First-line Treatment Setting Research Articles

Comparison of Healthcare Costs Between Rheumatoid Arthritis Patients Treated with Infused Biologics After Switching from Another Biologic

IntroductionWhile there is a substantial body of literature on the comparative healthcare costs of biologics used to treat rheumatoid arthritis (RA), nearly all of these investigations have been exclusively focused on anti-tumor necrosis factor-α (anti-TNF) agents in the setting of first-line biologic treatment. This study compared healthcare costs between RA patients treated with infused biologics after previously using at least one other biologic agent.MethodsUsing a large US administrative claims dataset, adult RA patients initiating an infused biologic (abatacept, infliximab, tocilizumab) between January 1, 2010 and January 1, 2012 (initiation = index) were identified. Rituximab was excluded because of unique dosing intervals, which make it difficult to determine treatment discontinuation using a claims database. Patients were required to have used one or more other biologic (infused or injected) at any time before index. Patients could contribute multiple observations to the dataset; one for each infused biologic they initiated between January 1, 2010 and January 1, 2012. A 6-month period before index was used to measure patient characteristics. A variable-length follow-up period after index was used to measure per-patient per-month (PPPM) healthcare costs, including biologic costs, RA-related healthcare costs, and all-cause healthcare costs. Generalized estimating equations models compared healthcare costs between the biologic agents, adjusting for patients’ demographics and clinical characteristics.ResultsThe sample comprised 3,771 infused biologic initiations (abatacept = 1,759; infliximab = 922; tocilizumab = 1,090); the mean age of participants was 55 years, 82 % were female, and the median follow-up ranged from 251 to 280 days. Compared with other patients, patients treated with tocilizumab had significantly lower (all P < 0.05) PPPM biologic costs (abatacept = $2,597, infliximab = $3,141, tocilizumab = $1,894), RA-related healthcare costs (abatacept = $2,929, infliximab = $3,598, tocilizumab = $2,236), and all-cause healthcare costs (abatacept = $3,735, infliximab = $4,600, tocilizumab = $3,042).ConclusionsAmong RA patients treated with infused biologics after previously using at least one other biologic, patients treated with tocilizumab had the lowest real-world healthcare costs, largely driven by lower costs directly related to biologic treatment. Such biologic-related cost differences may be driven by variations in real-world treatment patterns (e.g., dose, escalation, treatment frequency).

Novel covalent modification of human anaplastic lymphoma kinase (ALK) and potentiation of crizotinib-mediated inhibition of ALK activity by BNP7787.

BNP7787 (Tavocept, disodium 2,2′-dithio-bis-ethanesulfonate) is a novel, investigational, water-soluble disulfide that is well-tolerated and nontoxic. In separate randomized multicenter Phase II and Phase III clinical trials in non-small-cell lung cancer (NSCLC) patients, treatment with BNP7787 in combination with standard chemotherapy resulted in substantial increases in the overall survival of patients with advanced adenocarcinoma of the lung in the first-line treatment setting. We hypothesized that BNP7787 might interact with and modify human anaplastic lymphoma kinase (ALK). At least seven different variants of ALK fusions with the gene encoding the echinoderm microtubule-associated protein-like 4 (EML4) are known to occur in NSCLC. EML4–ALK fusions are thought to account for approximately 3% of NSCLC cases. Herein, we report the covalent modification of the kinase domain of human ALK by a BNP7787-derived mesna moiety and the functional consequences of this modification in ALK assays evaluating kinase activity. The kinase domain of the ALK protein crystallizes as a monomer, and BNP7787-derived mesna-cysteine adducts were observed at Cys 1235 and Cys 1156. The BNP7787-derived mesna adduct at Cys 1156 is located in close proximity to the active site and results in substantial disorder of the P-loop and activation loop (A-loop). Comparison with the P-loop of apo-ALK suggests that the BNP7787-derived mesna adduct at Cys 1156 interferes with the positioning of Phe 1127 into a small pocket now occupied by mesna, resulting in a destabilization of the loop’s binding orientation. Additionally, in vitro kinase activity assays indicate that BNP7787 inhibits ALK catalytic activity and potentiates the activity of the ALK-targeted drug crizotinib.

Comparison of Levofloxacin- and Moxifloxacin-Based Triple Therapies with Standard Treatment in Eradication of Helicobacter Pylori as First-Line Therapy

Aim: It is recommended that treatments that include clarithromycin should be avoided in eradication of Helicobacter pylori (HP) in cases where clarithromycin resistance is higher than 20%. We aimed to compare levofloxacin- and moxifloxacin-based triple therapies with standard treatment and with each other in eradication of helicobacter pylori as first-line therapy. Materials and Methods: Patients were randomized prospectively as three groups. There were 102 patients in the levofloxacin group, 101 patients in the moxifloxacin group, and 103 patients in the standard treatment group. The patients received levofloxacin 500 mg daily, amoxicillin 1 g b.i.d. and lansoprazole 30 mg b.i.d. for ten days (LAL) in the levofloxacin group; moxifloxacin 400 mg daily, amoxicillin 1 g b.i.d. and lansoprazole 30 mg b.i.d. (MAL) in the moxifloxacin group; and clarithromycin 500 mg b.i.d., amoxicillin 1 g b.i.d. and lansoprazole 30 mg b.i.d. (CAL) in the standard treatment group. At post-treatment week 6, HP was checked by using stool antigen test. Results: In the eradication of Helicobacter pylori, the success rate as determined by per protocol (PP) analysis was 92% in the LAL group, 91.8% in the MAL group, and 82.4% in the CAL group. A statistically significant difference was found in the LAL and MAL groups compared to the CAL group (p < 0.05). There was no difference between the LAL and MAL groups. Conclusions: It was determined that levofloxacin- and moxifloxacin-based triple therapies were more effective than the standard treatment in first-line setting in the eradication of Helicobacter pylori. In addition, no difference was found between levofloxacin- and moxifloxacin-based triple therapies. Currently observed high efficacy may be evaluated in treatment. Although quinolon resistance is not considered a major problem, it appears to be a factor that may reduce treatment success over a period of time.

Towards Response Prediction Using Integrated Genomics in Chronic Lymphocytic Leukaemia: Results on 250 First-Line FCR Treated Patients from UK Clinical Trials

Background: Major progress has been made in understanding disease biology and therapeutic options for patients with chronic lymphocytic leukaemia (CLL). Recurrent mutations have been discovered using next generation sequencing, but with the exception of TP53 disruption their potential impact on response to treatment is unknown. In order to address this question, we characterised the genomic landscape of 250 first-line chemo-immunotherapy treated CLL patients within UK clinical trials using targeted resequencing and whole-genome SNP array.Methods: We studied patients from two UK-based Phase II randomised controlled trials (AdMIRe and ARCTIC) receiving FCR-based treatment in a first-line treatment setting. A TruSeq Custom Amplicon panel (TSCA, Illumina) was designed targeting 10 genes recurrently mutated in CLL based on recent publications.Average sequencing depth was 2260X. The cumulated length of targets sequenced was 7.87 kb from 330 amplicons covering 160 exons. Alignment and variant calling included a combination of three pipelines to confidently detect SNVs, indels and low level frequency mutations. SNP array testing was performed using HumanOmni2.5-8 BeadChips, (Illumina) and data analysed using Nexus 6.1 Discovery Edition, Biodiscovery. We performed targeted resequencing and genome-wide SNP arrays using selected samples’ germline material to confirm somatic mutations (n=40). Univariate and multivariate analyses using minimal residual disease (MRD) as the outcome measure were performed for 220 of the 250 patients.Results: Pathogenic mutations were identified in 165 (66%) patients, totalling 268 mutations in 10 genes. ATM was the most frequently mutated gene affecting 67 patients (29%) followed by SF3B1 (n=56, 24%), NOTCH1 (n= 32, 14%), TP53 (n= 21, 9%), BIRC3 (n= 17, 7%) and XPO1 (n=14, 6%). Less frequently recurrent mutations were seen in SAMHD1 (n=8, 3%), MYD88 (n= 4, 2%), MED12 (n=7, 3%) and ZFPM2 (n=5, 2%). Integrating sequencing and array results increased the patients with one or more CLL driver mutation from 66% to 94%. As previously reported del17p and TP53 mutations are co-occurring and associate with MRD positivity in all cases (n=15, p=0.0002). We report on minor TP53 subclones in 11 patients (VAF 1-5%), 8 of whom have MRD data available and were also associated with MRD positivity. Deletions of 11q were present in 44 patients. These lesions always included ATM but not always BIRC3. Bialleleic disruption was present in ATM for 27 patients (significantly associated with MRD positivity) and in BIRC3 for 4 patients. Rather surprisingly, trisomy 12 (n=33) and NOTCH1 mutations (n=28) were associated with MRD negativity (p=0.006 and 0.097, respectively). Analysing clonal and subclonal mutations per gene revealed the majority of mutations in SF3B1 and BIRC3 were subclonal (65% and 87% respectively). In contrast almost all SAMHD1 and MYD88 mutations were clonally distributed. There was an association between NOTCH1 subclonal mutations and MRD negativity, compared to clonal mutations, but this difference was not seen in the remaining mutated genes. From our copy number data, the presence of subclones was associated with MRD positivity (p=0.05). Combining important lesions in a multiple logistic regression analysis to predict MRD positivity, bialleleic ATM disruption, together with TP53 disruption, were the strongest predictors, followed by SAMHD1, whereas BIRC3 monoalleleic mutations were a medium predictor for MRD negativity.Conclusion: This is the first integrated genome-wide analysis of the distribution and associations of CLL drivers, using targeted deep resequencing and whole genome SNP arrays in an FCR-based first-line treatment setting. We have shown subclonal and clonal mutation profiles in all patients. For patients with two or more CLL-associated mutations we have begun to unravel clonal hierarchies. We have developed a comprehensive model using MRD as an outcome measure and have found bialleleic ATM mutations and SAMHD1 disruption to strongly predict for MRD positivity. Using MRD status as a robust proxy for PFS not only enables us to confirm results of previous studies, but is advantageous also in considerably reducing the timeframe for results. Indeed, we suggest that MRD status should be assessed routinely in future studies to complement modern integrated genomics approaches. DisclosuresHillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding.

Initial LDH level can predict the survival benefit from bevacizumab in the first-line setting in Chinese patients with metastatic colorectal cancer.

BackgroundMarkers to predict the efficacy of bevacizumab treatment have been not fully validated in most cancers, including metastatic colorectal cancer (mCRC). The aim of this study was to investigate the potential role of lactate dehydrogenase (LDH) in predicting the survival benefit from first-line bevacizumab treatment, in Chinese patients with mCRC.MethodsAll the patients were diagnosed with mCRC at the Sun Yat-sen University Cancer Center from 2003 to 2013. The study group and the control group were classified by receiving bevacizumab or not. The serum LDH value of all the patients had been detected before the first-line treatment. The primary end point was progression-free survival (PFS).ResultsThe median PFS of the study and the control group (patients who received bevacizumab or not) was 11.3 and 9.1 months, respectively (P=0.004). In the control group, the median PFS of the high LDH level and the low LDH level groups was 6.9 and 10.2 months, respectively (P<0.001). However, in the study group, the corresponding median PFS was 9.9 and 11.9 months, respectively (P=0.145). In addition, for the low LDH level group, the median PFS was 11.9 and 10.2 months for patients who received bevacizumab or not, respectively (P=0.066); however, the median PFS of patients receiving bevacizumab or not was significantly different in the high LDH level group (9.9 and 6.9 months, respectively) (P=0.012).ConclusionThe addition of bevacizumab in the first-line treatment setting could improve the PFS of mCRC patients notably. However, the benefit could only be potentially reflected on patients with high serum LDH level.

Cetuximab in advanced non-small cell lung cancer (NSCLC): the showdown?

Cetuximab in advanced non-small cell lung cancer (NSCLC): the showdown?

Adoptive T-cell Transfer and Chemotherapy in the First-line Treatment of Metastatic and/or Locally Recurrent Nasopharyngeal Carcinoma

The outcomes for patients with metastatic or locally recurrent Epstein–Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) remain poor. Adoptive immunotherapy with EBV-specific cytotoxic T lymphocytes (EBV-CTLs) has proven clinical efficacy, but it has never been evaluated in the first-line treatment setting in combination with chemotherapy. To evaluate the safety and efficacy of a chemotherapy in combination with adoptive EBV-CTL transfer, we conducted a phase 2 clinical trial consisting of four cycles of gemcitabine and carboplatin (GC) followed by up to six doses of EBV-CTL. Thirty-eight patients were enrolled, and 35 received GC and EBV-CTL. GC-CTL therapy resulted in a response rate of 71.4% with 3 complete responses and 22 partial responses. With a median follow up of 29.9 months, the 2-year and 3-year overall survival (OS) rate was 62.9 and 37.1%, respectively. Five patients did not require further chemotherapy for more than 34 months since initiation of CTL. Infusion of CTL products containing T cells specific for LMP2 positively correlated with OS (hazard ratio: 0.35; 95% confidence interval: 0.14–0.84; P = 0.014). Our study achieved one of the best survival outcomes in patients with advanced NPC, setting the stage for a future randomized study of chemotherapy with and without EBV-CTL.

Comment on ‘Histopathologic evaluation of liver metastases from colorectal cancer in patients treated with FOLFOXIRI plus bevacizumab’

Comment on ‘Histopathologic evaluation of liver metastases from colorectal cancer in patients treated with FOLFOXIRI plus bevacizumab’

Treatment-, Patient-, and Disease-Related Factors and the Emergence of Adverse Events with Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia

Four breakpoint cluster region (BCR)-ABL1 tyrosine kinase inhibitors (TKIs) are currently available for the treatment of chronic myeloid leukemia (CML): imatinib, nilotinib, dasatinib, and bosutinib. Choosing the most appropriate TKI requires clinicians to consider a host of patient-, disease-, and treatment-related factors, not the least of which include the safety profiles of the agents. This review discusses the potential impact of treatment-, patient-, and disease-related characteristics on the emergence of adverse events during TKI therapy, with a focus on the underlying mechanisms believed to be responsible for a number of important adverse events associated with these agents and what implications they may have for treatment choice, particularly in the setting of first-line treatment. A literature search of the PubMed database was conducted to identify articles that described the molecular mechanisms of BCR-ABL1-mediated leukemic transformation, the efficacy and safety of imatinib, nilotinib, dasatinib, and bosutinib in patients with CML, the kinase-binding spectrum of each TKI, and evidence suggesting a link between the TKI-binding profile and adverse events. The pattern of adverse events associated with each agent is important when selecting treatment with a TKI. Clinical studies suggest that imatinib, nilotinib, dasatinib, and bosutinib have differing safety profiles, which are in part attributable to the specificity and selectivity of each agent. Although much basic research must be conducted to further illuminate the mechanisms responsible for TKI-related adverse events, on- and off-target effects are believed to be at least partly responsible for cardiovascular toxicity, myelosuppression, fluid retention, gastrointestinal toxicity, and dermatologic toxicity. Increased understanding of the factors that affect TKI-associated adverse events and long-term safety data will enable a more informed approach to the selection of therapy best suited to the individual needs of patients with CML.

Amrubicin for treating elderly and poor-risk patients with small-cell lung cancer

This study was conducted to evaluate the efficacy of amrubicin as first-line chemotherapy for elderly and poor-risk patients with extensive-disease small-cell lung cancer (ED-SCLC). Untreated SCLC patients who were >75years of age or had a performance status of 2 or more were eligible. Amrubicin (35 or 40mg/m(2) on days 1-3 every 3weeks) was administered. Between January 2003 and May 2009, 27 patients were evaluated. The median number of treatment cycles was 4 (1-6). Grade 3 or 4 hematologic toxicities comprised neutropenia (63%), leukopenia (56%), thrombocytopenia (15%), and anemia (19%). Febrile neutropenia was observed in four (15%) patients. No treatment-related deaths occurred. The nonhematologic toxicities were mild. The overall response rate was 70%. Progression-free survival, median survival time, and the 1-year survival rate were 6.6months, 9.3months, and 30%, respectively. The 40mg/m(2) dose was feasible and had a tendency to be more effective than the 35mg/m(2) dose. Amrubicin exhibits activity and acceptable toxicities for elderly and poor-risk patients with ED-SCLC in the first-line treatment setting.

Phase III Trial of FOLFOX plus Bevacizumab or Cediranib (AZD2171) as First-Line Treatment of Patients with Metastatic Colorectal Cancer: HORIZON III

Cediranib is a highly potent and selective inhibitor of the 3 vascular endothelial growth factor receptors and has a halflife suitable for once-daily oral dosing. It is currently in phase III development for the first-line treatment of metastatic colorectal cancer. This article summarizes the clinical development program, which includes 2 global phase III studies, HORIZON II and HORIZON III, in the first-line treatment setting and a phase II study in second-line treatment (HORIZON I).

Unmet Needs in the Treatment of Metastatic Non-small-cell Lung Cancer

Today, lung cancer remains the most common cause of cancer-related mortality in the world. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer, and 40% of these patients present at an advanced stage, including patients with metastatic disease and those with locally advanced disease with malignant pleural or pericardial effusion.1 Platinum-based chemotherapy with third-generation agents (gemcitabine, vinorelbine, docetaxel or paclitaxel) improves survival and quality of life compared with best supportive care alone. Despite these advances in treatment, a therapeutic plateau has been reached using conventional chemotherapy. Over the past decade, large randomised studies have demonstrated the relative equivalence of platinum-based doublets, with response rates of 16‐32% and median survival ranging from eight to 11 months, with one- and two-year survival rates of 35‐45% and 10‐20%, respectively. The majority of patients experience disease progression, generally after a median of three to six months of initiating chemotherapy, and the long-term prognosis is still poor.2 Therefore, there is a great unmet need to provide more effective therapeutic strategies to further improve outcome in patients with advanced NSCLC. Further understanding of cancer biology has allowed the development of several potential molecular targets for cancer treatment. Numerous targeted agents have been evaluated in clinical trials of cancer treatment, and a number of phase III trials have generated definite results. In particular, several agents that target the epidermal growth factor receptor (EGFR) and the angiogenesis pathway have proved efficacious in the management of NSCLC. To further improve the outcome of first-line therapy for advanced NSCLC, there is much interest in adding these targeted agents to platinumbased chemotherapy. This article will focus on the potential beneficial role of these targeted agents in the management of advanced NSCLC in the first-line treatment setting.

Treatment options in renal cell carcinoma: past, present and future

Cytokine therapies have been the standard of care in metastatic renal cell carcinoma (RCC). However, these agents only provide clinical benefit to a small subset of patients and are associated with significant toxicity. A better understanding of the molecular biology of RCC has identified the vascular endothelial growth factor (VEGF) and platelet-derived growth factor signalling pathways as rational targets for anticancer therapy. The multitargeted receptor tyrosine kinase inhibitors sunitinib and sorafenib have both demonstrated improved efficacy as second-line therapy in patients with RCC. Sunitinib has also been shown to be effective in the first-line setting, and has recently received European Union approval as first-line treatment for advanced and/or metastatic RCC. There is also recent evidence that temsirolimus (an inhibitor of the mammalian target of rapamycin) and bevacizumab (a mAb targeted against VEGF) may provide benefits in the first-line treatment setting. These results confirm that inhibiting these tumour targets is a feasible approach to treatment and provides a more positive outlook for the future management of metastatic RCC.

Sunitinib: a novel tyrosine kinase inhibitor. A brief review of its therapeutic potential in the treatment of renal carcinoma and gastrointestinal stromal tumors (GIST).

Sunitinib malate is a novel oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Sunitinib was recently approved in first-line treatment for patients with advanced renal cell carcinoma (RCC) and for the treatment of patients with gastrointestinal stromal tumors (GIST) after disease progression or intolerance to imatinib mesylate therapy. We report the very interesting results of the phase II trials after cytokin failure and of the randomized recent trial of sunitinib versus cytokin-based therapy in first-line treatment for patients with metastatic RCC, as well as the promising results of the recent trials on patients with GIST after disease progression or intolerance to imatinib mesylate therapy. Oral sunitinib demonstrates a high level of efficacy with acceptable tolerability with the 50 mg daily for 4 weeks followed by 2 weeks off schedule; a continuous schedule could be of interest. Hypertension and asthenia are the most common side effects with sunitinib. Regardless of these encouraging results, studies investigating sunitinib in first-line treatment (for patients with GIST), adjuvant and neoadjuvant settings are awaited, as well as trials using sunitinb in combination with chemotherapy or other targeted therapies. Clinical trials investigating sunitinib in other tumor types are ongoing.

Cisplatin plus continuous infusion vinorelbine for the treatment of advanced non-small cell lung cancer: a phase I-II study

In this Phase I/II trial, the maximumtolerated dose (MTD) and activity of cisplatin plus vinorelbine (VRL) administered in continuous infusion as first-line treatment of advanced non small cell lung cancer (NSCLC) was determined in 12 consecutive chemotherapy-naive patients with advanced NSCLC. The dose of cisplatin was 100 mg/m(2) in all patients, and vinorelbine was administered as an initial intravenous (iv) bolus of 8 mg/m(2) on day 1 followed by a 4-day continuous iv infusion at 4 different 24 h dose levels (DLs) to be repeated every 21 days. All 12 patients (47 cycles) were evaluable for response and toxicity. The MTD was 8 mg/m(2) bolus followed by a continuous iv infusion of 8 mg/m(2) per day over 4 days. The dose limiting toxicities (DLT) were febrile neutropenia in 4 patients and grade 3 mucositis in 1 patient. There was less neuro-toxicity and compared to the weekly bolus scheme. There was no significant cumulative toxicity after 3 cycles. Partial responses were observed in 6 patients; an overall response rate of 50% (95% CI: 30-65%). Median time to progression was 5,5 months (95% CI: 1,5-11 months) and median survival was 11 months (95% CI: 5-20 months). The results demonstrate that, in this setting of first-line treatment of NSCLC, cisplatin plus vinorelbine at 8 mg/m(2) bolus followed by a continuous infusion of 8 mg/m(2) per day over 4 days is the recommended schedule. Further trials would be useful to establish activity of this combination.

Continuous-Infusion Vinorelbine for the Treatment of Advanced Non–Small-Cell Lung Cancer: A Phase I/II Study

BACKGROUND: In this phase I/II trial, the maximum tolerated dose (MTD) and activity of vinorelbine administered in continuous infusion as first-line treatment for advanced non–small-cell lung cancer (NSCLC) was determined in 25 consecutive chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Vinorelbine was administered as an initial intravenous (I.V.) bolus of 8 mg/m2 on day 1 followed by a 4-day continuous I.V. infusion at 5 different 24-hour dose levels to be repeated every 21 days. All 25 patients (159 cycles) were evaluable for response. The MTD was 8 mg/m2 bolus followed by a continuous I.V. infusion of 11 mg/m2 per day over 4 days. RESULTS: The dose-limiting toxicities were febrile neutropenia in 6 patients and grade 3 mucositis in 2 patients. There was less neurotoxicity and constipation and more mucositis compared with the weekly bolus scheme. There was no significant cumulative toxicity after 3 cycles. Treatment responses were observed in 6 patients: 1 complete response and 5 partial responses. The overall response rate was 24% (95% confidence interval [CI], 8%–40%). Median time to progression was 4 months (95% CI, 2-11 months), and median survival was 6 months (95% CI, 2-18 months). CONCLUSION: The results demonstrate that, in this setting of first-line treatment of NSCLC, vinorelbine administered as an 8 mg/m2 bolus followed by a continuous infusion of 11 mg/m2 per day over 4 days is the recommended schedule. Further trials are necessary to establish activity and possible benefits of combination with other agents.

TLK-286: a novel glutathione S-transferase-activated prodrug

Telik, Inc. (Palo Alto, CA, USA) is currently developing TLK-286, a novel prodrug that is preferentially activated by glutathione S-transferase P1-1 (GST-π). TLK-286 is the lead clinical candidate from a group of rationally designed glutathione analogues designed to exploit high GST-π levels in solid tumours and drug-resistant cell populations. This concept was based on extensive literature showing that the overexpression of GST-π in human tumours is associated with malignancy, poor prognosis and the development of drug resistance. Thus, the selective targeting of susceptible tumour phenotypes is a strategy that should result in the release of more active drug in malignant cells compared with normal tissue, thereby achieving an improved therapeutic index. A number of published preclinical studies have confirmed the mechanism of action of this drug. In a series of Phase II clinical trials, TLK-286 was initially shown to have clinical activity and a favorable toxicity profile as a single agent in the salvage setting in ovarian, non-small cell lung, breast and colorectal cancers. Recently, Phase II trials have been reported that demonstrated TLK-286 is active and did not increase the toxicity in combination treatment regimens with standard chemotherapeutic agents, including platinums, taxanes and anthracyclines in previously treated patients with ovarian and non-small cell lung cancers, and in the first-line treatment setting in non-small cell lung cancer patients. TLK-286 is also presently under active testing in Phase III settings for non-small cell lung and ovarian cancers.

Hepatic Arterial Chemotherapy of Liver Metastases from Colorectal Cancer: Treatment Results, Limitations and Future Aspects

Background: For more than three decades, hepatic arterial chemotherapy (HAI) has been used in the treatment of liver metastases from colorectal cancer. This approach achieves significantly higher concentrations of various cytotoxic agents within the hepatic parenchyma and tumour tissue while minimizing systemic toxicity. Methods: In this article, we briefly review and discuss the results of recently published clinical studies of HAI, limitations of the technique, possible options for improvement, as well as future aspects of liver-directed therapy. Results: In the clinical setting, there is no doubt that higher objective response rates can be achieved compared to systemic delivery of the same cytotoxic drugs. However, HAI requires laparotomy, is not without risks and side effects, and recent results of randomized trials have raised certain doubts concerning its role in the palliative first-line and adjuvant treatment setting. Conclusions: One of the major drawbacks of HAI is its inability to prevent or delay the development of extrahepatic disease. A number of recently published studies have demonstrated, however, that HAI can be safely combined with intravenous irinotecan or oxaliplatin. HAI continues to represent a valuable alternative therapy in patients with liver-only metastases failing previous systemic fluoropyrimidine-based chemotherapy.

Combination of oxaliplatin, fluorouracil, and leucovorin in the treatment of fluoropyrimidine-pretreated patients with metastatic colorectal cancer.

There has been no standard therapy for patients with metastatic colorectal cancer who have failed to first-line fluorouracil-based treatment. The present study was designed to assess the efficacy and toxicities of a combination of oxaliplatin, 5-fluorouracil (5-FU) and leucovorin in fluoropyrimidine-pretreated patients with metastatic colorectal cancer. Chemotherapy consisted of oxaliplatin 85 mg/m2 on day 1, followed by leucovorin 20 mg/m2 and 5-FU 1,200 mg/m2 on days 1 and 2. Treatment courses were repeated every two weeks. Thirty-nine patients were enrolled in this study. All patients previously received fluoropyrimidine-based chemotherapy. Thirty-one patients were assessable for response and 33 for treatment toxicity. Six patients required dose reduction of 5-FU due to grade III/IV cytopenia. Nausea/vomiting and peripheral neuropathy were common non-hematologic toxicities. Overall response rate was 42.0% including 3 complete response and 10 partial response. The median response duration was 91 days (range, 28-224+). The median duration of progression-free survival was 132 days (range, 40-308). A combination of oxaliplatin, 5-FU, and leucovorin showed high response rate in fluoropyrimidine-pretreated patients with metastatic colorectal cancer, but the duration of response was relatively short. It may be worthwhile to explore its therapeutic potential in the first-line treatment setting.

Novel chemotherapy agents for colorectal cancer: oral fluoropyrimidines, oxaliplatin, and raltitrexed.

Agents now under investigation for treatment of advanced colorectal cancer (CRC) include the oral fluoropyrimidines, oxaliplatin, and raltitrexed. Research efforts directed at finding agents that conveniently and effectively deliver 5-fluorouracil (5-FU) in a protracted fashion have led to the development of several oral fluoropyrimidines. These agents, which include capecitabine; tegafur and uracil plus leucovorin (UFT/LV); eniluracil plus oral 5-FU; and S-1, are convenient and less toxic than intravenous bolus 5-FU. Oxaliplatin has a uniquely different mechanism of action compared with that of 5-FU and has demonstrated activity not only in the first-line treatment setting but also in patients whose disease has progressed during or following 5-FU treatment. In the first-line setting, when oxaliplatin is combined with 5-FU plus LV, response rates and time to disease progression are remarkably improved compared with 5-FU/LV alone. Raltitrexed, a unique thymidylate synthase inhibitor, has undergone extensive phase III evaluation in CRC. The advent of these novel agents has led to development of combined chemotherapy regimens now being introduced into the adjuvant setting.