Second-line Systemic Therapies Research Articles

An imaging-based review of systemic therapies and associated toxicities in metastatic pancreatic cancer as per the 2018 ASCO guidelines: what every radiologist should know.

To provide an overview of what radiologists should know about systemic agents utilized in the modern treatment of metastatic pancreatic cancer and their associated toxicities. The clinical landscape of metastatic pancreatic cancer has significantly evolved in recent years, with the advent of new first- and second-line systemic therapies. As these systemic treatment options continue to expand, knowledge of their clinically relevant features is becoming critical for radiologists. While the issues of surgical resectability and tumor response evaluation of advanced stages of pancreatic cancer have been thoroughly discussed in the radiology literature, the diagnostic importance of systemic therapies has tended to be less well appreciated. In this review, we provide a primer for radiologists outlining the radiologically pertinent features of modern systemic therapies used in the treatment of metastatic pancreatic ductal adenocarcinoma. These systemic agents are discussed from the standpoint of the newly updated 2018 ( https://doi.org/10.1007/s00261-019-01954-z ) guidelines for the treatment of metastatic pancreatic cancer from the American Society of Clinical Oncology (ASCO). Understanding the radiology relevance of these modern therapeutic agents is critical, especially with regard to treatment response and toxicity assessment. Knowledge of the modern systemic therapies utilized in the treatment of metastatic pancreatic cancer and their associated toxicity profiles is critical in diagnostic imaging interpretation.

A systematic review and meta-analysis of second-line therapies for treatment of mesothelioma.

Advanced malignant pleural mesothelioma (MPM) is generally treated with platinum/pemetrexed-based first-line therapy. Once the disease progresses, evidence for the efficacy of palliative treatments is lacking, and platinum re-challenge or single-agent chemotherapy are commonly used. To assess the effects of cytostatic or targeted therapy for treating MPM, we performed a systematic review and meta-analysis. PubMed, the Cochrane Library, and Embase databases were searched to identify published articles on second-line treatments for recurrent or advanced mesothelioma. Inclusion criteria were publication in the English language, describing clinical trials with 20 or more patients, and evaluability for efficacy and for receiving second-line systemic therapies. Data were pooled using number of events/number of evaluable patients, median overall survival (OS) and progression-free survival (PFS), according to a fixed or random effect model. Pooled median OS was the primary endpoint. A total of 49 eligible studies (n = 3938 patients; range, 12-400) were identified. Median progression-free survival (PFS) was 3.4 months (95%CI 2.87-3.93). Median pooled OS was 7.86 (95%CI 7.01-8.72). The pooled overall response rate (ORR) was 8.63% (95%CI 6-11.26), and the pooled disease control rate (DCR) was 54.8% (95%CI 48.9-60.6). Median pooled OS with platinum- and pemetrexed-based chemotherapy were 7.93 and 7.78 months, respectively. There remains uncertainty about the ideal second-line agent for MPM. Based on this meta-analysis, palliative chemotherapy or other experimental agents can be considered for patients with MPM who desire further treatment after their disease has progressed, during or after first-line therapy.

Medical Management of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) typically occurs in patients with advanced liver disease, so therapeutic decisions must account for the degree of underlying liver dysfunction and patient performance status in addition to tumor burden. Curative treatment options, including liver transplantation, surgical resection, and local ablative therapies, offer 5-year survival rates exceeding 60% but are restricted to patients with early-stage HCC. Surgical resection and local ablative therapies are also limited by high recurrence rates, highlighting a need for adjuvant and/or neoadjuvant therapies. A majority of patients with HCC are diagnosed beyond an early stage, when the tumor is no longer amenable to curative options. For patients with liver-localized HCC in whom curative options are not possible, transarterial therapies, either chemoembolization or radioembolization, can prolong survival but are rarely curative. Sorafenib and regorafenib are the only approved first-line and second-line systemic therapies, respectively, with a survival benefit for patients with advanced HCC; however, the benefit is primarily observed in patients with intact liver function and good performance status. There are several ongoing phase II and III trials evaluating novel systemic therapies, including immunotherapies. Patients with poor performance status or severe hepatic dysfunction do not derive any survival benefit from HCC-directed therapy and have a median survival of approximately 6 months. These patients should be treated with best supportive care, with a focus on maximizing quality of life. Multidisciplinary care has been shown to improve appropriateness of treatment decisions and overall survival and should be considered standard of care for patients with HCC.

801P - Second-line metastatic urothelial carcinoma treatment and survival in real-world patients in the US

Currently, there is no global standard of care for treatment of patients with metastatic urothelial cancer (mUC) who progress despite platinum-based chemotherapy. Practice guidelines recommend varied approaches from supportive care alone to single-agent chemotherapy based largely on the results of small single-arm trials that demonstrated modest activity. The treatment and outcomes of real-world patients with mUC treated with second-line (2L) systemic therapies remains underexplored. Pts diagnosed with stage IV transitional cell carcinoma of the bladder from 1/2004 to 12/2011 were identified in the US SEER-Medicare database. Other criteria included ≥ 66 y of age at diagnosis (1 y after Medicare eligibility), with no prior cancer diagnosis and enrolled in Medicare Parts A and B. 2L chemotherapy regimens were defined as any change in 1L chemotherapy or start of new treatment upon completion of 1L. Kaplan-Meier methods were used to assess survival by 2L treatment approach (follow up through 12/2013). 240 mUC pts treated with 2L chemotherapy were included. Median age at diagnosis was 75 y (IQR 71-79 y), and 81% of pts were aged ≥ 70 y; 74% were male and 93% were white. Most pts (199/240, 83%) received cisplatin- or carboplatin-based prior 1L therapies. The most common comorbidities included diabetes (16%) and chronic obstructive pulmonary disease (10%). Among pts receiving 2L chemotherapy, 40% (97/240) received single agents. The majority of pts who received single-agents had taxanes (paclitaxel 37/97, 38%; docetaxel 20/97, 21%), followed by gemcitabine (19/97, 20%) and other single agents (21/97, 21%). The median overall survival (OS) in pts receiving any single-agent 2L chemotherapy was 6.4 mo (95% CI, 4.4,-8.5 mo), with a 24-mo OS rate of 13%. The median OS in pts receiving single-agent taxanes was 5.2 mo (95% CI, 3.5-8.6 mo), with a 24-mo OS rate of 8%. In this real-world mUC population, pts received a wide variety of therapies in the 2L setting. Regardless of the treatment approach, outcomes were generally poor with a low likelihood of durable disease control. These results may serve as a benchmark for the effectiveness of novel therapies currently being developed for the treatment of mUC.

Treatments for gastrointestinal stromal tumors that are resistant to standard therapies.

The advent of the tyrosine kinase inhibitors imatinib and sunitinib dramatically revolutionized the therapeutic approach to gastrointestinal stromal tumor (GIST) and improved the outcomes of patients who were affected by this rare tumor, becoming the standard first- and second-line systemic therapies for advanced/metastatic GIST. Most patients obtain good, durable responses to treatment; nevertheless, almost all patients develop acquired resistance, which is commonly related to secondary mutations in receptors. Resistance represents an important clinical problem in oncology, underlining the need to identify novel agents in order to overcome it. In this article, we focus on the most recent developments in the therapy of advanced GIST that is resistant to standard therapies, including both new single drugs or drug-drug combinations, and the integration of systemic and locoregional treatment.

Evaluation of oral cyclophosphamide activity by CTC enumeration in patients with docetaxel-refractory castration-resistant metastatic prostate cancer: Potential utility in primary refractory disease.

166 Background: Recent data suggest that circulating tumor cell (CTC) enumeration is a surrogate predictive endpoint for survival in metastatic castration-resistant prostate cancer (mCRPC). Data supporting the notion of changing therapy from docetaxel based on CTC numbers is limited in PC, due to a limited experience with second-line systemic therapies following docetaxel failure. Methods: Peripheral blood from patients receiving cyclophosphamide following progression on docetaxel was analyzed by CellSearch Methodology (Veridex, LLC; Warren NJ) enumerate CTC. Circulating tumor cells were enumerated prior to and at least three weeks following the initiation of cyclophosphamide. Patients were categorized as responsive, defined as a follow up CTC of <5 cells or a greater than a 90% decline in counts between CTC determinations, or refractory (all others). Cyclophosphamide responsiveness was then correlated with docetaxel responsiveness using a Fisher-exact test. Results: Twenty two patients received oral cyclophosphamide therapy (50-150 mg/day). Of these, twelve (55%) were clinically primary docetaxel refractory, assessed by either clinical or PSAWG2 criteria while on docetaxel, and ten (45%) were initially responsive but subsequently progressed on docetaxel. Of the twelve patients who were primarily refractory to docetaxel, seven (58%) exhibited a cyclophosphamide response. In the majority of these cases, this response was durable with a complete disappearance of CTC. Conversely, only one patient (10%) who initially responded to docetaxel was sensitive to cyclophosphamide (P=0.031). Conclusions: Using a CTC endpoint cyclophosphamide appears to be active in patients initially refractory to docetaxel, but not those who initially responded. These data support the further evaluation of the potential for selective clinical utility of cyclophosphamide as second-line chemotherapy. [Table: see text]

Outcome of patients (pts) with renal medullary carcinoma (RMC) treated in the era of targeted therapies (TT): A multicenter experience.

386 Background: RMC is a rare, highly aggressive primary neoplasm of the kidney that almost exclusively afflicts young black pts with sickle cell hemoglobinopathies, primarily sickle cell trait. The primary objectives of this study were to evaluate the clinical characteristics and treatment outcome of RMC pts. Methods: We retrospectively reviewed the medical records of pts diagnosed with RMC at four US institutions between 2000 and 2010. Overall survival (OS) was determined from initial diagnosis to date of death or last follow up (F/U). The time interval from date of metastasis to death or last F/U (OSm) was also determined. Kaplan-Meier methods were used to estimate OS and OSm. Results: 20 RMC pts were identified. All pts were black; 14 (70%) were males; 18 had sickle cell trait, 1 had sickle thalassemia and 1 not tested. 19 presented with stages III or IV; 7 (35%) had nephrectomy. Nineteen pts had ≥ 2 metastatic sites. Twelve pts had performance status [PS] 0/1; eight pts had PS 2/3. For the OS analysis, data on 16 pts were available and for the OSm analysis, data on 20 pts were available. The median follow up time for the OS analysis was 722 days. Thirteen of 16 pts died with median OS of 421 days [95%CI: 225–546]. Sixteen of 20 pts died in the OSm analysis with median OSm of 378 days [95%CI: 225–487]. Frontline therapy consisted of TT [sunitinib (5), bevacizumab + erlotinib (1), imatinib (2)], chemotherapy (C) [platinum/gemcitabine or taxane (7), gemcitabine/doxorubicin (2)], C + TT [gemcitabine/cisplatinum/bevacizumab (2), imatinib/doxorubicin (1)]. Three pts achieved a partial response (PR) in first-line (2 with C, 1 with C + TT). Twelve pts received second-line systemic therapies; 4 achieved PR (1 with bevacizumab/erlotinib, 2 with C, 1 with C + TT). Among 15 pts who had TT at any time during their treatment course, only 1 pt had PR. Conclusions: The prognosis of RMC pts remains poor despite initial palliation with systemic therapy. Collaborative multi-institutional efforts are needed to better understand the biology of this disease and improve treatment strategies. No significant financial relationships to disclose.

Second-line systemic therapy and emerging drugs for metastatic transitional-cell carcinoma of the urothelium

Front-line platinum-based combination chemotherapy leads to high response rates but suboptimum overall survival for patients with advanced transitional-cell carcinoma of the urothelium. Bevacizumab is being assessed in combination with platinum-based first-line chemotherapy in a large phase 3 trial. Current second-line systemic therapies, including taxanes, yield disappointing outcomes. Vinflunine, a novel vinca alkaloid, showed some activity and was recently approved in Europe based on results of the first completed phase 3 trial in the second-line setting. Better understanding of molecular biology and the emergence of novel biological agents now offer the possibility of improved outcomes. Neoadjuvant therapy before cystectomy and consolidation therapy with biological agents after first-line therapy provide a framework for the development of new drugs. We propose that trials to approve new drugs target two separate populations; multicentre non-randomised phase 2 trials should include patients with chemotherapy-resistant disease progressing within 6 months of first-line therapy, and randomised trials might be appropriate for chemotherapy-sensitive disease progressing more than 6 months after first-line therapy. A multidisciplinary approach is necessary to make therapeutic advances. This review discusses current second-line therapy and emerging drugs for advanced transitional-cell carcinoma.