Positron Emission Tomography-Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001.

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity. METHODS: Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy. RESULTS: Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes. CONCLUSION: To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.

Pemetrexed, Bevacizumab, or the Combination As Maintenance Therapy for Advanced Nonsquamous Non-Small-Cell Lung Cancer: ECOG-ACRIN 5508.

PURPOSE: Pemetrexed or bevacizumab is used for maintenance therapy of advanced nonsquamous non-small-cell lung cancer (NSCLC). The combination of bevacizumab and pemetrexed has also demonstrated efficacy. We conducted a randomized study to determine the optimal maintenance therapy. PATIENTS AND METHODS: Patients with advanced nonsquamous NSCLC and no prior systemic therapy received carboplatin (area under the curve, 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg) for up to four cycles. Patients without progression after four cycles were randomly assigned to maintenance therapy with bevacizumab (15 mg/kg), pemetrexed (500 mg/m2), or a combination of the two agents. The primary end point was overall survival, with bevacizumab serving as the control group. RESULTS: Of the 1,516 patients enrolled, 874 (57%) were randomly assigned after induction therapy to one of the three maintenance therapy groups. With a median follow-up of 50.6 months, median survival with pemetrexed was 15.9 months, compared with 14.4 months with bevacizumab (hazard ratio [HR], 0.86; P = .12); median survival with pemetrexed and bevacizumab was 16.4 months (HR, 0.9; P = .28); median progression-free survival was 4.2, 5.1 (HR, 0.85; P = .06), and 7.5 months (HR, 0.67; P < .001) for the three groups, respectively. Incidence of worst grade 3 to 4 toxicity was 29%, 37%, and 51%, respectively, for bevacizumab, pemetrexed, and the combination regimen. CONCLUSION: Single-agent bevacizumab or pemetrexed is efficacious as maintenance therapy for advanced nonsquamous NSCLC. Because of a lack of survival benefit and higher toxicity, the combination of bevacizumab and pemetrexed cannot be recommended.

Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature.

Anaplastic large cell lymphoma (ALCL) is an aggressive neoplasm of T- or null cell phenotype and is recognized as a distinct clinicopathologic subtype of non-Hodgkin lymphoma (NHL) in the revised World Health Organization (WHO) classification of hematopoietic neoplasms. It is rarely associated with leukemic phase. Most cases with leukemic involvement are the small cell variant of ALCL. These cases often lack the pleomorphism seen in the common variant of ALCL and may be misdiagnosed. We report a series of three patients who presented with leukemic phase ALCL. The patients included an 11-year-old boy, a 29-year-old man, and a 59-year-old woman. The clinical and pathologic features of these cases are reviewed. The patients in our case series with leukemic phase ALCL exhibited rare clinical features. The patients presented with massive extranodal disease involving cerebrospinal fluid (CSF), liver, spleen, lungs, and bone marrow. CSF involvement was documented morphologically as well as by flow cytometry in two patients. Two of the patients had small cell variant and the third patient had common type ALCL. The neoplastic cells in all three patients were ALK positive; however these patients died within months of diagnosis. Leukemic phase ALCL is rare, and behaves in an aggressive manner. Some, but not all, cases in the literature presenting with peripheral blood involvement had small cell variant ALCL, as seen in two of our cases. The leukemic phase of ALCL should be considered when a T-cell leukemia with unusual morphologic features is encountered.

Phase II trial of temozolomide and irinotecan as second-line treatment for advanced non-small cell lung cancer.

BACKGROUND: This study was performed to evaluate the tolerability and efficacy of temozolomide and irinotecan as a second-line regimen in recurrent/metastatic non-small cell lung cancer (NSCLC). METHODS: Patients with recurrent/metastatic NSCLC, including those with treated brain metastases, following one prior platinum-based regimen received temozolomide 75 mg/m daily on days 1 through 15 and irinotecan 100 mg/m on days 8 and 15 every 21 days. RESULTS: The authors treated 46 patients, of whom more that 90% had a performance status of 0 or 1. Four patients (8.7%) attained partial response and 17 (37.0%) had disease stabilization as their best response. The median time to progression was 1.8 months, median overall survival was 9.8 months, and 1-year overall survival was 34%. Grade 1/2 fatigue (63%), anemia (61%), nausea (52%), and diarrhea (44%) were the most common toxicities. Grade 3/4 leukopenia and diarrhea were each observed in 9% of patients. One unexpected death occurred, possibly related to the regimen. CONCLUSION: Second-line treatment with temozolomide and irinotecan showed tolerable toxicities. The response rates, median survival times, and 1-year survival rates were comparable to other active NSCLC agents.

A phase II study of bryostatin-1 and paclitaxel in patients with advanced non-small cell lung cancer.

BACKGROUND: Bryostatin-1 is a macrocyclic lactone, which exhibits pleiotropic biological effects via protein kinase C and has shown preclinical synergy with paclitaxel for enhanced tumor cell apoptosis. PATIENTS AND METHODS: Patients had stage IIIB (pleural effusion)/IV non-small cell lung cancer, measurable disease, performance status 0-2 Eastern Cooperative Oncology Group, adequate organ function, and no prior chemotherapy. Patients received dexamethasone premedication followed by paclitaxel at a dose of 90 mg/m(2) on days 1, 8, and 15 along with bryostatin-1 50 microg/m(2) on days 2, 9, and 16 every 28 days until disease progression. Correlative assays measuring serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and T-lymphocyte numbers were performed based on a previous study showing cytokine induction in vivo by bryostatin-1. Fifteen patients were enrolled. RESULTS: Thirty cycles of the bryostatin-1 and paclitaxel were delivered with a median of 2 per patient (range 1-4). Myalgia was the predominant non-hematologic toxicity encountered as 3 patients developed grade 4 and 1 patient developed grade 3 myalgia. Four patients were removed from the study during cycle 1 for rapid disease progression or myalgia. Eleven patients could be evaluated for response. Five patients had stable disease, two had a mixed response, and four had progressive disease. Ten patients received second-line chemotherapy after leaving the study. Median survival was 31 weeks (95% confidence interval: 5.4-49.3). Correlative data showed a trend towards decreased plasma IL-6 and TNF-alpha after each cycle of therapy presumably due to the dexamethasone premedication and/or paclitaxel. CONCLUSIONS: This drug combination showed no significant clinical response and was associated with reproducible toxicity. The predominance of myalgia in the absence of elevated serum cytokines suggests a non-inflammatory etiology of this toxicity.