Management of adverse events from the treatment of encorafenib plus cetuximab for patients with BRAF V600E-mutant metastatic colorectal cancer: insights from the BEACON CRC study.

Colorectal cancer is the second leading cause of cancer deaths worldwide, with a 5-year relative survival of 14% in patients with metastatic colorectal cancer (mCRC). Patients with BRAF V600E mutations, which occur in ∼10%-15% of patients with mCRC, have a poorer prognosis compared with those with wild-type BRAF tumours. The combination of the BRAF inhibitor encorafenib with the epidermal growth factor receptor inhibitor cetuximab currently represents the only chemotherapy-free targeted therapy approved in the USA and Europe for previously treated patients with BRAF V600E-mutated mCRC. As a class, BRAF inhibitors are associated with dermatologic, gastrointestinal, and renal events, as well as pyrexia and secondary skin malignancies. Adverse event (AE) profiles of specific BRAF inhibitors vary, however, and are affected by the specific agents given in combination. In patients with mCRC, commonly reported AEs of cetuximab monotherapy include infusion reactions and dermatologic toxicities. Data from the phase III BEACON CRC study indicate that the combination of encorafenib with cetuximab has a distinct safety profile. Here we review the most frequently reported AEs that occurred with this combination in BEACON CRC and best practices for managing and mitigating AEs that require more than standard supportive care.

Use of paclitaxel in patients with pre-existing cardiomyopathy: a review of our experience.

Cardiac toxicity is frequently the indication for discontinuation of an anthracycline in patients with tumors which remain anthracycline-sensitive. During the 1990s, the most frequently used second-line agents at the Yale Cancer Center (YCC) were the taxanes. The goal of this retrospective analysis was to determine the effect of paclitaxel on cardiac function in patients with cardiomyopathy. YCC outpatient clinic pharmacy order forms were used to identify all patients who had received paclitaxel between December 1995 and November 1997. The clinic records of those patients with a left ventricular ejection fraction (LVEF) of < or = 50% were reviewed to determine the temporal relation between the decreased LVEF and paclitaxel therapy. In addition, clinic records were examined for evidence of prior doxorubicin therapy and history of prior cardiac disease. Between December 1995 and November 1997, 225 patients were treated with paclitaxel in the YCC outpatient clinic. Nine patients had LVEF < or = 50% (mean 37%) prior to initiation of paclitaxel therapy. Six of these patients had equilibrium radionuclide angiocardiographic (ERNA) scans following completion of paclitaxel. In these 6 patients, the mean change in LVEF was +6% (range -3% to +29%). Four patients had improved LVEF following paclitaxel (mean 11%, range 2% to 29%), while 2 patients experienced a decrease in LVEF following paclitaxel treatment (mean 2.5%). The 3 patients who did not have ERNA scans following paclitaxel therapy had no clinical evidence of congestive heart failure. Our experience confirms the results of prior studies that paclitaxel can be safely administered in patients with underlying cardiac dysfunction.

Translational regulation as a novel mechanism for the development of cellular drug resistance.

Cellular drug resistance is one of the principal obstacles to the clinical efficacy of cancer chemotherapy. In this review, we describe the potential role for translational regulation as a novel mechanism for modulating chemosensitivity. The evidence for the translational control of thymidylate synthase, dihydrofolate reductase, and p53 will be presented, as will experimental data showing how disruptions in this important regulatory process can lead to the rapid emergence of cellular drug resistance.

The feasibility of high-dose chemotherapy in breast cancer patients with impaired left ventricular function.

Breast cancer patients with cardiac disease are usually excluded from clinical trials of high-dose chemotherapy. We treated 52 patients with inflammatory and/or metastatic disease with sequential high-dose melphalan and stem cell rescue followed by high-dose thiotepa and stem cell rescue. Stem cells were mobilized with cyclophosphamide and/or paclitaxel and filgrastim. Left ventricular ejection fraction (LVEF) was measured by equilibrium radionuclide angiocardiography (ERNA) at baseline, after each course of chemotherapy and 4 weeks after completing both transplants. The mean absolute decrease in LVEF after the two transplants was 3.6% (P = 0. 008 for the comparison with baseline LVEF), and most of this drop (-2.5%, P = 0.007) occurred after mobilization. Unexpectedly, paclitaxel was associated with a mean absolute decrease in LVEF of 3. 4% (P = 0.032, n = 19), cyclophosphamide alone was not associated with a significant change in LVEF (-1.3%, P = 0.23), but mobilization with sequential paclitaxel and cyclophosphamide resulted in a mean absolute drop of 4.9% in LVEF (P = 0.009). Twelve patients were found to have a reduced LVEF (<50%) at least once during treatment and had a mean absolute decrease in LVEF of 10% (P = 0.008) from baseline, compared with a drop of only 1.8% (P = 0. 176) in the patients without impaired LV function. Although two of these 12 patients developed symptomatic heart failure, their cardiac symptoms were easily treated and there were no cardiac deaths. We conclude that our protocol has acceptable cardiac toxicity and breast cancer patients with impaired LV function should not be denied high-dose chemotherapy if otherwise indicated.

Peripheral blood progenitor cell cycle kinetics following priming with pIXY321 in patients treated with the "ICE" regimen.

PURPOSE: Treatment with hematopoietic growth factors increases the percentage of hematopoietic progenitor cells in cell cycle. Following withdrawal of certain growth factors, preclinical data suggest that there is a transient fall in the percentage of progenitor cells in cycle below the baseline, thus providing a window to administer chemotherapy with reduced risk of myelotoxicity. PATIENTS AND METHODS: Patients with histologically confirmed, previously untreated neoplasia, were treated with pIXY321 by subcutaneous injection at a dose of 375 microg/m2 twice daily (total dose 750 microg/m2/day) for seven days (days -8 to -2), followed by a two-day rest (days -1 to 0). Patients received ICE (ifosfamide, carboplatin and etoposide) on days 1 to 3. On day 4, pIXY321 was resumed until hematologic recovery. Peripheral blood was collected on days -8, -2, -1, 1, and cell cycle distribution was determined using flow cytometry. RESULTS: Twenty patients were treated in this study and received a total of 54 cycles. Partial responses were observed in three of 13 patients with non-small cell lung cancer (23 percent) and two of five patients with small cell lung cancer (40 percent). Six of 15 patients had an increased number of cells in S+G2/M on day 1 of ICE following seven days of pIXY321 and two days off (days -1 to 0). The average increase was 63 percent (range 6-253). Seven patients had a decreased number of cells in S+G2/M. The average decrease was 55 percent (range 6.3-78). There were no significant differences among the fifteen patients with regards to the observed toxicity of the chemotherapy. DISCUSSION: pIXY321 in this schedule did not consistently decrease the percentage of cycling progenitor cells in the peripheral blood. Future studies should define whether other growth factors and/or schedules can synchronize progenitor cell cycling and protect the marrow compartment from cycle specific chemotherapy.

p53 mutations do not predict response to paclitaxel/radiation for nonsmall cell lung carcinoma.

BACKGROUND: Mutations in the tumor suppressor gene p53 have been associated with resistance to ionizing radiation and chemotherapy. Paclitaxel and concurrent radiation (paclitaxel/RT) achieve high response rates with locally advanced nonsmall cell lung carcinoma (NSCLC). In vitro data and animal studies suggest that paclitaxel may have a unique ability to activate tumor cell apoptosis in the absence of wild-type p53 function. The authors sought to determine whether p53 mutations affect response to paclitaxel/RT in patients with locally advanced NSCLC. METHODS: Thirty patients with Stage IIIA or IIIB NSCLC who participated in Brown University Oncology Group protocols utilizing paclitaxel/RT had tumor tissue that was adequate for analysis. Mutations were detected in tumor tissue by single-strand conformation polymorphism analysis of exons 5 through 8 of the p53 gene, and confirmed by direct sequencing. RESULTS: Mutations in p53 were found in 12 of 30 patients (40%). The response rates (complete plus partial) of 75% for patients with tumors with p53 mutations, and 83% for patients with wild-type p53, did not differ significantly (P = 0.70). CONCLUSIONS: p53 mutations do not predict response of patients with NSCLC to paclitaxel/RT. This finding is in striking contrast to results with other chemotherapeutic agents and ionizing radiation. These clinical data support in vitro data and animal studies regarding the unique mechanism of the action of paclitaxel. Further investigation is needed to determine the mechanism of lung tumor cell death after paclitaxel/RT. These results suggest that paclitaxel/RT may be an active regimen for patients with other locally advanced neoplasms with high rates of p53 gene mutations.

Management of persistent B19 parvovirus infection in AIDS.

An HIV+ 26-year-old white man with a CD4 count of 0.06 x 10(9)/l was found to have red blood cell aplasia secondary to B19 parvovirus infection. Regular infusions of intravenous immunoglobulin (IVIG) were begun and resulted in marked reticulocytosis and correction of anaemia. The patient has been followed for over 4 years and has become anaemic and reticulocytopenic whenever IVIG was interrupted. Serial dot blot analysis of the patient's sera for B19 parvovirus DNA showed absence of DNA immediately following IVIG treatments but reappearance within 3-6 weeks. Regular IVIG was effective in controlling but not eradicating B19 parvovirus infection in this HIV+ patient.