2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer.

PURPOSE: An American Society of Clinical Oncology (ASCO) focused update updates a single recommendation (or subset of recommendations) in advance of a regularly scheduled guideline update. This document updates one recommendation of the ASCO Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer (NSCLC) regarding switch maintenance chemotherapy. CLINICAL CONTEXT: Recent results from phase III clinical trials have demonstrated that in patients with stage IV NSCLC who have received four cycles of first-line chemotherapy and whose disease has not progressed, an immediate switch to alternative, single-agent chemotherapy can extend progression-free survival and, in some cases, overall survival. Because of limitations in the data, delayed treatment with a second-line agent after disease progression is also acceptable. RECENT DATA: Seven randomized controlled trials of carboxyaminoimidazole, docetaxel, erlotinib, gefitinib, gemcitabine, and pemetrexed have evaluated outcomes in patients who received an immediate, non-cross resistant alternative therapy (switch maintenance) after first-line therapy. RECOMMENDATION: In patients with stage IV NSCLC, first-line cytotoxic chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is stable but not responding to treatment. Two-drug cytotoxic combinations should be administered for no more than six cycles. For those with stable disease or response after four cycles, immediate treatment with an alternative, single-agent chemotherapy such as pemetrexed in patients with nonsquamous histology, docetaxel in unselected patients, or erlotinib in unselected patients may be considered. Limitations of this data are such that a break from cytotoxic chemotherapy after a fixed course is also acceptable, with initiation of second-line chemotherapy at disease progression.

American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer.

The purpose of this article is to provide updated recommendations for the treatment of patients with stage IV non-small-cell lung cancer. A literature search identified relevant randomized trials published since 2002. The scope of the guideline was narrowed to chemotherapy and biologic therapy. An Update Committee reviewed the literature and made updated recommendations. One hundred sixty-two publications met the inclusion criteria. Recommendations were based on treatment strategies that improve overall survival. Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life. For first-line therapy in patients with performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For patients with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with carboplatin-paclitaxel, except for patients with certain clinical characteristics. Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs. Data are insufficient to recommend routine use of molecular markers to select chemotherapy.

A Phase II study of SU5416 in patients with advanced or recurrent head and neck cancers.

BACKGROUND: SU5416 (semaxanib) is a synthetic small molecule inhibitor of the tyrosine kinase domain of vascular endothelial growth factor receptor 2 (VEGFR2). This Phase II study was conducted to determine the safety and efficacy of SU5416 in patients with recurrent or metastatic head and neck cancers. PATIENTS AND METHODS: This was an open label, single arm, Phase 2 study for patients who had received no more than 2 cytotoxic regimens. Thirty-five patients received intravenous SU5416 (145 mg/m(2)) twice per week by intravenous catheter. Radiologic imaging for response assessment was planned at the conclusion of each 8 week cycle. Serum VEGF levels and power Doppler ultrasound tumor imaging were explored as potential surrogate markers for SU5416 activity. RESULTS: Thirty-two patients had received prior radiotherapy, including 18 patients who received prior concurrent chemoradiotherapy. Twelve patients had received prior chemotherapy in the recurrent disease setting. Thirty-one patients were evaluable for response. There was one partial response and one minor response. The median number of 8-week cycles received was 1 (range 1-4). Median overall survival was 6.25 months. The most common > or = grade 3 toxicity was headache (31%). There was one fatal carotid artery hemorrhage. Fatigue, nausea, and vomiting were common grade 1-2 adverse events. Power Doppler ultrasound demonstrated decreased tumor vascularity in 5 of 7 patients. CONCLUSIONS: Treatment with SU5416 in patients with head and neck cancers is feasible, but objective responses are rare. Studies evaluating more potent anti-angiogenic agents in this disease are of interest.

Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm.

PURPOSE: Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor. Cetuximab has activity in squamous cell carcinoma and enhances both chemotherapy and radiotherapy. We conducted a pilot phase II study of a new combined-modality paradigm of targeted therapy (cetuximab) with chemoradiotherapy. PATIENTS AND METHODS: Eligible patients had stage III or IV, M0, squamous cell head and neck cancer. Treatment included concomitant boost radiotherapy (1.8 Gy/d weeks 1 to 6; boost: 1.6 Gy 4 to 6 hours later weeks 5 to 6; 70 Gy total to gross disease), cisplatin (100 mg/m2 intravenously weeks 1 and 4), and cetuximab (400 mg/m2 intravenously week 1, followed by 250 mg/m2 weeks 2 to 10). RESULTS: Twenty-two patients were enrolled (median age, 57 years; range, 41 to 72 years; median Karnofsky status, 90%; range, 70% to 90%; oropharynx primary tumor, 59% of patients; T4, 36%; N2/3, 77%; stage IV disease, 86%). One patient did not receive study treatment because of an ineligible diagnosis. The severity of expected, acute toxicities was typical of concurrent cisplatin and radiotherapy alone. Grade 3 or 4 cetuximab-related toxicities included acne-like rash (10%) and hypersensitivity (5%). However, the study was closed for significant adverse events, including two deaths (one pneumonia and one unknown cause), one myocardial infarction, one bacteremia, and one atrial fibrillation. With a median follow-up of 52 months, the 3-year overall survival rate is 76%, the 3-year progression-free survival rate is 56%, and the 3-year locoregional control rate is 71%. CONCLUSION: This regimen is not currently recommended outside of the clinical trial setting. Further investigation of its safety profile is needed. However, preliminary efficacy is encouraging, and further development of this targeted combined-modality paradigm is warranted.

Pentostatin and cyclophosphamide: an effective new regimen in previously treated patients with chronic lymphocytic leukemia.

PURPOSE: Purine analogs and alkylators are important agents in the treatment of chronic lymphocytic leukemia (CLL). Previously, combinations of fludarabine and chlorambucil were abandoned because of increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin may be least myelosuppressive. We hypothesized that combining pentostatin with cyclophosphamide would have less myelotoxicity than combinations using other purine analogs. PATIENTS AND METHODS: We studied 23 patients with previously treated CLL. All patients received pentostatin 4 mg/m(2). Seventeen patients received cyclophosphamide 600 mg/m(2), and six patients received cyclophosphamide 900 mg/m(2). Both drugs were administered on day 1 of each cycle, and cycles were repeated every 3 weeks for six treatments. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median number of prior treatment regimens was three (range, one to five) with 13 patients (57%) refractory to prior fludarabine therapy. RESULTS: The cyclophosphamide 900 mg/m(2) dose level was associated with moderate to severe nausea, and we chose cyclophosphamide 600 mg/m(2) as the dose for further study. There were 17 responses (74%; 95% confidence interval, 63% to 85%), including four complete responses. The response rate was 77% in fludarabine-refractory patients. Myelosuppression was acceptable with grade 3/4 neutropenia and thrombocytopenia, seen in 35% and 30% of patients, respectively. The relative sparing of thrombopoiesis can be seen in that only one patient (5%) with an initial platelet count of more than 20,000 required platelet transfusions while receiving therapy. CONCLUSION: Pentostatin 4 mg/m(2) with cyclophosphamide 600 mg/m(2) is safe and effective in previously treated patients with CLL. On the basis of these results, we are currently studying pentostatin, cyclophosphamide, and rituximab (PCR) therapy in patients with CLL.

Refractory Aspergillus pneumonia in patients with acute leukemia: successful therapy with combination caspofungin and liposomal amphotericin.

BACKGROUND: Pulmonary aspergillosis and other invasive fungal infections (IFIs) commonly complicate the management of patients with acute leukemia. Standard amphotericin-based therapies may be ineffective for many patients and the available salvage agents (itraconazole and caspofungin) are reported to possess only moderate activity against resistant infections. Laboratory evidence suggests a synergistic interaction between amphotericin and caspofungin. The authors treated a group of patients with amphotericin-refractory IFIs with the combination of caspofungin and amphotericin (or liposomal amphotericin). METHODS: A retrospective evaluation of patients with amphotericin-resistant IFIs was conducted. Diagnosis was based on clinical, radiographic, and when available, microbiologic data. Response to combination antifungal therapy was graded as either favorable or unfavorable. Favorable responses included improvement of both clinical and radiographic signs of fungal pneumonia. All other responses were graded as unfavorable. RESULTS: Thirty patients were included in this analysis. Twenty-six patients had acute leukemia. Based on recently published criteria, the IFIs were classified as proven in 6 patients, probable in 4 patients, and possible in 20 patients. The median duration and dose of amphotericin monotherapy were 12 days (range, 4-65 days) and 7.8 mg/kg (range, 4.2-66.1 mg/kg), respectively. The median duration of combination therapy was 24 days (range, 3-74 days). Eighteen patients (60%) experienced a favorable antifungal response. Twenty patients with acute leukemia received combination therapy for fungal pneumonias arising during intensive chemotherapy treatments. Favorable responses were observed in 15 of these patients (75%), and antifungal response did not depend on the response of the underlying leukemia. Survival to hospital discharge was significantly better (P < 0.001) in patients having a favorable response. Mild to moderate nephrotoxicity was noted in 50% of patients, necessitating the substitution of liposomal amphotericin. Mild elevation of alkaline phosphatase levels occurred in 30% of patients. Caspofungin was temporarily withheld from one patient who developed moderate but reversible biochemical hepatotoxicity. CONCLUSIONS: The antifungal combination of caspofungin and amphotericin can be administered safely to high-risk patients with hematologic malignancies. Although an absolute assessment of efficacy is limited by the design of this study, encouraging outcomes were noted for many patients. The authors plan to evaluate this regimen further in a randomized clinical trial.

A single, high dose of idarubicin combined with cytarabine as induction therapy for adult patients with recurrent or refractory acute lymphoblastic leukemia.

BACKGROUND: The majority of adult patients who are treated for lymphoblastic disease will either develop recurrent disease or will be refractory to their initial therapy. One option for patients with recurrent/refractory disease is to administer a reinduction regimen that employs a dose-intense combination of anthracycline and cytarabine. These salvage regimens are relatively distinct from the traditional vincristine/prednisone-based programs that are used typically as primary induction therapy. The authors studied a regimen that contained high-dose cytarabine and a single high dose of idarubicin as salvage induction therapy for patients with recurrent or refractory lymphoblastic disease. METHODS: Twenty-nine previously treated adult patients with recurrent or refractory acute lymphoblastic leukemia were treated with a new intensive regimen. Eight patients had primary refractory disease. Twenty-one patients had recurrent disease, and 16 of these patients developed recurrent disease while they were still receiving their primary therapy. The treatment regimen consisted of cytarabine 3.0 g/m(2) by 3-hour infusion daily for 5 days and idarubicin 40 mg/m(2) given as a single dose on Day 3. Filgrastim (granulocyte-colony stimulating factor) 5 microg/kg administered subcutaneously every 12 hours was started on Day 7 and was continued until the absolute neutrophil count was > 5000/microL. Response was assessed using standard criteria. RESULTS: There were 11 complete responses (38%; 95% confidence interval, 20-56%). Four patients subsequently underwent allogeneic bone marrow transplantation. Moderate but acceptable toxicity was observed given the severely myelosuppressive nature of the regimen. There was only one treatment-related death (3%). Two patients, both with significant prior exposure to anthracyclines, suffered reductions in left ventricular function to the 20-30% range during episodes of severe systemic infection. After recovery from infection, the ejection fraction in one patient improved to 50%. CONCLUSIONS: The authors conclude that this regimen has moderate activity and a relatively low incidence of mortality for this high-risk group of patients. This regimen may be most suitable for patients who can undergo potentially curative allogeneic bone marrow transplantation if they achieve a complete response.