Anticancer Treatment Regimens Research Articles

Adherence Issues for Oral Antineoplastics

Nonadherence to antineoplastics is a growing concern because of the increasing number of novel oral targeted anticancer therapies. Many of these agents are administered on a chronic continuous schedule for an indefinite period of time where adherence is crucial to achieve optimal disease control and prolong survival. Many factors are known to contribute to medication nonadherence. Prevention, early detection, and management of adverse drug reactions associated with oral targeted therapies require close vigilance. Knowing how to prevent and manage adverse drug reactions will help clinicians develop strategies to promote patient adherence to oral anticancer treatment regimens. Optimal adherence requires a dynamic patient-provider alliance through education, communication, ongoing monitoring, and follow-up.

Abstract 3404: Exploring the role of Twist1 in the pathogenesis of malignant pleural mesothelioma (MPM)

Abstract Background: MPM is caused by lethal neoplastic growth of the pleura surrounding lungs. It is resistance to most standard anti-cancer treatment regimens and needs discovery of newer therapeutic approaches. MPM is characterized by massive loco-regional invasion of the malignant pleural cells into the lung parenchyma. Twist1 is a transcription factor, which promotes invasion and metastasis of tumor cells, increases chemotherapeutic resistance and is involved in the pathobiology of many cancers. Also recent studies have highlighted the potential of twist1 as a therapeutic target in cancer. But there is no report investigating its function in mesothelioma. Methods: We extracted total RNA from 53 frozen resected tumor tissue specimens, comprised of 39 epitheloid, 7 sarcomatoid and 7 biphasic histotypes, along with paired normal tissue. The RNA was labeled and hybridized to Affymetrix U133 plus 2.0 microarray to obtain transcriptomic profiles. Bioinformatic analysis of the microarray data using a 2 sample t-test was applied, on a probe-by-probe basis followed by Beta-uniform Mixture for multiple comparisons, to determine the differences between tumor vs normal specimens. The microarray results were validated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) using Taqman assays on the ABI 7300 platform. For all qRT-PCR experiments the twist1 transcript levels were determined relative to endogenous GAPDH as control using ΔΔCT calculation. We performed Western blot analysis on a panel of 16 mesothelioma cell lines including Met-5A (SV-40 immortalized) and HCT-4012 (telomerase immortalized) pleural mesothelial control cell lines. Results: The bioinformatic analysis of microarray data showed that twist1 transcript level was 8.7 fold higher in tumors (p = 1.1E-16) compared to paired normal specimens. Using qRT-PCR, we compared twist1 transcript levels in 12 pairs of tumor vs paired normal tissue specimens and found that twist1 was upregulated to more than 10 fold in MPM tumors (p < E-4). Western blot showed that 10 MPM cancer cell lines had higher expression of twist1 protein compared to Met-5A and HCT-4012 cell lines. The highest expression was seen in 2 of the sarcomatoid cell lines - RS5 and DM3, suggesting a correlation with metastatic phenotype since sarcomatoid tumors are highly metastatic in nature. Conclusion: Our preliminary findings suggest that twist1 is upregulated in MPM tumors and cell lines and may play a role in the development of MPM. Further studies are needed to investigate its role in the process of tumorigenesis and metastasis. Supported by Grants: DoD W81XWH-07-1-0306 (I.I.W and AST), Fleming Foundation, IASLC Young Investigator Award 2011-2013 (MS). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3404. doi:1538-7445.AM2012-3404

Abstract B95: Disparities in cancer drug use in the geriatric patient

Abstract Background: Many older patients with cancer have multiple co-morbidities requiring multiple medications in addition to their anticancer therapies. Ensuring appropriate medication use in this population, including adequate treatment dosage and adhering to treatment guidelines, is therefore a public health priority. We reviewed the epidemiological literature regarding anticancer treatment administration to older cancer patients. Methods: We conducted a systematic literature review of population-based, epidemiological studies published between 1983 and 2006 on medication use involving chemotherapy and hormonal therapy among cancer patients aged 65 and older. Articles were classified into content areas based on processes of care and adverse drug reactions. Searches were conducted using PubMed, CancerLit, and Ageline. Medical subheadings were used to supplement searches. Only population-based, epidemiological studies published in English between 1983 and 2006 that examined medication use involving anticancer therapies (chemotherapies and hormonal therapies) and included cancer patients 65 years and older were included. Articles were systematically reviewed and classified based on Chassin's paradigm of quality problems in health services use: underuse, overuse, and misuse. For this study, underuse reflected the use of substandard, low-intensity anticancer drug therapies or the omission of standard drug treatments. Overuse included greater than appropriate use of pharmaceuticals, such as polypharmacy or over-dosage. Misuse included avoidable improper use of anticancer therapies, such as inappropriate drug choices, and adverse interactions among drugs or between pharmacotherapies and co-morbidities. Results: A total of 78 articles were identified. Sixty five articles about overuse, underuse, and misuse of medications involving anticancer therapies among older cancer patients were identified: 64 (98%) evaluated underuse, 1 (2%) overuse, and none evaluated misuse. An additional 13 retrieved articles focused on ADRs associated with chemotherapy or hormonal therapy administration to older patients with cancer. One article reported overuse of hormonal treatments in elderly cancer patients with localized prostate cancer. The 64 articles on underuse were further subcategorized into under-treatment (n=47), deviation from treatment criteria (n=16), and patient non-adherence (n=1). Forty-seven studies described under-treatment, operationally defined as: no therapy, less frequent administration, and other non-standard anticancer treatment regimens. Seven studies analyzed medical records and primarily included data from one geographical location or healthcare system. Breast cancer was the most frequently studied cancer diagnosis, being the focus of 22 studies on under-treatment (47%). Thirty-nine of these studies reported that advanced age, regardless of physiologic condition, was a significant risk factor for under-treatment in anticancer therapy. Conclusions: 98% of the epidemiological studies on processes of care associated with use of anticancer therapies among older patients with cancer evaluated underuse. Since cancer cases are expected to rise as the population ages and a tandem increase in the complexity of drug regimens is expected, additional research needs to focus how decisions are made relative to the utilization of cancer therapies older patients. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B95.

Development and assessment of novel all-in-one parenteral formulations with integrated anticoagulant properties for the concomitant delivery of 5-fluorouracil and calcium folinate

5-Fluorouracil in combination with its biomodulator folinic acid maintains a pivotal position in current anticancer treatment regimens. However, limitations in clinical management persist with the administration of these drugs. These limitations are associated with the use of a high pH to maintain 5-fluorouracil in solution, resulting in high rates of phlebitis and catheter blockages. Herein, we describe and compare initial studies on novel all-in-one formulations of 5-fluorouracil and folinic acid incorporating either sulfated or hydroxypropyl beta-cyclodextrins at physiological pH that potentially address these issues. All formulations markedly improved the stability of supersaturated solutions of 5-fluorouracil in the presence of folinic acid. In-vitro evaluation of the PC-3, HCT-116, MDA-MB-231, PC-14, and COLO-201 human carcinoma cell lines showed that all formulations exhibited equivalent or better cytotoxicity compared with cells exposed to 5-fluorouracil and folinic acid. Thus, these cyclodextrins do not compromise the cytotoxicity of 5-fluorouracil. Preliminary in-vivo dose tolerance profiles of the formulations were also equivalent to 5-fluorouracil and folinic acid administered separately. Furthermore, given the association between thrombosis and cancer, the potentially beneficial anticoagulant activity of the sulfated cyclodextrin-based formulations was also confirmed in vitro. Extended activated partial thromboplastin times and prothrombin times were observed for the sulfated cyclodextrins in human plasma both as individual compounds and as components of the formulations. In conclusion, these novel all-in-one formulations maintain the in-vitro potency while overcoming the accepted incompatibility of 5-fluorouracil and folinic acid, and represent improved injectable forms of 5-fluorouracil that may reduce phlebitis, catheter blockages, and thromboembolic events.

Spotlight

Lee et al., pp. 2755–2765 Heparin's powerful anticoagulant properties are clinically widely used. Other biological activities of heparin, however, remain therapeutically unexploited because of the increased risk of bleeding. Positive side effects of heparin include suppression of angiogenesis, tumor metastasis and cell proliferation. Lee and colleagues generated new bile acid-acylated heparin derivatives to study heparin's anticancer effects. Heparin is a highly sulfated glycosaminoglycan. The sulfation pattern is an important determinant of binding to antithrombin III or angiogenic growth factors, which suppresses blood coagulation or angiogenesis, respectively. The authors identified one compound (LHT7) which was fully saturated with taurocholate moieties and exerted potent anticancer and weak anticoagulant effects. LHT7 is oversulfated and binds with high affinity to vascular endothelial growth factor 165 (VEGF165), an important mediator of angiogenesis. The strength of this binding is comparable to the interaction of antithrombin III with regular heparin and potently suppresses VEGF165-dependent angiogenesis. In addition, LHT7 administration slowed tumor growth and prolonged survival in mice. Tumors induced by subcutaneous injection of squamous cell carcinoma (SCC7) cells were reduced in size by ∼70% when mice were treated systemically with LHT7. An ∼90% reduction in tumor growth was seen in mice inoculated with human breast cancer cells (MDA-MB231). The authors propose that the potent antiangiogenic properties of LHT7 could successfully supplement existing anticancer treatment regimens. LHT7 inhibits angiogenesis induced by VEGF. Hematoxylin and eosin stain of Matrigel plugs containing the indicated reagents. LMWH=low molecular heparin. Red arrows mark red blood cells, blue arrows blood vessel walls, and black arrows Matrigel background. Wong et al., pp. 2766–2770 Cytokine profiling was performed in individuals chronically infected with hepatitis B virus (HBV) in search of new biomarkers that predict development of hepatocellular carcinoma. Chronic HBV infection is the most common cause of hepatocellular carcinoma in Asia. Measurements of alpha fetal protein are commonly used to monitor HBV-infected patients, but the sensitivity for hepatocellular carcinoma is low (40–66 %). Wong and colleagues aimed to find new tumor markers in a prospective nested case control study of 37 HBV+ patients who eventually developed liver cancer and control patients with chronic HBV infection but no cancer. They identified high serum interleukin-6 (IL-6) levels as a new predictor of hepatocellular carcinoma development. Patients with IL-6 levels above 7 pg/ml were more likely to develop liver cancer or die over time (unadjusted hazard ratio 3.2; 95%CI 1.6, 6.3, p = 0.001). This was observed when alanine aminotransferase levels were highest, indicating active hepatic inflammation, but was independent of other risk factors such as age, male gender, cirrhosis and viral load. While temporary IL-6 treatment appears to be protective in mice receiving liver transplantations from a steatotic graft, ablation of IL-6 is known to abolish hepatic carcinogenesis. It is therefore believed that short-term IL-6 production is a natural response to liver injury, which produces a protective effect; in contrast, prolonged IL-6 exposure may increase liver injury and promote carcinogenesis. Monitoring serum IL-6 levels in patients chronically infected with HBV may assist in identifying individuals at high risk for developing hepatocellular carcinoma. Kabashima et al., pp. 2771–2779 There is increasing evidence that malignant tumors contain a small population of undifferentiated cancer stem cells. These cells play pivotal roles in tumor mass formation, resistance to chemotherapy, local invasion and distant metastasis. In some tumors, cancer stem cells are concentrated in a so-called side population (SP) of cells. These cells characteristically expel Hoechst 33342 dye through active membrane transport and can thereby be distinguished from main population (MP) cancer cells. Kabashima and colleagues focused on SP cells from pancreatic cancer cell lines. While Capan-2, PANC-1 and KP-1NL cell lines included substantial amounts of SP cells (8– 20 %), no SP cells were detected in MIAPaCa2 cell cultures. Isolated pancreatic SP cells caused enhanced liver metastasis as compared to MP cells and their invasion activities were notably increased after treatment with transforming growth factor beta (TGF-β). TGF-β plays a pivotal role in the so-called epithelial to mesenchymal transition (EMT), a process critical during embryonic development and cancer progression. The loss of the epithelial and gain of mesenchymal phenotype leads to enhanced motility mediated by downregulation of cell-to-cell adhesion proteins such as E-cadherin. The authors observed that TGF-β responsiveness was greater in pancreatic SP cells than in MP cells, resulting in enhanced induction of EMT and invasiveness. SP cells were also responsive to TGF-β removal, as seen in morphological changes and E-cadherin restoration. Because switches between epithelial and mesenchymal stages are critical for pancreatic cancer development, this study underlines the importance of SP cell-targeting strategies in the prevention and treatment of pancreatic cancer.

Patients’ perspectives and safe handling of oral anticancer drugs at an Asian cancer center

Background. In view of the increased usage of oral anticancer drugs in the contemporary treatment of cancer, we aimed to examine cancer patients' perspectives of oral anticancer drugs, through a survey at an Asian cancer centre. This study also intended to describe patients' behavior regarding storage, handling, and administration of oral anticancer drugs. This cross sectional survey was conducted at a single site. The interviewer-administered survey was undertaken at the outpatient pharmacy of National Cancer Centre Singapore (NCCS), the largest ambulatory cancer center in Singapore, between January and March 2008. Eligible patients had received at least one cycle of oral anticancer agent treatment or had been taking oral anticancer agents continuously for 3 months. A total of 126 patients were surveyed. Median age of surveyed patients was 58 years (range 31-85 years). The drugs involved were capecitabine (39.7% of patients), tamoxifen (23.1%), aromatase inhibitors (18.2%), gefitinib (9.1%), and imatinib (3.3%). Over 90% patients self-administered their oral anticancer drugs. The majority of the patients (94.2%) reported no difficulties in adherence to their oral anticancer treatment regimens. Forty per cent of patients reported habitually washing their hands after administering their anticancer drugs. None of the patients, except two patients receiving capecitabine, indicated that they habitually used gloves to handle their oral anticancer medications. The majority of patients receiving oral anticancer agents reported no difficulty in adhering to their oral anticancer treatment regimens as prescribed. However, this survey demonstrated the need to improve patients' understanding of the requirements for storage, handling and safe administration of oral anticancer drugs.

Different susceptibility of osteosarcoma cell lines and primary cells to treatment with oncolytic adenovirus and doxorubicin or cisplatin

Despite improvements in treatment regimens for osteosarcoma (OS) patients, survival rate has not increased over the last two decades. New treatment modalities are therefore warranted. Preclinical results with conditionally replicative adenoviruses (CRAds) to treat OS are promising. One type of CRAd that was effective against OS cells is Ad5-Δ24RGD. In other types of cancer, CRAds have been shown to interact synergistically with chemotherapeutic agents. Chemotherapy for OS often includes doxorubicin and cisplatin. Therefore, we explored combination treatment of OS cell lines and primary OS cell cultures with Ad5-Δ24RGD and doxorubicin or cisplatin. On OS cell lines, combination treatment was additive to synergistic. Surprisingly, however, on seven of eight primary OS samples no such combination effects were observed. In contrast, in many cases chemotherapy even inhibited CRAd-mediated cell killing. The inhibitory effect of doxorubicin on Ad5-Δ24RGD in primary OS cells appeared to correlate with slow cell growth rate; reduced viral replication and absence of chemotherapy-induced G2 cell cycle arrest. Our results point to the possibility that, at least for OS, virotherapy and chemotherapy should best not be performed simultaneously. In general, our work underscores the importance of testing new genetic anticancer agents and treatment regimens on primary cancer specimens.

288. Synergism between a Conditionally Replicating Adenovirus Expressing p53 and Oxaliplatin in the Antiproliferative Effects on Human Colon Cancer Cell Lines

Osteosarcoma (OS) is the most prevalent malignant bone tumor in children and young adults.OS treatment consists of chemotherapy (such as cisplatin and doxorubicin) in combination with surgery. Despite new chemotherapeutic regimens the outcome has not improved over the last two decades. New treatment modalities for OS are therefore warranted. We are evaluating the use of conditionally replicative adenoviruses (CRAds) to treat osteosarcoma and the first results with a targeted CRAd (Ad5-Δ24RGD) are promising (Clin Cancer Res, 10: 61–67, 2004). Since synergistic combination effects of CRAds with chemotherapeutic agents, including cisplatin and doxorubicin, have been reported, we hypothesized that combination treatment with Ad5-Δ24RGD and cisplatin or doxorubicin would lead to increased efficacy against OS. We tested this on a panel of three OS cell lines (SaOs-2, MG-63 and U2OS) and eight primary OS short-term cultures. Cells were treated for six days with Ad5-Δ24RGD, cisplatin or doxorubicin as single agent or in combination. Cell viability was analyzed by WST-1 conversion assay. On OS cell lines, combination treatments were more effective than single agent treatments. The CRAd was synergistic with cisplatin or doxorubicin on two of three cell lines, as determined by CalcuSyn analysis. Interestingly however, on seven of eight primary samples (except for the fastest growing cell culture) the beneficial combination effect was not observed. In contrast to the results from OS cell lines, cisplatin and doxorubicin reduced the cytotoxic effect of Ad5-Δ24RGD in primary OS cells. In line with these data, quantitative PCR analysis showed that in slowly growing primary OS cultures, but not in the single fast growing culture and in SaOs-2 cells, viral replication was decreased by adding a sub-toxic dose of doxorubicin. Our findings underscore the importance of testing new genetic anti-cancer agents and treatment regimens on primary cancer specimens, because the outcome can be entirely different from results on cell lines.

In vivo monitoring of fluoropyrimidine metabolites

Since 5-fluorouracil (5-FU) was synthesized in the late 1950s it has become an important component of many anticancer treatment regimens. The increasing volume of literature accumulating about this drug is evidence that the optimal administration schedule and its combination with modulators has yet to be determined. Much of the investigation of 5-FU, particularly in the clinical setting, has been in the development of administration schedules based on plasma pharmacokinetic data. Particularly with the development of modulators of 5-FU, investigators are looking more closely at its intracellular tissue pharmacology and metabolism. To study the tissue metabolism of 5-FU (and other drugs), patients often have to be willing to undergo invasive procedures, sometimes with significant discomfort, usually with little direct benefit to their management. The ability to conduct an investigation of the cellular effects of a drug in both tumor and normal tissue non-invasively will not only be more acceptable to patients, resulting in better compliance to protocols, but will give information about the in situ tissue which is not subject to the problems of invasive sampling techniques. Magnetic resonance spectroscopy is a non-invasive technique that has recently started to show potential in the area of investigating 5-FU metabolism and its impact on tumor and patient outcome. Further development of this method may ultimately have an impact on the investigation of any new anticancer agent.