prevalence of disease, as in the case of lung cancer, for example. Further, the UICC task team recommended the establishment of a regular evaluation of cancers to be included for review, and anti-neoplastic agents indicated for treatment. Results: The new approach led to 16 new cancer medicines being added to the List, from a total of 22 proposed, including all of those recommended for children, and a method for periodic review and evaluation. Implications: Establishment of a disease-based approach to defining where cancer medicines can have the largest impact has been critical, as has the establishment of a scheduled re-evaluation of the list based on new data. The UICC and partners are beginning efforts to utilize the new list of cancer medicines with policy-makers in low-income settings with the goal of narrowing the gap to essential therapies for cancer patients in low and middle income countries. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Lawrence Shulman No relationship to disclose Claire Wagner Consulting or Advisory Role: Silver Creek Pharmaceuticals Ronald Barr No relationship to disclose Gilberto Lopes Honoraria: AstraZeneca, Roche/Genentech, Merck Serono, Merck Sharp &amp; Dohme, Fresenius Kabi, Novartis, Bristol-Myers Squibb, Janssen-Cilag Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, Lilly/ImClone Research Funding: Lilly/ImClone, Pfizer, AstraZeneca, Merck Sharp &amp; Dohme, Eisai Expert Testimony: Sanofi Giuseppe Longo No relationship to disclose Jane Robertson No relationship to disclose Gilles Forte No relationship to disclose Julie Torode No relationship to disclose Nicola Magrini No relationship to disclose

Emerging Risks of AML/MDS and Other Myeloid Neoplasms Following Chemotherapy for First Primary Malignancy, 2000-2012

Introduction. Treatment-related acute myeloid leukemia/myelodysplastic syndrome (tAML/MDS) is a rare but often fatal complication of systemic therapy for primary malignancy. Leukemogenicity of specific agents is variable, with particularly high risks associated with platinum-containing agents, certain alkylating agents, topoisomerase II inhibitors, and purine analogs. Current treatment practices increasingly include (neo)adjuvant and multiple courses of systemic therapy for a number of first primary malignancies. However, no large-scale study has quantified risks of tAML/MDS and other myeloid neoplasms after chemotherapy in the modern treatment era.Methods. We identified a cohort of 746,007 adults who were initially treated with chemotherapy and survived ≥1 year following diagnosis with first primary malignancy during 2000-2012, as reported to 17 US population-based cancer registries from the Surveillance, Epidemiology, and End Results program. Risks for second primary AML/MDS, chronic myeloid leukemia (CML), and other myeloproliferative neoplasms (MPNs) and MDS/MPNs were compared to that expected in the general population (based on age-, race-, sex- and calendar period-specific incidence rates) using standardized incidence ratios (SIRs).Results. tAML/MDS was identified in 2071 individuals following chemotherapy, four times more than expected based on general population rates (SIR=4.1, 95%CI=3.9-4.2). We identified novel elevations in tAML/MDS risk after chemotherapy for most gastrointestinal malignancies, including the oral cavity/pharynx (N=45, SIR=2.6, 95%CI=1.9-3.5), esophagus (N=28, SIR=4.3, 95%CI=2.9-6.2), liver (N=10, SIR=2.6, 95%CI=1.2-4.8), stomach (N=22, SIR=2.7, 95%CI=1.7-4.0), rectum (N=65, SIR=1.5, 95%CI=1.2-1.9), and anus (N=22, SIR=3.6, 95%CI=2.3-5.5), but not colon (N=67, SIR=1.1, 95%CI=0.8-1.3). Novel increased risks of tAML/MDS also were observed after chemotherapy for cancers of the pancreas (N=15, SIR=3.3, 95%CI=1.8-5.4), larynx (N=20, SIR=4.2, 95%CI=2.6-6.5), bladder (N=30, SIR=1.8, 95%CI=1.2-2.6), and melanoma (N=4, SIR=3.7, 95%CI=1.0-9.6)Similar to previous studies, tAML/MDS occurred most commonly after female breast cancer (N=543, SIR=4.1, 95%CI=3.8-4.5), non-Hodgkin lymphoma (NHL; N=515, SIR=7.3, 95%CI=6.7-7.9), and lung cancer (N=185, SIR=4.1, 95%CI=3.5-4.7). We further confirmed previous observations of strikingly elevated risks of tAML/MDS after chemotherapy for cancers of the bone (N=10, SIR=35.1, 95%CI=16.9-64.6), testis (N=18, SIR=15.6, 95%CI=9.2-24.6), and soft-tissue (N=20, SIR=12.6, 95%CI=7.7-19.4), and more modestly elevated risks of tAML/MDS after chemotherapy for cancers of brain (N=18, SIR-7.8, 95%CI=4.6-12.4), ovary (N=84, SIR=5.5, 95%CI=4.3-6.7), endometrium (N=28, SIR=4.4, 95%CI=2.9-6.3), cervix (N=22, SIR=4.4, 95%CI=2.8-6.6), and prostate (N=15, SIR=2.7, 95%CI=1.5-4.4), as well as Hodgkin lymphoma (N=54, SIR=8.7, 95%CI=6.6-11.4), chronic lymphocytic leukemia (N=52, SIR=7.7, 95%CI=5.8-10.2), and myeloma (N=102, SIR=6.3, 95%CI=5.1-7.6). Risks were non-significantly heightened with radiotherapy plus chemotherapy for breast, lung, and stomach cancers compared with chemotherapy alone.Elevated risks also were observed for CML after chemotherapy for lung cancer (N=12, SIR=2.5, 95%CI=1.3-4.4), breast cancer (N=35, SIR=1.8, 95%CI=1.3-2.5), and NHL (N=16, SIR=2.1, 95%CI=1.2-3.4), and for chronic myelomonocytic leukemia after chemotherapy for breast cancer (N=15, SIR=3.0, 95%CI=1.7-5.0) and NHL (N=16, SIR=4.2, 95%CI=2.4-6.9). In contrast, risks were not increased for other MPNs after chemotherapy for any first primary malignancy.Conclusions. Despite the availability of modern cancer chemotherapy and targeted agents, risks of tAML/MDS are elevated across a broad spectrum of first primary cancers and extend to other myeloid neoplasms. Risks are consistent with those expected from expanded use of leukemogenic systemic therapy, particularly for specific cancers, such as cervical cancer, that are commonly treated with platinum-based regimens. More research is needed to quantify risks associated with specific agents and doses in the (neo)adjuvant and treatment setting. Risks for treatment-related myeloid neoplasms should be weighed against benefits of systemic therapy. DisclosuresNo relevant conflicts of interest to declare.

Proposing Essential Medicines to Treat Cancer: Methodologies, Processes, and Outcomes.

A great proportion of the world's cancer burden resides in low- and middle-income countries where cancer care infrastructure is often weak or absent. Although treatment of cancer is multidisciplinary, involving surgery, radiation, systemic therapies, pathology, radiology, and other specialties, selection of medicines that have impact and are affordable has been particularly challenging in resource-constrained settings. In 2014, at the invitation of the WHO, the Union for International Cancer Control convened experts to develop an approach to propose essential cancer medicines to be included in the WHO Model Essential Medicines Lists (EML) for Adults and for Children, as well as a resulting new list of cancer medicines. Experts identified 29 cancer types with potential for maximal treatment impact, on the basis of incidence and benefit of systemic therapies. More than 90 oncology experts from all continents drafted and reviewed disease-based documents outlining epidemiology, diagnostic needs, treatment options, and benefits and toxicities. Briefing documents were created for each disease, along with associated standard treatment regimens, resulting in a list of 52 cancer medicines. A comprehensive application was submitted as a revision to the existing cancer medicines on the WHO Model Lists. In May 2015, the WHO announced the addition of 16 medicines to the Adult EML and nine medicines to the Children's EML. The list of medications proposed, and the ability to link each recommended medicine to specific diseases, should allow public officials to apply resources most effectively in developing and supporting nascent or growing cancer treatment programs.

Current status of gene expression profiling to assist decision making in stage II colon cancer.

The decision regarding adjuvant therapy for patients with stage II colon cancer remains a challenge. In contrast to stage III colon cancer, for which compelling clinical data support the use of adjuvant chemotherapy, the clinical benefit of systemic therapy in unselected patients with stage II disease is modest at best. Risk stratification based on clinicopathologic features and DNA mismatch repair status is commonly used in adjuvant therapy decisions, but these factors do not have a desired level of precision in identifying patients at high risk. Recently, gene expression platforms have been developed to further define risk and to assist in therapeutic decision making for patients with stage II disease. This review describes those platforms that are furthest along in clinical development, in an effort to place their potential clinical application in context.

Academic and community PCPs underestimate benefits of systemic therapy for lung and breast cancer.

e16545 Background: In previous studies primary care physicians (PCP) under-appreciated systemic therapy for breast cancer (BC) and even more for lung cancer (LC). Lack of knowledge and a possible bias against lung cancer patients were suggested as potential causes. This study evaluates if the unawareness about beneficial systemic therapy persists in the era of targeted therapy, and if academic PCPs have a different perception than community PCPs. Methods: 3444 surveys were sent out, (printed 2,497, electronic 947) to 1,993 Family Medicine (57%) and 1,451 Internal Medicine MDs (43%), in academic (13%) and non-academic centers (87%). Case scenarios asked if respondents believed in the potential curative and palliative role of chemotherapy in the early and advanced stage of either lung cancer (LC) or breast cancer (BC). The study was testing a 20% difference in response rate between academic and non-academic MDs with a power of 80% and alpha of 5%. Results: 316 physicians (9.1%) responded, 89 academic MDs (28%), 227 non-academic MDs (72%). The rate of returned surveys was equal by specialty. PCPs believed less in curative systemic therapy for LC than BC (42% vs. 72.6%, (p&lt;0.001). PCPs believed less in systemic therapy to improve DFS for LC than BC (58.2% vs. 75.5%, p&lt;0.001). PCPs believed palliative chemotherapy can prevent symptoms and prolong life in advanced asymptomatic disease, 79.5% in LC and 84.6% in BC (ns). Half of the PCPs refer patients with symptomatic advanced disease to palliative care before seeing medical oncology, 50.8% in LC and 53.1% in BC (ns). Academic and community MDs responded in the same pattern for all scenarios (p&gt;0.5). Conclusions: Academic and community PCPs are very often not aware of the curative and palliative benefits of systemic therapy. This persistent lack of awareness by PCPs requires more educational effort by medical oncologists and academic institutions.

Financial Consequences of Improved Treatments for Colorectal Cancer

Improvements in translational research have led to improved survival in patients with both localized and metastatic colorectal cancer. However, these benefits come at high costs, and the introduction of six new agents since 1996 for colorectal cancer has resulted in much higher treatment related costs. Even insured patients may face very high treatment related costs through deductibles and co-payments. In addition, since colorectal cancer is a disease of the elderly, many patients may also be facing high treatment related costs for their other medical problems. Physicians should be aware of how these high costs may influence patients' treatment choices and adherence with therapy. This information may be important in counseling patients about the risks and benefits of systemic therapy. These challenges are not limited to patients with colorectal cancer, and physicians who take care of cancer patients across all disease sites will need to confront this increasingly complex issue.

Standards and Novel Therapeutic Options in the Treatment of Patients with Soft Tissue Sarcoma

Soft tissue sarcomas are a heterogeneous group of tumours arising predominantly from the embryonic mesoderm. They account for less than 1% of all adult malignancies. The prognosis of patients with advanced metastatic soft tissue sarcoma remains poor with a disease-free survival at 5 years less than 10%. Despite improvements in local tumour control due to surgery and radiotherapy, distant metastasis and death remain a significant problem in 50% of patients. Complete resection remains the major factor in providing cure with limited benefits in local tumour control by radiotherapy and only minimal benefit of systemic therapy for metastatic disease. Only few chemotherapeutic agents have been identified to be active with reported response rates for doxorubicin and ifosfamide around 20%. New strategies are urgently needed to improve patients' outcome. Progress in the molecular characteristics, the understanding of biology and pathogenesis of these tumours has been made and should in the near future translate into molecularly based therapies. We describe current treatment strategies and existing standards. Moreover, we give an overview on the emerging compounds for patients with soft tissue sarcoma including recent developments of targeted therapy focusing on antiangiogenic and immunomodulatory drugs, Bcl-2 antisense therapy, raf kinase and mTOR inhibition, minor groove binders, and other agents being developed.