Implementation of a pharmacogenetic panel-based test for pharmacotherapy-based supportive care in an adult oncology clinic.

The University of Florida Health conducted a pragmatic implementation of a pharmacogenetics (PGx) panel-based test to guide medications used for supportive care prescribed to patients undergoing chemotherapy. The implementation was in the context of a pragmatic clinical trial for patients with non-hematologic cancers being treated with chemotherapy. Patients were randomized to either the intervention arm or control arm and received PGx testing immediately or at the end of the study, respectively. Patients completed the MD Anderson Symptom Inventory (MDASI) to assess quality of life (QoL). A total of 150 patients received PGx testing and enrolled in the study. Clinical decision support and implementation infrastructure were developed. While the study was originally planned for 500 patients, we were underpowered in our sample of 150 patients to test differences in the patient-reported MDASI scores. We did observed a high completion rate (92%) of the questionnaires; however, there were few medication changes (n = 6 in the intervention arm) based on PGx test results. Despite this, we learned several lessons through this pragmatic implementation of a PGx panel-based test in an outpatient oncology setting. Most notably, patients were less willing to undergo PGx testing if the cost of the test exceeded $100. In addition, to enhance PGx implementation success, reoccurring provider education is necessary, clinical decision support needs to appear in a more conducive way to fit in with oncologists' workflow, and PGx test results need to be available earlier in treatment planning.

An Innovative Approach to the Diagnosis of Cardiac Angiosarcoma.

We present a case of a 32-year-old female presenting with shortness of breath and increasing oxygen requirements. Further imaging discovered a large mass extending circumferentially into the pericardium, cardiac wall, and chambers, involving the anterior and middle mediastinum. Direct tissue biopsy of the mass for a diagnosis was unsafe. Therefore, advanced flow cytometric analysis for tumor marker expression of the malignant effusion was used to differentiate the mass as a vascular sarcoma, consistent with cardiac angiosarcoma. Additionally, cytometric analysis for programmed cell death protein 1 (PD1), programmed death-ligand 1 (PDL1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) was also performed; a study seldom investigated for angiosarcomas but may have advantages over immunohistochemical analysis.

Immunotherapy Management in Special Cancer Patient Populations.

Patients with autoimmune disorders, multiple comorbidities, poor performance status, advanced age, and infection with SARS-CoV-2 (COVID-19) each represent unique subgroups of patients with cancer to whom little is known of the effects, benefits, and complications of checkpoint inhibitor (CPI) therapy. Although prospective trials are lacking in these populations, retrospective data and cohort series suggest that these patients can safely receive and benefit from CPI therapy. Here, we review the relevant data available and offer clinical recommendations in managing these complex patients with CPI therapy, where otherwise indicated.

How to Transition from Single-Gene Pharmacogenetic Testing to Preemptive Panel-Based Testing: A Tutorial.

There have been significant advancements in precision medicine and approaches to medication selection based on pharmacogenetic results. With the availability of direct-to-consumer genetic testing and growing awareness of genetic interindividual variability, patient demand for more precise, individually tailored drug regimens is increasing. The University of Florida (UF) Health Precision Medicine Program (PMP) was established in 2011 to improve integration of genomic data into clinical practice. In the ensuing years, the UF Health PMP has successfully implemented several single-gene tests to optimize the precision of medication prescribing across a variety of clinical settings. Most recently, the UF Health PMP launched a custom-designed pharmacogenetic panel, including pharmacogenes relevant to supportive care medications commonly prescribed to patients undergoing chemotherapy treatment, referred to as "GatorPGx." This tutorial provides guidance and information to institutions on how to transition from the implementation of single-gene pharmacogenetic testing to a preemptive panel-based testing approach. Here, we demonstrate application of the preemptive panel in the setting of an adult solid tumor oncology clinic. Importantly, the information included herein can be applied to other clinical practice settings.

Utilization of Antineoplastic Agents and Medicare Spending in Elderly Patients With Extensive-Stage Small-Cell Lung Cancer Between 2001 and 2013.

PURPOSE: Some elderly patients (≥ 65 years old) with small-cell lung cancer (SCLC) do not receive chemotherapy likely because of fear of toxicity and uncertainty regarding benefits. Thus, we aimed to study real-world trends in utilization of antineoplastics over the years and predictors of utilization, survival, and Medicare expenditure in elderly patients with extensive-stage (ES) SCLC. PATIENTS AND METHODS: Using the linked SEER and Medicare database, we identified elderly patients with newly diagnosed ES-SCLC between 2001 and 2013. The Wald test was used to determine the significance of trends. Cox proportional hazards models were applied for survival analyses. We used SAS, version 9.4 (SAS Institute, Cary, NC). RESULTS: We identified 15,763 patients with newly diagnosed ES-SCLC. Approximately 6,838 patients (43.38%) received antineoplastics, and 8,925 patients (56.61%) received supportive care only. Every year since 2001, the percentage of patients receiving antineoplastics has decreased (45.8% v 36.6% in 2001 and 2013, respectively; Ptrend < .0001). Patients with advanced age (P < .001), patients from high-poverty areas (P < .001) or rural areas (P = .005), patients with Charlson comorbidity index ≥ 3 (P < .001), and non-Hispanic blacks (P = .003) and Hispanics (P = .001) were less likely to receive antineoplastics. Mean Medicare spending per patient decreased over the study period for patients treated with antineoplastics ($45,998 in 2001 and $35,053 in 2013; Ptrend < .001) and for those receiving supportive care only ($34,197 in 2001 and $25,265 in 2013; Ptrend < .001). CONCLUSION: Decreasing utilization of antineoplastics in elderly patients with ES-SCLC since 2001 could be partly secondary to higher comorbidities and physiologic age, leading to poor candidacy. Medicare expenditures decreased likely as a result of value-based treatment initiatives by the Centers for Medicaid and Medicare Services. However, expenditures are likely to increase with use of expensive novel agents.

Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition.

Malignant pleural mesotheliomas (MPM) are most often surgically unresectable, and they respond poorly to current chemotherapy and radiation therapy. Between 23 and 64% of malignant pleural mesothelioma have somatic inactivating mutations in the BAP1 gene. BAP1 is a homologous recombination (HR) DNA repair component found in the BRCA1/BARD1 complex. Similar to BRCA1/2 deficient cancers, mutation in the BAP1 gene leads to a deficient HR pathway and increases the reliance on other DNA repair pathways. We hypothesized that BAP1-mutant MPM would require PARP1 for survival, similar to the BRCA1/2 mutant breast and ovarian cancers. Therefore, we used the clinical PARP1 inhibitors niraparib and olaparib to assess whether they could induce synthetic lethality in MPM. Surprisingly, we found that all MPM cell lines examined, regardless of BAP1 status, were addicted to PARP1-mediated DNA repair for survival. We found that niraparib and olaparib exposure markedly decreased clonal survival in multiple MPM cell lines, with and without BAP1 mutations. This clonal cell death may be due to the extensive replication fork collapse and genomic instability that PARP1 inhibition induces in MPM cells. The requirement of MPM cells for PARP1 suggests that they may generally arise from defects in HR DNA repair. More importantly, these data demonstrate that the PARP1 inhibitors could be effective in the treatment of MPM, for which little effective therapy exists.

Drugging the Cancers Addicted to DNA Repair.

Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects.

ESMO / ASCO Recommendations for a Global Curriculum in Medical Oncology Edition 2016.

The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies.

A Phase I Protocol of Hydralazine and Valproic Acid in Advanced, Previously Treated Solid Cancers.

Smokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.

Nicotine induces the up-regulation of the α7-nicotinic receptor (α7-nAChR) in human squamous cell lung cancer cells via the Sp1/GATA protein pathway.

Nicotine, the addictive component of cigarettes, promotes lung cancer proliferation via the α7-nicotinic acetylcholine receptor (α7-nAChR) subtype. The present manuscript explores the effect of nicotine exposure on α7-nAChR levels in squamous cell carcinoma of the lung (SCC-L) in vitro and in vivo. Nicotine (at concentrations present in the plasma of average smokers) increased α7-nAChR levels in human SCC-L cell lines. Nicotine-induced up-regulation of α7-nAChR was confirmed in vivo by chicken chorioallantoic membrane models. We also observed that the levels of α7-nAChR in human SCC-L tumors (isolated from patients who are active smokers) correlated with their smoking history. Nicotine increased the levels of α7-nAChR mRNA and α7-nAChR transcription in human SCC-L cell lines and SCC-L tumors. Nicotine-induced up-regulation of α7-nAChR required GATA4 and GATA6. ChIP assays showed that nicotine induced the binding of GATA4 or GATA6 to Sp1 on the α7-nAChR promoter, thereby inducing its transcription and increasing its levels in human SCC-L. Our data are clinically relevant because SCC-L patients smoked for decades before being diagnosed with cancer. It may be envisaged that continuous exposure to nicotine (in such SCC-L patients) causes up-regulation of α7-nAChRs, which facilitates tumor growth and progression. Our results will also be relevant to many SCC-L patients exposed to nicotine via second-hand smoke, electronic cigarettes, and patches or gums to quit smoking.

A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma.

OBJECTIVES: The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy. MATERIALS AND METHODS: Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinum-refractory R/M HNSCC and ECOG performance status 0-2. The primary endpoint was progression-free survival (PFS). Correlative studies determined PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre- and post-treatment plasma levels of 20 immunomodulatory cytokines. RESULTS: Twelve patients enrolled; six withdrew within 6 weeks due to toxicity or death, prompting early closure of the trial. Grade ≥ 3 toxicities included fatigue, diarrhea, gastrostomy tube infection, peritonitis, pneumonia, dyspnea, and HN edema. Median PFS was 1.9 months. Median overall survival was 4.0 months. Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferon-gamma levels marginally associated with tumor progression. CONCLUSIONS: The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in R/M disease. Investigation of more tolerable combinations of EGFR and PI3K/Akt/mTOR pathway inhibitors in selected HNSCC patients is warranted.

A Phase II study of pulse dose imatinib mesylate and weekly paclitaxel in patients aged 70 and over with advanced non-small cell lung cancer.

BACKGROUND: In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR). METHODS: This single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged ≥ 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index (CCI) and Vulnerable Elder Survey-13 (VES-13) were correlated with outcomes. RESULTS: Thirty-four patients with median age 75 enrolled. Eleven of 29 (38%) were frail by VES-13 score. Overall RR was 11/34 (32%; 95% CI 17%-51%), meeting the primary endpoint. Median PFS and OS were 3.6 and 7.3 months, respectively. High tumoral PDGF-B expression predicted inferior PFS. Frail patients by VES-13 had significantly worse median PFS (3.2 vs. 4.5 months; p=0.02) and OS (4.8 vs. 12 months; p=0.02) than non-frail. CONCLUSIONS: The combination of imatinib and paclitaxel had encouraging activity as measured by the primary endpoint of RR. However, PFS and OS were typical for elderly patients treated with single agent chemotherapy and the regimen is not recommended for further study. Adjunct imatinib did not overcome the established association of tumoral PDGF-B expression with inferior PFS. VES-13 was a powerful predictor of poor survival outcomes. Frailty should be further studied as a predictor of non-benefit from chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01011075.

A phase I study of 5-azacytidine and erlotinib in advanced solid tumor malignancies.

INTRODUCTION: The epidermal growth factor receptor (EGFR) is a validated target in malignancy; however, patients with wild type EGFR obtain little sustained benefit from anti-EGFR monotherapy. Epigenetic therapy to reactivate tumor suppressor genes may enhance the anti-proliferative effect of erlotinib. This phase I study evaluated the combination of erlotinib and 5-azacytidine for safety and maximal tolerated dose (MTD). METHODS: Thirty patients with advanced solid tumors were treated in a standard 3 + 3 cohort design. Erlotinib was dosed at 150 mg daily, and 5-azacytidine was escalated by increasing the number of daily doses of 75 mg/m(2) per cycle. Patients were followed for dose-limiting toxicity (DLT). Efficacy was assessed by RECIST criteria. RESULTS: Common non-hematologic toxicities included rash, diarrhea, nausea, and fatigue; the majority was ≤ Grade 2. DLTs included conjunctivitis in cohort 1 and infusion reaction in cohort 2. No DLTs occurred in cohorts 3, 4, or 5; however, 2 serious neutropenic infections arose in cohort 5 after cycle 1. Cohort 4 was expanded to 6 patients and was the MTD. Partial response (lung, ovarian) and stable disease occurred in 2 and 11 patients, respectively. Median progression-free survival was 2 months. Two patients with lung and larynx cancer had prolonged stable disease. CONCLUSION: The combination of erlotinib and 5-azacytidine was well tolerated with interesting clinical activity in lung, head and neck, and ovarian cancer. The recommended dose for phase II study is erlotinib 150 mg daily and 5-azacytidine 75 mg/m(2) daily on days 1-4 and 15-18 of a 28-day cycle.

An open-label, multicenter, three-stage, phase II study of s-1 in combination with cisplatin as first-line therapy for patients with advanced non-small cell lung cancer.

INTRODUCTION: S-1 is a rationally designed oral agent that combines the 5-fluorouracil prodrug tegafur with gimeracil and oteracil, which inhibit 5-fluorouracil degradation by dihydropyrimidine dehydronase and phosphorylation within the gastrointestinal tract, respectively, to increase antineoplastic activity while reducing gastrointestinal toxicity. We investigated the activity and toxicity of S-1 in combination with cisplatin in patients with unresectable non-small cell lung cancer (NSCLC). METHODS: Cisplatin, 75 mg/m, was administered intravenously on day 1, with S-1, 25 mg/m PO two times a day, days 1 to 14, every 21 days for a maximum of six cycles. Primary end point was overall response. RESULTS: A total of 58 patients received at least one cycle of protocol-specified therapy. The best overall response rate was 23.2% (95% confidence interval: 13.0-36.4), and the disease control rate was 67.9%. The median progression-free survival was 4.0 months (95% confidence interval: 3.3-5.5). There did not appear to be any relationship between response to therapy and tumor histology. The most frequently reported adverse events of G3 or more (≥10%) were neutropenia (28%), hyponatremia (19%), diarrhea (17%), hypokalemia (12%), fatigue (10%), dehydration (10%), and deep vein thrombosis (10%). CONCLUSIONS: Although the S-1 + cisplatin regimen used in this study appeared to have a similar level of antitumor activity and toxicity to that of established cisplatin-based doublets in NSCLC, the protocol-specified criteria of sufficient efficacy to warrant further study with an objective response rate ≥30% was not achieved. Therefore, while S-1 appears to be a promising agent in NSCLC, further evaluation should be conducted to determine the optimal S-1-based regimen to take forward for additional study.

Multicenter phase II trial of Motexafin gadolinium and pemetrexed for second-line treatment in patients with non-small cell lung cancer.

BACKGROUND: Motexafin gadolinium (MGd) disrupts redox-dependent pathways by inhibiting oxidative stress-related proteins leading to apoptosis. MGd selectively targets tumor cells, disrupting energy metabolism and repair mechanisms, rendering cells more prone to apoptosis. Preclinical studies with MGd and pemetrexed show significant tumor growth delay in lung cancer cell lines. METHODS: Patients with non-small cell lung cancer, Eastern Cooperative Oncology Group performance status 0 to 1, who had received one previous platinum containing regimen and normal organ function were treated with MGd 15 mg/kg and pemetrexed 500 mg/m q21days. Patients were allowed to receive more than one regimen if the initial treatment was in the adjuvant or curative setting and administered >12 months earlier. The primary end point was to demonstrate a 40% rate of 6-month progression free survival (PFS). RESULTS: Seventy-two patients (30 women, 42 men), performance status 0/1 (30/42), and a median age of 63 years were enrolled. Most patients (96%) were current or former smokers. All histologic types were represented (squamous/adenocarcinoma/other: 28%, 42%, 31%). Number of prior regimens: 1: 69%; 2: 26%, and >2: 4%. Median number of cycles administered was (range) 2 (1-12). TOXICITY: grade 3/4 neutropenia was noted in 8.3% with febrile neutropenia in 1.4%, thrombocytopenia in 8.3%, fatigue in 9.7%, and pneumonia in 11.1%. There were no complete responses, 8.1% had partial response, 56.5% had stable disease, and 35.5% had progressive disease as their best response. Twenty-three percent of patients were progression free at 6 months and the median PFS was 2.6 months with an overall survival of 8.1 months. CONCLUSIONS: The combination of MGd and pemetrexed was well tolerated with toxicity similar to that of pemetrexed alone. However, the study did not achieve its end point of 40% 6-month PFS. The response rate, PFS, and overall survival did not seem markedly different than prior phase II and phase III studies of pemetrexed alone. Consequently, there are no further plans for development of this combination.

Development of bronchiolitis obliterans organizing pneumonia with platinum-based chemotherapy for metastatic rectal cancer.

Bronchiolitis obliterans organizing pneumonia (BOOP) is an adverse event known to occur after cancer chemotherapy and radiotherapy. We present a case of a 47-year-old patient who was diagnosed with BOOP after treatment for metastatic rectal cancer with oxaliplatin/capecitabine/bevacizumab. Removal of oxaliplatin from the regimen and replacement with irinotecan resulted in a resolution of his pulmonary symptoms.

Disease-specific survival for limited-stage small-cell lung cancer affected by statistical method of assessment.

BACKGROUND: In general, prognosis and impact of prognostic/predictive factors are assessed with Kaplan-Meier plots and/or the Cox proportional hazard model. There might be substantive differences from the results using these models for the same patients, if different statistical methods were used, for example, Boag log-normal (cure-rate model), or log-normal survival analysis. METHODS: Cohort of 244 limited-stage small-cell lung cancer patients, were accrued between 1981 and 1998, and followed to the end of 2005. The endpoint was death with or from lung cancer, for disease-specific survival (DSS). DSS at 1-, 3- and 5-years, with 95% confidence limits, are reported for all patients using the Boag, Kaplan-Meier, Cox, and log-normal survival analysis methods. Factors with significant effects on DSS were identified with step-wise forward multivariate Cox and log-normal survival analyses. Then, DSS was ascertained for patients with specific characteristics defined by these factors. RESULTS: The median follow-up of those alive was 9.5 years. The lack of events after 1966 days precluded comparison after 5 years. DSS assessed by the four methods in the full cohort differed by 0-2% at 1 year, 0-12% at 3 years, and 0-1% at 5 years. Log-normal survival analysis indicated DSS of 38% at 3 years, 10-12% higher than with other methods; univariate 95% confidence limits were non-overlapping. Surgical resection, hemoglobin level, lymph node involvement, and superior vena cava (SVC) obstruction significantly impacted DSS. DSS assessed by the Cox and log-normal survival analysis methods for four clinical risk groups differed by 1-6% at 1 year, 15-26% at 3 years, and 0-12% at 5 years; multivariate 95% confidence limits were overlapping in all instances. CONCLUSION: Surgical resection, hemoglobin level, lymph node involvement, and superior vena cava (SVC) obstruction all significantly impacted DSS. Apparent DSS for patients was influenced by the statistical methods of assessment. This would be clinically relevant in the development or improvement of clinical management strategies.

Phase II trial of combined irinotecan and oxaliplatin given every 3 weeks to patients with metastatic colorectal cancer.

BACKGROUND: Both irinotecan and oxaliplatin are active agents in the treatment of patients with metastatic colorectal cancer, and there is a strong preclinical rationale for combining these 2 agents. Therefore, a Phase II trial was designed and conducted to determine the efficacy and tolerability of combined irinotecan and oxaliplatin given every 3 weeks to patients with metastatic colorectal cancer. METHODS: Patients with previously untreated metastatic colorectal cancer received irinotecan at a dose of 175 mg/m2 and oxaliplatin at a dose of 130 mg/m2, both given intravenously every 3 weeks. Objective responses were evaluated every 2 courses and were confirmed at least 4 weeks after the initial determination. RESULTS: Fifty-five patients were enrolled and treated in the current trial. Of the 53 patients whose responses were evaluable, 18 (34%) achieved a partial response, 27 (51%) had stable disease, and 8 (15%) developed disease progression as their best response to the treatment. The intent-to-treat median survival for all patients was 16.4 months and the time to progression was 4.8 months. All 55 patients were available for toxicity analysis (according to version 2.0 of the National Cancer Institute Common Toxicity Criteria). The most common Grade 3-4 toxic effect was neutropenia, which was reported to occur in 22 patients (40%). CONCLUSIONS: The combination of irinotecan and oxaliplatin appears to be safe and active when used to treat patients with metastatic colorectal cancer. Treatment results with this regimen were similar to those reported for other combined frontline chemotherapy regimens for colorectal cancer. When this particular regimen wa used, neutropenia was found to be the predominant toxicity.