Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer.

BACKGROUND: Neoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non-small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients. RESULTS: The median event-free survival was 31.6 months (95% confidence interval [CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression, disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P = 0.005). The percentage of patients with a pathological complete response was 24.0% (95% CI, 18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94; 99% CI, 3.49 to 55.75; P<0.001). Results for event-free survival and pathological complete response across most subgroups favored nivolumab plus chemotherapy over chemotherapy alone. At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI, 0.30 to 1.07) and did not meet the criterion for significance. Of the patients who underwent randomization, 83.2% of those in the nivolumab-plus-chemotherapy group and 75.4% of those in the chemotherapy-alone group underwent surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group. CONCLUSIONS: In patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or impede the feasibility of surgery. (Funded by Bristol Myers Squibb; CheckMate 816 ClinicalTrials.gov number, NCT02998528.).

Plain language summary of the CheckMate 816 study results: nivolumab plus chemotherapy given before surgery for non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: In this article, we summarize results from the ongoing phase 3 CheckMate 816 clinical study that were published in The New England Journal of Medicine in 2022. The goal of CheckMate 816 was to find out if nivolumab, an immunotherapy that activates a person's immune system (the body's natural defense system) to fight cancer, plus chemotherapy works better than chemotherapy alone when given before surgery in people with non-small-cell lung cancer (NSCLC) that can be removed surgically (resectable NSCLC). WHAT HAPPENED IN THE STUDY?: Adults who had not previously taken medications to treat NSCLC and whose cancer could be removed with surgery were included in CheckMate 816. During this study, a computer randomly assigned the treatment each person would receive before surgery for NSCLC. In total, 179 people were randomly assigned to receive nivolumab plus chemotherapy, and 179 people were randomly assigned to receive chemotherapy alone. The researchers assessed whether people who received nivolumab plus chemotherapy lived longer without the cancer geting worse or coming back and whether there were any cancer cells left in the tumor and lymph nodes removed by surgery. The researchers also assessed how adding nivolumab to chemotherapy affected the timing and outcomes of surgery and whether the combination of these drugs was safe. WHAT WERE THE RESULTS?: Researchers found that people who took nivolumab plus chemotherapy lived longer without the cancer getting worse or coming back compared with those who took chemotherapy alone. More people in the nivolumab plus chemotherapy group had no cancer cells left in the tumor and lymph nodes removed by surgery. Most people went on to have surgery in both treatment groups; the people who took nivolumab plus chemotherapy instead of chemotherapy alone had less extensive surgeries and were more likely to have good outcomes after less extensive surgeries. Adding nivolumab to chemotherapy did not lead to an increase in the rate of side effects compared with chemotherapy alone, and side effects were generally mild and manageable. WHAT DO THE RESULTS OF THE STUDY MEAN?: Results from CheckMate 816 support the benefit of using nivolumab plus chemotherapy before surgery for people with resectable NSCLC. Clinical Trial Registration: NCT02998528 (ClinicalTrials.gov).

Bempegaldesleukin plus nivolumab in untreated, unresectable or metastatic melanoma: Phase III PIVOT IO 001 study design.

Nivolumab, a PD-1 inhibitor, has demonstrated prolonged survival benefit in patients with advanced melanoma. Bempegaldesleukin (BEMPEG; NKTR-214), a first-in-class CD122-preferential IL-2 pathway agonist, provides sustained signaling through the IL-2ßγ receptor, which activates effector T and natural killer cells. In the Phase I/II PIVOT-02 trial, the combination of bempegaldesleukin plus nivolumab was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. Here, we describe the design of and rationale for the Phase III, global, randomized, open-label PIVOT IO 001 trial comparing bempegaldesleukin plus nivolumab with nivolumab alone in patients with previously untreated, unresectable or metastatic melanoma. Primary end points include objective response rate, progression-free survival and overall survival. Key secondary end points include further investigation of safety/tolerability, previously assessed in the PIVOT-02 trial. Clinical Trial Registration: NCT03635983 (ClinicalTrials.gov).

BRAF and beyond: Tailoring strategies for the individual melanoma patient.

Until recently, options for therapy in metastatic melanoma were limited. The understanding of immune check-point blockade and the discovery of molecular pathways involving driver mutations like BRAF has transformed the therapeutic landscape in this disease. Ipilimumab was the first drug shown to improve survival while vemurafenib demonstrated rapid responses never seen before in melanoma. Drugs from these classes and others are now in advanced stages of development and primed to positively impact patient survival in an incremental fashion. In this review, we highlight some of the developments during this renaissance in melanoma therapy and discuss agents of promise. Clinical challenges we face include individualizing therapy for patients, overcoming resistance to molecularly targeted therapy and developing rationale combinations or sequences of drugs. A concerted bench and bedside effort in this direction will undoubtedly keep melanoma in the forefront in an era of personalized medicine.

Controversies in the management of advanced melanoma: "gray" areas amid the "black and blue".

OBJECTIVE: To examine the current controversies and discuss consensus recommendations regarding treatment sequencing and the role of BRAF inhibitor at disease progression. DATA SOURCE: An English-language literature search of MEDLINE/PubMed (1966-May 2014), using the keywords advanced melanoma, ipilimumab, cytotoxic T-lymphocyte antigen 4, dabrafenib, vemurafenib, BRAF inhibitor, trametinib, MEK inhibitor, and treatment sequencing was conducted. Data were also obtained from package inserts, meeting abstracts, and clinical registries. STUDY SELECTION AND DATA EXTRACTION: All relevant published articles and abstracts on ipilimumab, vemurafenib, dabrafenib, and trametinib were reviewed. Clinical trial registries and meeting abstracts were used for ongoing studies. DATA SYNTHESIS: The availability of new agents has made therapy selection more complex. Immunotherapy supporters reason that immunotherapy offers the best chance for long-term benefit and does not compromise the antitumor activity of subsequent BRAF inhibitors. Targeted therapy advocates rely on the high probability and rapid onset of response to BRAF inhibitors. Currently, there is insufficient evidence regarding the role of BRAF inhibitor at disease progression. CONCLUSIONS: Therapy should be individualized based on patient- and disease-specific factors. Immunotherapy represents the best option for durable remission; however, targeted therapy is more appropriate for patients who are symptomatic or have rapidly growing tumors. The novel therapies have also demonstrated meaningful intracranial activity; thus, the presence of brain metastases should be taken into consideration in selecting therapy. Limited data exist about the continuation of BRAF inhibitors after therapeutic failure. Active research is ongoing to define the best option for patients with BRAF inhibitor refractory disease.

Dose rounding of ipilimumab in adult metastatic melanoma patients results in significant cost savings.

PURPOSE: To assess cost savings incurred with a dose rounding process that was implemented for ipilimumab. Secondarily, to assess response rates, patient tolerance, and adverse effects associated with ipilimumab upon implementation of dose rounding. METHODS: All patients with a diagnosis of metastatic melanoma and who received at least one dose ipilimumab were included for analysis. Doses of ipilimumab were calculated based upon the actual body weight (in kg) of the patient at the FDA approved regimen of 3 mg/kg every 21 days × 4 doses. The exact total mg dose was then rounded to the nearest 50 mg vial size. The potential effect on cost was calculated in US dollars for both the calculated and rounded doses. Waste, in mg, was defined as the amount of drug that may have been discarded if the calculated dose was used for therapy. The acquisition cost applied was US$120 per mg. RESULTS: 22 patients have received at least one dose of ipilimumab. 11 patients have completed therapy and received all four induction doses. 9 patients discontinued therapy early and 2 patients were still actively receiving induction at the time of this analysis. A total of 63 doses were given. The maximum potential cost savings by giving ipilimumab to the nearest 50 mg over the period was 155,400. CONCLUSIONS: Dose rounding of ipilimumab to the nearest 50 mg has the potential to result in a significant cost savings by eliminating drug waste.

A new era for castrate resistant prostate cancer: a treatment review and update.

PURPOSE: The purpose of this review article is to present the current treatment options for castrate resistant prostate cancer in addition to the recently approved agents and their role in treatment. SUMMARY: The biology of prostate cancer and the data supporting the use of traditional chemotherapeutic options in castrate resistant prostate cancer are reviewed. The newly approved agents, sipuleucel-T, cabazitaxel, and abiraterone, are presented as well. The studies that led to the approval of these three agents are discussed in this article as well as their current and potential roles in the treatment of castrate resistant prostate cancer. CONCLUSION: New mechanisms, drugs, and clinically relevant molecular targets show survival advantage and are new options available for patients after traditional chemotherapy. The roles of these new agents have yet to be further clarified in future studies.

Characterization of vancomycin pharmacokinetics in the adult acute myeloid leukemia population.

Current vancomycin dosing guidelines in our acute myeloid leukemia population too often achieve suboptimal initial drug concentrations. Our aim was to assess vancomycin pharmacokinetic parameters in acute myeloid leukemia patients and develop an improved dosing equation to attain more accurate initial therapeutic trough levels. Acute myeloid leukemia patients receiving vancomycin for a presumed or documented gram positive infection were eligible. Patients hospitalized in the intensive care unit, those with creatinine clearance <30 mL/min or with limb amputation were excluded. Three samples were collected at the following post-infusion time ranges: 1 h, 3-8 h, and 8-24 h post-infusion, contingent on the dosing interval. Pharmacokinetic data were then fit using a Bayesian-based population pharmacokinetic model. A total of 25 acute myeloid leukemia patients were studied with a mean volume in the central compartment (Vc; L/65 kg), volume of distribution at steady state (Vss; L/65 kg) and distributional clearance (CLd; L/h/65 kg) of 15, 38.9, and 9.32, respectively. CLslope was 0.59 (mg of vancomycin clearance per unit of creatinine clearance in mL/min); this value is 21.4% lower than the established literature value (0.75). The derived equation, based upon these values, was reasonably precise at achieving the desired trough concentration using a priori dosing. The mean (CV%) of the achieved trough was 94% (29%) with a range of 66-188%; 3/25 at <75% and >125%]. We have established that the derived dosing equation can place ≈ 75% of adult acute myeloid leukemia patients at vancomycin trough levels within 75-125% of the target trough level.

Treatment of concurrent metastatic renal cell carcinoma and chronic myelogenous leukemia--easier said than done? A case report.

Treating two active malignancies concurrently can be exceedingly difficult. Complications can occur from the different treatment regimens, especially if they share common targets, and the progressing diseases can make managing treatment side-effects even more challenging. We report a case of a patient with coexisting CML and mRCC who progressed on multiple lines of mRCC therapy while experiencing significant dose limiting side-effects.

Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial.

Importance: Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. Objective: To assess safety and objective response rate of durvalumab combined with tremelimumab. Design, Setting, and Participants: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. Interventions: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. Main Outcomes and Measures: Safety and tolerability and efficacy measured by objective response rate. Results: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. Conclusions and Relevance: In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way. Trial Registration: clinicaltrials.gov Identifier: NCT02319044.

Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with ≥25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy.

BACKGROUND: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC. PATIENTS AND METHODS: Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 [TC ≥ 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS). RESULTS: Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9-24.4); 29.4% (95% CI, 15.1-47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5-21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9-3.7) and 7.1 months (95% CI, 4.9-9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5-22.1) and 33.6% (95% CI, 24.8-42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up. CONCLUSION: Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients.

Nilotinib: a new tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder arising from a single genetic mutation that leads to an increase in immature myeloid cells in the bone marrow and the accumulation of these cells in the blood. Typically, CML represents 15-20% of all adult leukemias, with 4830 new cases expected in 2008. The cytogenetic hallmark of CML is the Philadelphia chromosome, which is the result of the reciprocal translocation and conjugation of the breakpoint cluster region (BCR) gene, BCR, on chromosome 22 and the Abelson (ABL) kinase gene, ABL, on chromosome 9. Current treatment is aimed at inhibiting BCR and ABL kinase with novel agents, the first being imatinib in 2003, and more recently dasatinib in 2006. Nilotinib is a new small-molecule inhibitor of tyrosine kinase rationally developed from the crystalline structure of the imatinib-ABL complex. It represents an aminopyrimidine derivative of imatinib with approximately 30 times more potency in vitro against imatinib-sensitive BCR-ABL-expressing cell lines and activity against 32 of 33 point mutations conferring resistance to imatinib. Data from phase I and II studies show that nilotinib has activity against all phases of CML in patients who are intolerant or have failed therapy with imatinib or dasatinib. Nilotinib represents a new therapeutic option for patients with CML who are intolerant or have failed therapy with imatinib. Ongoing clinical trials are assessing nilotinib's role in the treatment of patients with newly diagnosed CML and its long-term efficacy and safety.

Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer.

This Review Article provides a multi-stakeholder view on the current status of neoadjuvant therapy in lung cancer. Given the success of oncogene-targeted therapy and immunotherapy for patients with advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes. There are unique opportunities and challenges with the neoadjuvant approach to drug development. To achieve more rapid knowledge turns, study designs, endpoints, and definitions of pathologic response should be standardized and harmonized. Continued dialogue with all stakeholders will be critical to design and test novel induction strategies, which could expedite drug development for patients with early lung cancer who are at high risk for metastatic recurrence.

Systemic Therapy in Advanced Cutaneous Squamous Cell Carcinoma (CSCC): The Roswell Park Experience and a Review of the Literature.

OBJECTIVES: Treatment of locally advanced unresectable or metastatic cutaneous squamous cell carcinoma (mCSCC) is suboptimal with a paucity of robust data on systemic therapy. This retrospective study aimed to evaluate the efficacy and outcomes of patients with locally advanced unresectable or mCSCC treated with systemic therapy. METHODS: Records of patients with CSCC treated with systemic therapy from January 2001 to January 2011 were reviewed. Response was assessed using WHO criteria. Descriptive results were assessed using Wilcoxon rank-sum test for ordinal responses and Pearson χ test for categorical responses. Survival was calculated by the Kaplan-Meier method. RESULTS: Of 28 patients identified, 25 patients (M:F=18:7), median age 66 years (range, 39 to 85 y), had the required data for final analysis. Partial response was 44% and stable disease (SD) was 24%. The median progression-free survival (PFS) and overall survival (OS) were 5.5 months (2.3, 13.2) and 10.9 months (5.3, 21.3) respectively; 3-year OS was 22%. Patients with WHO response had improved PFS (20.8 mo; 4.4, NR) and OS (37.5 mo; 10.3, NR) compared with patients with SD/PD (PFS 2.7 mo; OS 5.9 mo). Use of platinum-based therapy significantly improved PFS and OS, whereas taxanes and cetuximab had no impact in this small cohort. There was no difference in PFS or OS with multiagent versus single-agent therapy. CONCLUSIONS: Platinum-based therapy remains as one of the standard options in advanced CSCC management. Agents to improve response rates are needed and future trials should address the use of novel targeted and new chemotherapy combinations in CSCC.

Immunotherapy in Melanoma: Recent Advances and Promising New Therapies.

The incidence and mortality of melanoma are on the rise. Historically, patients diagnosed with metastatic melanoma were faced with a grim prognosis, with survival rates of 15% at 5 years. Prior to 2011, no drug or therapeutic regimen had been shown to improve overall survival (OS) in metastatic melanoma. Chemotherapeutic agents, such as dacarbazine or temozolomide, are often given to patients for palliative purposes; high-dose interleukin 2 and biochemotherapy are immunotherapeutic options that could be offered to patients with a good performance status at specialized centers. Neither has been shown to impact OS, but durable complete responses are seen in a minority of patients. Since 2011, 4 new drugs have been approved by the US Food and Drug Administration for the treatment of metastatic melanoma, all of which improve survival. Three of these agents (vemurafenib, dabrafenib, and trametinib) are targeted therapies, with ipilimumab being the only new immunotherapy. With a focus on immunotherapeutic agents, this review seeks to summarize the treatment options currently available for metastatic melanoma and to examine those on the near horizon.

Retrospective analysis of the safety and efficacy of high-dose interleukin-2 after prior tyrosine kinase inhibitor therapy in patients with advanced renal cell carcinoma.

Although tyrosine kinase inhibitors (TKI) are the most common first-line therapy for metastatic renal cell carcinoma, high-dose interleukin-2 (HD-IL2) remains the only agent that provides durable complete responses. The optimal sequence of these agents remains uncertain. This retrospective multi-institutional study examined the safety and efficacy of HD-IL2 following TKI therapy. After IRB approval at 7 HD-IL2 centers, data relating to patient, disease, and treatment characteristics among 40 consecutive patients with metastatic renal cell carcinoma who were treated with HD-IL2 after at least 1 prior TKI therapy were retrospectively collected. The most common cardiac adverse events were grade 3 hypotension and vascular leak syndrome. Six patients (15%) experienced other grade ≥3 cardiac adverse events. There were 2 treatment-related deaths due to congestive heart failure, occurring in 1 patient with short TKI to HD-IL2 interval and another patient with an abnormal baseline cardiac stress test. Best responses included 2 CRs (5%, duration 40+ and 62+ mo), 3 PRs (8%, duration 6, 11, and 24 mo), 13 SD (32%, median duration 12 mo), 20 PD (50%), and 2 not evaluable patients. Median overall survival was 22 months. Administration of HD-IL2 could be safe and effective after TKI therapy; however, careful selection of patients is critical. We recommend baseline cardiac risk factor assessment, screening with both cardiac stress test and echocardiogram, and allowing a TKI to HD-IL2 interval of at least 2 months.

Case report of pneumatosis intestinalis secondary to sunitinib treatment for refractory gastrointestinal stromal tumor.

Pneumatosis intestinalis (PI) occurs when inter-luminal air enters the bowel wall of the gastrointestinal tract via a mucosal defect. The condition is caused by numerous disease states, direct trauma, and various drugs. When PI is secondary to drug therapy, discontinuation of the offending agent results in the resolution of PI. We report on the case of a 73-year-old male with a history of refractory gastrointestinal stromal tumor experiencing PI while on sunitinib treatment. PI was noted via computed tomography (CT) scans 68 days after starting sunitinib therapy and showed near complete resolution on a follow up CT performed one month after discontinuing sunitinib. Given that a CT scan performed five months prior to the initiation of sunitinib did not show PI, lack of abdominal symptoms in our patient, and resolution of PI after discontinuing sunitinib, the cause of PI in our patient was likely due to sunitinib treatment.

Heart failure caused by molecularly targeted therapies for cancer.

Cancer therapeutics is undergoing a revolution with the advent of new drugs that can selectively target molecules responsible for carcinogenesis and tumor growth. The type and mechanism of these targeting drugs vary. Some are small molecules that specifically target a binding site on a receptor or signal transduction molecule. Antibodies have been engineered to bind to the receptors or the corresponding ligands that mediate a critical cancer activity. In almost all cases, the intent is to inhibit or shut down a specific molecular pathway. Unprecedented activity against the cancer is seen without overt traditional toxicities such as alopecia, nausea and/or vomiting, and cytopenias. Unfortunately, an increase in toxicity has now become evident as more experience accumulates with the use of these drugs. In some cases, unexpected cardiotoxicities have arisen when these new drugs have been added to more conventional chemotherapies. Heart failure is the unfortunate manifestation for many of these toxicities. We outline the scope of this problem and examine the mechanisms of drug-induced heart failure. The distinctive signs and symptoms specific to each drug are described, and the diagnosis and treatment of the condition are discussed. Our aim is to allow the practitioner to recognize the unusual manifestations of heart failure in this setting in order to make a timely diagnosis and begin appropriate treatment measures.

Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing.

Colistin is a polymyxin antibiotic that was discovered in the late 1940s for the treatment of gram-negative infections. After several years of clinical use, its popularity diminished because of reports of significant nephrotoxicity and neurotoxicity. Recently, the antibiotic has resurfaced as a last-line treatment option for multidrug-resistant organisms such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. The need for antibiotics with coverage of these gram-negative pathogens is critical because of their high morbidity and mortality, making colistin a very important treatment option. Unfortunately, however, resistance to colistin has been documented among all three of these organisms in case reports. Although the exact mechanism causing colistin resistance has not been defined, it is hypothesized that the PmrA-PmrB and PhoP-PhoQ genetic regulatory systems may play a role. Colistin dosages must be optimized, as colistin is a last-line treatment option; in addition, suboptimal doses have been linked to the development of resistance. The lack of pharmacokinetic and pharmacodynamic studies and no universal harmonization of dose units, however, have made it difficult to derive optimal dosing regimens and specific dosing guidelines for colistin. In critically ill patients who may have multiorgan failure, renal insufficiency may alter colistin pharmacokinetics. Therefore, dosage alterations in this patient population are imperative to achieve maximal efficacy and minimal toxicity. With regard to colistin toxicity, most studies show that nephrotoxicity is reversible and less frequent than once thought, and neurotoxicity is rare. Further research is needed to fully understand the impact that the two regulatory systems have on resistance, as well as the dosages of colistin needed to inhibit and overcome these developing patterns.

Response to sorafenib after sunitinib-induced acute heart failure in a patient with metastatic renal cell carcinoma: case report and review of the literature.

Cardiotoxicity is an emerging concern with a new class of drugs known as targeted agents, which include trastuzumab and sunitinib. Sunitinib is a small molecule that inhibits multiple tyrosine kinase receptors. This drug was approved by the United States Food and Drug Administration in 2006 for the treatment of clear cell metastatic renal cell carcinoma and advanced gastrointestinal stromal tumors. We describe a 65-year-old woman who was treated with sunitinib for metastatic clear cell renal cell carcinoma. After 5 months of therapy, she developed acute heart failure requiring hospitalization; sunitinib was immediately discontinued. The patient had classic symptoms of heart failure, including pleural effusion. An echocardiogram revealed a left ventricular ejection fraction of 30%. She received standard treatment for heart failure, including a beta-blocker, an angiotensin-converting enzyme inhibitor, and diuretics. Within 1 month, the patient's symptoms resolved, and subsequent cardiac evaluation showed that her left ventricular ejection fraction returned to normal. According to the Common Terminology Criteria for Adverse Events developed by the National Cancer Institute, her cardiac event associated with sunitinib was defined as grade III toxicity. One month later, sorafenib, another tyrosine kinase inhibitor, was started with the aim of continuing her previous response to sunitinib. After 7 months of sorafenib therapy, the patient had no evidence of heart failure, and her condition was responding to treatment. Clinicians should be aware that sunitinib-induced heart failure occurs occultly and that many--but not all--cases resolve with discontinuation of the drug. Use of sorafenib after sunitinib-induced heart failure appears to be safe and effective, which suggests that cardiotoxicity is not a general class effect of the tyrosine kinase inhibitors.