Therapy For Metastatic Cancer Research Articles

182P - Durable response to second-line m-FOLFIRINOX for advanced pancreatic adenocarcinoma in patients with performance status of two or less

BackgroundThe efficacy of FOLFIRINOX in the treatment of pancreatic adenocarcinoma is well known and documented. However, most published data involves young patients with a performance status ≤1 (ACCORD study). Thus, traditionally FOLFIRINOX has been regarded as a first line only treatment for patients with good performance status. Patients requiring second line therapy are not regarded as being fit enough to receive FOLFIRINOX. We have previously published our experience that m-FOLFIRINOX can be utilised safely in these individuals, with appropriate dose reductions. Our position has been supported by a subsequent systematic review (Tong et al.). This updated report of our dual institution experience adds further evidence supporting the use of m-FOLFIRINOX as a second line treatment for pancreatic adenocarcinoma. MethodsA retrospective analysis was conducted on patients with locally advanced or metastatic pancreatic adenocarcinoma from two institutions who received first-line gemcitabine plus nab-paclitaxel, followed by second-line m-FOLFIRINOX between December 2011 and July 2019. All patients had an ECOG performance status of 2 or less. Overall survival (OS) was estimated via the Kaplan-Meier method. ResultsWe identified 85 patients in our analysis, with 64% patients having metastatic disease at diagnosis. The median age of our patients at diagnosis was 65 (range, 26 – 81). The dose intensity of m-FOLFIRINOX was the following: 65% for oxaliplatin, 68% for irinotecan, 18% for bolus 5-fluorouracil (5-FU) and 68% for infusional 5-FU. The median OS of all patients was 46.0 months (95% CI, 35.0 – 68.0). The median OS of locally advanced and metastatic pancreatic cancer from diagnosis was 68.0 months (95% CI, 45.0 – 68.0) and 23.0 months (95% CI, 19.0 – 49.0), respectively. ConclusionsOur expanded case series continues to demonstrate the growing role of m-FOLFIRINOX as a second line therapy for advanced metastatic pancreatic cancer, after the failure of first-line gemcitabine plus nab-paclitaxel. We continue to suggest that formal clinical trials are needed to further investigate this efficacy. Legal entity responsible for the studySt John of God Hospital, Subiaco. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Targeted therapies in metastatic gastric cancer: Current knowledge and future perspectives.

Gastric cancer (GC) represents a leading cause of cancer related morbidity and mortality worldwide accounting for more than 1 million of newly diagnosed cases and thousands of deaths every year. In the last decade, the development of targeted therapies and the optimization of already available chemotherapeutic drugs has expanded the available treatment options for advanced GC and granted better survival expectations to the patients. At the same time, global efforts have been undertaken to investigate in detail the genomic and epigenomic heterogeneity of this disease, resulting in the identification of new specific and sensitive predictive and prognostic biomarkers and in innovative molecular classifications based on gene expression profiling. Nonetheless, several randomized studies aimed at exploring new innovative agents, such as immune checkpoint inhibitors, failed to demonstrate clinically meaningful survival advantages. Therefore, it is essential to further improve the molecular characterization of GC subgroups in order to provide researchers and medical oncologists with new tools for patients’ selection and stratification in future clinical development programs and subsequent trials. The aim of the present manuscript is to provide a global overview of the recent molecular classifications from The Cancer Genome Atlas and the Asian Cancer Research Group and to present key promising developments in the field of immunotherapy and targeted therapies in metastatic GC.

Experience of using atezolizumab in 1st line therapy of metastatic urothelial cancer

The article presents 2 clinical examples of using a PD-L1 inhibitor atezolizumab in treatment of urothelial cancer. In the 1st clinical case of bladder cancer, due to concomitant pathology any platinum-containing therapy was impossible. After 9 months of treatment with atezolizumab target lesions decreased by 55 %, and the patient’s condition improved significantly: pain intensity decreased, dysuria frequency decreased, appetite became normal. In the 2 nd clinical case of urothelial cancer, complete response to therapy was achieved after 10 months of treatment. Pain intensity decreased significantly, dysuria was cured. Both patients continue atezolizumab immunotherapy without any adverse events. Therefore, use of up-to-date oncoimmunological medications has entered clinical practice and allows to achieve good therapeutic effect with high treatment safety.

Volatile Compounds Are Involved in Cellular Crosstalk and Upregulation.

Cell-cell cross talk is of great importance in cancer research due to its major role in proliferation, differentiation, migration, and influence on the apoptotic pathway. Different cell-cell communication mechanisms have come mainly from proteomic and genomic approaches. In this paper, a new route is reported for cross talk between cancer cells that occurs, even when they are far away from each other. Single-cell and culture analysis shows that upregulation of cancer cells emits hundreds of volatile organic compounds (VOCs) into their headspace. Part of the VOCs remains without any change, disregarding the biological environment around it. The other part of the VOCs is exchanged between monocultures of the cells as well as between co-cultures of the cells with no physical contact between them, leading to different changes in growth than when left on their own. The chemical nature and composition of these VOCs have been determined and are discussed herein. Cell-to-cell cross talk has the advantage of being suitable for transfer/diffusion over relatively long distances. It would thus be expected to serve as a shuttling pad toward the development of advanced approaches that could enable very early detection of cancer and/or monitoring of metastasis and related cancer therapy.

Long-Term Survival Outcomes of Metabolically Supported Chemotherapy with Gemcitabine-Based or FOLFIRINOX Regimen Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy in Metastatic Pancreatic Cancer

Background: Despite introduction of new chemotherapeutic agents, outcomes of patients with metastatic pancreatic cancer are still poor. Metabolically supported chemotherapy (MSCT) is a novel approach targeting dysregulated energy mechanism of the tumor cell. Objectives: This study aimed to examine the efficacy of metabolically supported administration of chemotherapy combined with ketogenic diet, hyperthermia, and hyperbaric oxygen therapy (HBOT) in patients with metastatic pancreatic cancer. Method: This retrospective observational study included 25 patients with metastatic pancreatic ductal carcinoma (stage IV) who received MSCT (either gemcitabine-based or FOLFIRINOX regimen administered concomitantly with induced hypoglycemia) plus ketogenic diet, hyperthermia, and HBOT combination. Survival outcomes were evaluated. Results: During the mean follow-up duration of 25.4 ± 19.3 months, median overall survival and median progression-free survival were 15.8 months (95% CI, 10.5–21.1) and 12.9 months (95% CI, 11.2–14.6), respectively. Age and gender did not have any effect on overall survival (p > 0.05 for all). Conclusions: MSCT administered together with ketogenic diet, hyperthermia, and HBOT appears to be a viable option with the potential to improve survival outcomes in patients diagnosed with metastatic pancreatic cancer. Further research, particularly with larger comparative clinical trials, is warranted.

Bioengineered adipose-derived stem cells for targeted enzyme-prodrug therapy of ovarian cancer intraperitoneal metastasis

The objective of this study was to develop a stem cell-based system for targeted suicide gene therapy of recurrent, metastatic, and unresectable ovarian cancer. Malignant cells were obtained from the ascites of a patient with advanced recurrent epithelial ovarian cancer (named OVASC-1). Cancer cells were characterized to determine the percentages of drug-resistant ALDH+ cells, MDR-1/ABCG2 overexpressing cells, and cancer stem-like cells. The sensitivity and resistance of the OVASC-1 cells and spheroids to the metabolites of three different enzyme/prodrug systems were assessed, and the most effective one was selected. Adipose-derived stem cells (ASCs) were genetically engineered to express recombinant secretory human carboxylesterase-2 and nanoluciferase genes for simultaneous disease therapy and quantitative imaging. Bioluminescent imaging, magnetic resonance imaging and immuno/histochemistry results show that the engineered ASCs actively targeted and localized at both tumor stroma and necrotic regions. This created the unique opportunity to deliver drugs to not only tumor supporting cells in the stroma, but also to cancer stem-like cells in necrotic/hypoxic regions. The statistical analysis of intraperitoneal OVASC-1 tumor burden and survival rates in mice shows that the administration of the bioengineered ASCs in combination with irinotecan prodrug in the designed sequence and timeline eradicated all intraperitoneal tumors and provided survival benefits. In contrast, treatment of the drug-resistant OVASC-1 tumors with cisplatin/paclitaxel (standard-of-care) did not have any statistically significant benefit. The histopathology and hematology results do not show any toxicity to major peritoneal organs. Our toxicity data in combination with efficacy outcomes delineate a nonsurgical and targeted stem cell-based approach to overcoming drug resistance in recurrent metastatic ovarian cancer.

From perinuclear to intranuclear localization: A cell-penetrating peptide modification strategy to modulate cancer cell migration under mild laser irradiation and improve photothermal therapeutic performance

Tumor metastasis is a key cause that leads to the failure of cancer treatment. Inhibition of metastasis, rather than the simple removal of the primary tumor, is critical to the survival improvement. Here, we report a cell-penetrating peptide-modification strategy to realize substantial perinuclear accumulation and subsequent near-infrared (NIR) laser-triggered nuclear entry of palladium nanosheets (Pd NSs) for inhibition of cancer cell metastasis and photothermal cancer therapy. Specifically, it was found that the cell-penetrating peptide TAT-modified Pd NSs (abbreviated as Pd-TAT) mainly accumulated in the perinuclear region and showed the enhanced endocytosis and reduced efflux compared with the counterpart without TAT modification. On the one hand, Pd-TAT could inhibit cell migration and invasion. It was proposed that Pd-TAT located in the perinuclear region could promote the overexpression of lamin A/C proteins (related with nuclear stiffness) and increase the mechanical stiffness of the nucleus. More importantly, the introduction of NIR laser irradiation with a laser density of 0.3 W/cm2 (below the permitted value 0.329 W/cm2 for skin exposure) significantly enhanced the inhibitory effect of Pd-TAT on cancer cell migration, which might be due to the increased nuclear stiffness caused by the enhanced nuclear entry of Pd-TAT under the effect of mild laser-induced local hyperthermia in the perinuclear region. On the other hand, the increased nuclear entry of Pd-TAT under NIR laser irradiation greatly enhanced their photothermal therapeutic efficacy due to the susceptibility of the nucleus to hyperthermia. Taken together, the Pd-TAT-based and laser-promoted perinuclear-to-intranuclear localization strategy allows us to not only destroy the primary tumor more effectively, but also inhibit cancer metastasis more persistently.

Local therapy for cancer therapy-associated uveitis: a case series and review of the literature

Background/aimsImmunotherapy and targeted therapy for metastatic cancer may cause immune-related adverse events (irAEs) such as uveitis. If irAEs are severe or require systemic steroids, cancer therapy is often held or...

Evaluating vandetanib in the treatment of medullary thyroid cancer: patient-reported outcomes.

Medullary thyroid cancers (MTCs) are neuroendocrine tumors, which secrete calcitonin and carcinoembryonic antigen, both of which can serve as tumor markers. Extensive and accurate surgical resection is the primary treatment for MTC, whereas the use of external beam radiotherapy is limited. Moreover, since MTC is derived from thyroid parafollicular cells or C cells, it is not responsive to either radioiodine or thyroid-stimulating hormone suppression, and therefore, they cannot be considered as treatment strategies. Traditional therapies for advanced or metastatic progressive medullary thyroid cancer (pMTC) are poorly effective. Among the new approaches tested in clinical trials, targeted chemotherapies with tyrosine kinase inhibitors (TKIs) are now available and they represent effective interventions for progressive disease, with additional investigational options emerging. This paper reviews the efficacy and safety of vandetanib in patients with a pMTC, as it has been shown to improve progression-free survival (30.5 vs 19.3 months in controls). Vandetanib is approved by the FDA and EMA for symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease in adults, adolescents, and children older than 5 years. The most common adverse events in vandetanib-treated patients are diarrhea, rash, folliculitis, nausea, QTc prolongation, hypertension, and fatigue. More data are required to deepen our knowledge on molecular biology of tumor and host defense, with the aim to achieve better prognosis and higher quality of life for affected patients.

Multidrug Cancer Therapy in Metastatic Castrate-Resistant Prostate Cancer: An Evolution-Based Strategy.

Integration of evolutionary dynamics into systemic therapy for metastatic cancers can prolong tumor control compared with standard maximum tolerated dose (MTD) strategies. Prior investigations have focused on monotherapy, but many clinical cancer treatments combine two or more drugs. Optimizing the evolutionary dynamics in multidrug therapy is challenging because of the complex cellular interactions and the large parameter space of potential variations in drugs, doses, and treatment schedules. However, multidrug therapy also represents an opportunity to further improve outcomes using evolution-based strategies. We examine evolution-based strategies for two-drug therapy and identify an approach that divides the treatment drugs into primary and secondary roles. The primary drug has the greatest efficacy and/or lowest toxicity. The secondary drug is applied solely to reduce the resistant population to the primary drug. Simulations from the mathematical model demonstrate that the primary-secondary approach increases time to progression (TTP) compared with conventional strategies in which drugs are administered without regard to evolutionary dynamics. We apply our model to an ongoing adaptive therapy clinical trial of evolution-based administration of abiraterone to treat metastatic castrate-resistant prostate cancer. Model simulations, parameterized with data from individual patients who progressed, demonstrate that strategic application of docetaxel during abiraterone therapy would have significantly increased their TTP. Mathematical models can integrate evolutionary dynamics into multidrug cancer clinical trials. This has the potential to improve outcomes and to develop clinical trials in which these mathematical models are also used to estimate the mechanism(s) of treatment failure and explore alternative strategies to improve outcomes in future trials.

Successful anti-PD-1 therapy in metastatic endometrial cancer with microsatellite instability: a case report

High efficacy of anti-PD-1 therapy has been shown in malignant tumors with mismatch repair deficiency. According to the literature review, mismatch repair deficiency is determined in 20–40 % of all endometrial cancer cases and up to 48 % of its endometrioid subtype. We report the short review of the recent literature and the case of durable partial response on pembrolizumab immunotherapy in a patient with a metastatic endometrioid adenocarcinoma with MMR-deficiency progressed on 2 chemotherapy lines. Partial response was achieved after 6th course, treatment was stopped after 8th course. Patient is on follow-up without any anticancer treatment for 11 months. Partial response lasts for 13 months, with further reduction in tumor size. The treatment was well tolerated without adverse events.

Efficacy of first-line systemic therapy for left-sided primary metastatic colon cancer: a single-centre retrospective cohort analysis of 186 patients

Efficacy of first-line systemic therapy for left-sided primary metastatic colon cancer: a single-centre retrospective cohort analysis of 186 patients

Abstract SY38-02: Personalized adaptive therapy for metastatic cancer: An integrated approach

Abstract SY38-02: Personalized adaptive therapy for metastatic cancer: An integrated approach

Maintenance Olaparib for Germline

Although systemic therapy for metastatic pancreatic cancer has improved, overall survival (OS) is still less than 1 year, and no targeted or

Bevacizumab plus chemotherapy versus combination chemotherapy only in metastatic, recurrent, and persistent cervical cancer

Objective: The paclitaxel-cisplatin-bevacizumab triplet is a standard therapy in metastatic, recurrent, and advanced cervical cancer. Before bevacizumab was introduced for cervical cancer, we used both the paclitaxel-cisplatin-ifosfamide triplet (TIP) or the paclitaxel-cisplatin doublet (TP). To date, the efficacy of the paclitaxel-cisplatin-bevacizumab triplet (TPA) has not been compared with that of TIP. In this study, we compared the efficacy of chemotherapy with that of TPA in patients with recurrent, persistent, or metastatic cervical cancer.

Consensus Report From the Miami Liver Proton Therapy Conference.

An international group of 22 liver cancer experts from 18 institutions met in Miami, Florida to discuss the optimal utilization of proton beam therapy (PBT) for primary and metastatic liver cancer. There was consensus that PBT may be preferred for liver cancer patients expected to have a suboptimal therapeutic ratio from XRT, but that PBT should not be preferred for all patients. Various clinical scenarios demonstrating appropriateness of PBT vs. XRT were reviewed.

Anti-angiogenic therapy for persistent, recurrent and metastatic cervical cancer

Anti-angiogenic therapy for persistent, recurrent and metastatic cervical cancer

Camrelizumab combined with capecitabine and oxaliplatin followed by camrelizumab and apatinib as first-line therapy for advanced or metastatic gastric or gastroesophageal junction cancer: Updated results from a multicenter, open label phase II trial.

4031 Background: Capecitabine plus oxaliplatin (CAPOX) is one of the standard first-line treatments for advanced or metastatic gastric cancer. Camrelizumab (SHR-1210, an anti–PD-1 antibody) shows promising anti-tumor activity in patients (pts) with advanced or metastatic gastric or gastroesophageal junction (G/GEJ) cancer. Camrelizumab combined with CAPOX for untreated G/GEJ cancer was assessed as a part of an ongoing multicenter, open-label phase 2 trial (cohort 1), and encouraging preliminary results were reported. Here, we present the updated safety and efficacy data. Methods: In this cohort, systemic treatment naïve pts with HER2– advanced or metastatic G/GEJ adenocarcinoma were given camrelizumab 200 mg on Day 1, capecitabine 1000 mg/m2 bid on Days 1–14 and oxaliplatin 130 mg/m2 on Day 1 of each 21-day-cycle for 4 to 6 cycles followed by camrelizumab 200 mg every 3 weeks plus apatinib 375 mg qd until disease progression or intolerable toxicity. The primary endpoint was objective response rate. Results: At data cutoff (Jan 20, 2019), 43 of the 48 enrolled pts were evaluable. Partial response was observed in 28 pts (65%), and 19 (44%) were confirmed. Stable disease in 14 pts and progressive disease in 10 pts were reported. Median estimates for duration of response and progression-free survival were not reached. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 9 pts (21%), included neutropenia, diarrhea, rash and elevated ALT, whereas none of the TRAEs was fatal. Ten pts without progression after 4–6 cycles of camrelizumab and CAPOX combination therapy all received camrelizumab plus apatinib as sequential therapy, and no new safety signals were observed. Conclusions: The updated results confirmed that camrelizumab plus CAPOX followed by camrelizumab plus apatinib was well tolerated with noteworthy responses as first-line therapy in advanced or metastatic G/GEJ cancer pts. Expansion of this cohort in a phase 3 study are under way. Clinical trial information: NCT03472365.

Distance from the anal verge as an indirect measure to predict response to anti-EGFR therapy in left side metastatic colon cancer.

e15153 Background: Right and left sided colon cancers (RC, LC) differ with respect to biology and response to therapy. Several retrospective analyses have assessed the clinical effect of epidermal growth fator receptor (EGFR) targeted agents in patients with metastatic CRC (mCRC) according to the primary tumor location. Differentiating only right from left. But can in the LC responses differ according to the distance from the anal verge (DAV)? Methods: Exploratory retrospective analyses was planned to evaluate if LC responses differ according to the DAV. LC was defined as tumors originating anywhere from the distal rectum to the left colic flexure (splenic flexure). DAV was describe in cm measured by previous to surgery or treatment, colonoscopy, CT or MRI. Patients were divided for analysis purposes in two groups: Group A (tumors above 12cm from de anal verge), Group B (tumors below 12cm from the anal verge). Results: We retrospectively evaluated 29 patients with left metastatic colorectal cancer treated with anti-EGFR therapy as part of their treatment at the Paulistano Hospital -São Paulo from 2011 to 2018. Median population age 51.8 years (48.5-62.3). Median DAV 14.5 (4.6-25 cm). Median follow-up 12.8 months. No significant difference on stable and partial response rate was detected (Group A 43.7% vs Gropup B 56.3%), p=0.211. Long-rank test with a median pFS 8,5 meses and a PFS at 6 months of 66.7 vs 78,8 (Group A and Group B respectively ), p=0.901. Two-year OS was 58.4 % in Group A and 100% in Group B, p=0.17. Conclusions: Although no significant diferences were detected, responses rates were numerically higher in patients with tumors located below 12 cm from the anal verge. Further studies are needed to evaluate the association between response and DAV.

Target therapies in recurrent or metastatic head and neck cancer: state of the art and novel perspectives. A systematic review.

Recurrent or metastatic head and neck squamous-cell carcinomas (R/M HNSCC) are a group of cancers with a very poor prognosis. Many clinical trials testing novel target therapies in this setting are currently ongoing. We performed a systematic review focusing our attention on all clinical trials, ongoing or already published, concerning the use of novel drugs for treatment of R/M HNSCC. We found that the research of novel molecules effective in treatment of R/M HNSCC has been intense during last decade, and nowadays it is still very active. Unfortunately, the results in this setting have been, overall, disappointing: until now, only cetuximab and, recently, nivolumab and pembrolizumab received authorization for treatment of R/M HNSCC. Nevertheless, the promising results showed by some novel drugs may lead to continue the research in this field, with the aim of producing more evidence and finding new therapeutic indication.