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Background: Bortezomib has preclinical and clinical in B-cell lymphomas, both alone and in combination with other agents. A phase 1 evaluation was conducted of bortezomib with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with untreated diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL)., Methods: Twenty patients (16 with DLBCL and 4 with MCL) with a median age of 66 years (range, 29-84 years) were enrolled. Eleven subjects (55%) had an elevated lactate dehydrogenase level, and 10 patients (50%) had International Prognostic Index scores of 3 to 5. Standard R-CHOP was administered on a 21-day cycle for 6 cycles, with 1 of 3 dose levels of bortezomib (0.7 mg/m2 [n=4 patients], 1.0 mg/m2 [n=9 patients], or 1.3 mg/m2 [n=7 patients]) administered on Days 1 and 4 of each cycle., Results: The maximum tolerated dose of bortezomib with R-CHOP was not reached, and the 1.3-mg/m2 dose level had acceptable tolerability. A dose-limiting toxicity (pulmonary) was only observed in 1 patient receiving 1.0 mg/m2 of bortezomib. Neuropathy occurred in 13 patients (65%), but was mostly grade 1 (45%) and reached grade 3 in only 1 patient (all toxicities were graded using the Common Terminology Criteria for Adverse Events, version 3.0). Grade 4 hematologic toxicity occurred in 7 patients (35%). Of 19 evaluable patients, all responded, with 18 (95%) cases of complete response/complete response unconfirmed achieved and 1 (5%) partial response reported. At a median follow-up of 56 months, overall survival at 4 years was 75% and progression-free survival was 58%., Conclusions: Bortezomib at a dose of 1.3 mg/m2 twice per cycle can be added to R-CHOP chemotherapy with acceptable toxicity. Multi-institutional and cooperative group follow-up studies of this regimen are currently ongoing., (Copyright © 2010 American Cancer Society.)

Background: Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results with the rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide (RT-PEPC) regimen in patients with recurrent mantle cell lymphoma (MCL)., Methods: RT-PEPC included induction (Months 1-3) of rituximab 4 times weekly, daily thalidomide (50 mg), and PEPC followed by maintenance thalidomide (100 mg), oral PEPC titrated to the neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies, including tumor angiogenic phenotyping, plasma vascular endothelial growth factor (VEGF), and circulating endothelial cells., Results: Twenty-five patients were enrolled, and 22 were evaluable. The median age was 68 years (range, 52-81 years), 24 patients (96%) had stage III or IV disease, 18 patients (72%) had an International Prognostic Index (IPI) score of 3 to 5, and 20 patients (80%) had high-risk Mantle Cell International Prognostic Index (MIPI) scores. Patients had received a median of 2 previous therapies (range, 1-7 previous therapies), and 15 patients (60%) had progressed on bortezomib. At a median follow-up of 38 months, the overall response rate was 73% (complete response [CR]/unconfirmed CR rate, 32%; partial response [PR] rate, 41%; n = 22 patients), and the median progression-free survival was 10 months. Four CRs were ongoing (> or =6 months, > or =31 months, > or =48 months, and > or =50 months). Toxicities included grade 1 and 2 fatigue, rash, neuropathy, and cytopenias, including grade 1 and 2 thrombocytopenia (64%) and grade 3 and 4 neutropenia (64%). Two thromboses and 5 episodes of grade 3 or 4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGF A and VEGF receptor 1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF levels and circulating endothelial cells trended down with treatment., Conclusions: RT-PEPC had significant and durable activity in MCL with manageable toxicity and maintained QoL. Novel, low-intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients., ((c) 2010 American Cancer Society.)

Background: In this international, multicenter trial, the authors evaluated rituximab (anti-CD20) plus epratuzumab (anti-CD22) in patients with postchemotherapy relapsed/refractory, indolent non-Hodgkin lymphoma (NHL), including long-term efficacy., Methods: Forty-nine patients with follicular NHL (FL) (N = 41) or small lymphocytic lymphoma (SLL) (N = 7) received intravenous epratuzumab 360 mg/m2 and then intravenous rituximab 375 mg/m2 weekly x4. The regimen was tolerated well., Results: Twenty-two of 41 patients with FL (54%) had an objective response (OR), including 10 (24%) complete responses (CR) (CR/unconfirmed CR [CRu]), whereas 4 of 7 patients with SLL (57%) had ORs, including 3 (43%) with CR/CRu. Rituximab-naive patients (N = 34) had an OR rate of 50% (26% CR/CRu rate), whereas patients who previously responded to rituximab (N = 14) had an OR rate of 64% (29% CR/CRu rate). An OR rate of 85% was observed in patients with FL who had Follicular Lymphoma International Prognostic Index (FLIPI) risk scores of 0 or 1 (N = 13), whereas 28 patients with intermediate or high-risk FLIPI scores (> or =2) had an OR rate of 39% (18% CR/CRu rate). In patients with FL, the median response duration was 13.4 months, and that duration increased to 29.1 months for 10 patients who had a CR/CRu, including 4 patients who had durable responses with remissions that continued for >4 years. In patients with SLL, the median response duration was 20 months, including 1 patient who had a response that continued for >3 years., Conclusions: The combination of epratuzumab and rituximab induced durable responses in patients with recurrent, indolent NHL.

Background: Many patients with recurrent lymphoma are unable to tolerate intensive therapies, or have disease that is refractory. Metronomic chemotherapy offers a novel, potentially less toxic yet effective treatment strategy., Methods: An analysis was performed on 75 lymphoma patients who were treated with the PEP-C regimen at a single institution. The program consisted of oral prednisone 20 mg after breakfast, cyclophosphamide 50 mg after lunch, etoposide 50 mg after dinner, and procarbazine 50 mg at bedtime with an oral antiemetic. All medications were administered daily until the white blood cell count fell to less than 3.0 x 10(9)/L, whereupon treatment was withheld until recovery from the nadir. Therapy was then reinstituted on a daily, alternate day, or fractionated weekly basis (eg, 5 of 7 days), depending on patient tolerance. Doses given per day were held constant., Results: Eighty percent of patients had previously received 2 or more treatments. Overall, 69% achieved an objective response after PEP-C treatment, with 36% complete responses and 33% partial responses. Subjects with indolent histologies had superior overall responses, complete responses, and time on therapy relative to those with aggressive histologies. The regimen was generally well tolerated., Conclusions: Metronomic therapy with low-dose oral agents administered in combination for continuous, prolonged periods with minimal drug-free intervals represents a novel, active, easily tolerated approach to management of patients with recurrent lymphoma, particularly those with indolent histologies., ((c) 2008 American Cancer Society.)

Background: Early prediction of response to therapy may offer the potential to identify patients who will benefit from standard conventional therapy. The objective of this study was to determine the predictive value of FDG-PET as an early response indicator after 1 cycle of chemotherapy for progression-free survival (PFS) in diffuse large cell lymphoma (DLCL) and classic Hodgkin disease (HD)., Methods: FDG-PET was performed before, after 1 cycle, and after completion of chemotherapy in 47 patients. The patients were followed with a median follow-up of 21 months (range, 3-47 months). PFS was compared between PET-positive and PET-negative patients after 1 cycle and after completion of therapy., Results: All PET-negative patients after 1 cycle (n = 31) had sustained complete remission with a median follow-up of 28 months. Fourteen of 16 PET-positive patients after 1 cycle had refractory disease or relapsed (median PFS, 5.5 months). There were 2 false-positive results, 1 with an active infection at the biopsy site and the other in a patient who had been in remission after radiation therapy. There was good agreement between the results obtained after 1 cycle and at completion of therapy (kappa, 0.80); however, the negative predictive value was higher for FDG-PET after 1 cycle than after completion of chemotherapy (100% vs 91.4%), although not statistically different (P = .40)., Conclusions: FDG-PET had a high prognostic value after 1 cycle of chemotherapy, thus it can be a valid alternative for posttreatment evaluation of DLCL and HD and may offer the potential for change in treatment paradigms., ((c) 2006 American Cancer Society.)

The identification of refractory or nonresponding tumors at an early period during therapy may lead to abbreviation of the current therapy regimen or timely institution of an alternative therapy protocol. Nevertheless, evaluation of treatment response is consequential clinically if the tumor potentially is curable and if effective treatment alternatives exist, so that change in treatment ultimately may increase the probability of response and survival. Hodgkin disease (HD) and diffuse large cell lymphoma (LCL) fit in this model well. However, a subset of patients is either refractory to first-line treatment or develops recurrent disease after an initial remission. Improvements in the treatment of these diseases rely not only on new therapy modalities and accurate assessment of disease extent but also on the assessment of disease extent and on timely and accurate therapy response to enable a more effective management plan. Although the International Prognostic Score for HD and International Prognostic Index for LCL have proved valuable for the stratification of patients in clinical trials, there is variability in outcome within the individual risk groups. Recently, positron emission tomography using (18)F-labeled fluoro-2-deoxy-D-glucose (FDG-PET) imaging has been suggested as a sensitive and relatively more specific means to reflect tumor biologic changes after therapy. With increasingly compelling evidence, early FDG-PET provides a reliable means to assess tumor response accurately that may lead to better management with an effective therapeutic approach., ((c) 2006 American Cancer Society.)

Background: Iodine I-131 tositumomab is a well tolerated and effective therapy for recurrent low-grade and transformed low-grade non-Hodgkin lymphoma (NHL). Hematologic reserve after radioimmunotherapy (RIT) is an important consideration when subsequent therapy is required., Methods: One hundred fifty-five patients who received treatment with I-131 tositumomab were assessed, and 68 patients had progressive disease after RIT. The median age (n=68 patients) was 59 years (range,18-82 yrs), and patients received a median of 2 pre-RIT regimens (range,1-8 regimens), including 66% who received anthracycline, 19% who received platinum, and 50% who received fludarabine., Results: The median time to disease progression (among progressors) was 168 days (range, 19-771 days). At the time they developed recurrent disease, patients had median white blood cell count (WBC) of 4.9 K cells/microL (range, 1.1-21.4 K cells/microL), a median absolute neutrophil count (ANC) of 3.25 K cells/microL (range, 0.59-8.20 K cells/microL), a median platelet count of 130 K cells/microL (range, 9-440 K cells/microL), and there was no significant difference between pre-RIT and recurrence values except for the platelet count (P<0.05). No patient demonstrated a WBC<1.0 K cells/microL or an ANC<0.5 K cells/microL, although 1 patient had a platelet count<10 K cells/microL. Twenty-four patients subsequently received no further chemotherapy; and, in 21 patients (88%), hematologic parameters appeared to allow subsequent chemotherapy if necessary (blood counts: National Cancer Institute Grade 0-2). Among 44 patients (65%) who received further chemotherapy (median, 2 regimens; range, 1-4 regimens), 19 patients (43%) were treated with anthracyclines, 17 patients (39%) were treated with platinum, 10 patients (23%) were treated with fludarabine, and 13 patients (30%) underwent stem cell transplantation. Disease improvement occurred in most patients, although 18 patients died (40%) after further chemotherapy, predominantly from refractory lymphoma., Conclusions: Most patients with progressive disease after treatment with iodine I-131 tositumomab were able to receive subsequent therapy, including cytotoxic chemotherapy and stem cell transplantation., (Copyright (c) 2005 American Cancer Society.)

Background: The accuracy of fluorodeoxyglucose positron emission tomography (FDG-PET; dual-head camera with attenuation correction) and Ga-67 scintigraphy was compared to identify disease sites in patients with Hodgkin disease (HD) and intermediate and high-grade non-Hodgkin lymphoma (NHL) at initial diagnosis or clinical recurrence., Methods: Fifty-one contemporaneous FDG-PET and Ga-67 scintigraphies were performed on patients with NHL (35 intermediate grade, 3 high grade) or HD (13 patients). Sites of disease were correlated on a site-by-site basis on FDG-PET and Ga-67 images. Tumor-to-background (T/B) ratios were obtained for both techniques. Discordant FDG-PET and Ga-67 findings were correlated with computed tomography findings or clinical evaluation including repeat FDG-PET scans obtained after therapy., Results: Fluorodeoxyglucose positron emission tomography was positive at all 158 sites in 51 patients compared with 113 sites in 41 positive studies with Ga-67 scintigraphy (single positron emission computed tomography [SPECT] and/or planar images). In 44 patients who had complete Ga-67 SPECT data on all tumor sites, FDG-PET was positive at 126 sites and Ga-67 SPECT was positive at 81 sites. Ga-67 SPECT failed to demonstrate disease at 45 sites (35.7%). In 10 of 44 patients, Ga-67 SPECT completely failed to detect any disease at 22 of 45 sites (17.5%) and partially identified disease sites at 23 of 45 sites (18.2%) in 11 patients regardless of the tumor site and histology. In these patients, the lesions measured between 0.6 and 14.0 cm by CT. Fluorodeoxyglucose positron emission tomography revealed higher stage disease in 13 patients compared with Ga-67 imaging. Tumor-to-background ratios were statistically different between the two techniques with higher ratios obtained with FDG-PET (P < 0.0001)., Conclusions: In imaging aggressive lymphoma and HD before therapy, FDG-PET has significantly higher site and patient sensitivity than Ga-67 scintigraphy (100% vs. 71.5% and 100% vs. 80.3%, respectively). The change in disease stage by FDG-PET may result in a change in therapy strategy., (Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10336)

Nine patients with multiple myeloma were treated with whole bone marrow irradiation. Six had heavily pretreated disease refractory to chemotherapy. Three had stable disease lightly pretreated by chemotherapy. A modification of the "three and two" total nodal radiation technique was employed. Although varying and often severe treatment related cytopenia occurred, infectious complications, clinical bleeding, and nonhematalogic complications were minimal. Five of nine patients showed a decrease in monoclonal protein components, and one showed an increase during treatment. These preliminary results indicate that a reduction of tumor cell burden may occur in patients following whole bone marrow irradiation and that the technique is feasible. Whole bone marrow irradiation combined with chemotherapy represents a new conceptual therapeutic approach for multiple myeloma.

Prolymphocytic leukemia is characterized by marked splenomegaly, distinctive cellular morphologic characteristics, and a poor clinical course. Five patients with typical PL were treated systematically with vincristine/prednisone, chlorambucil/prednisone, splenic irradiation, splenectomy, and other chemotherapy regimens. No patient responded to vincristine/prednisone. Two patients responded to chlorambucil/prednisone, and four patients had brief responses to splenic irradiation. Two patients underwent splenectomy, one of whom had a prolonged clinical remission. There were no complete remissions. No other chemotherapy combinations were of value. The median survival was 33 months. Recommendations are made to use chlorambucil/prednisone or splenic irradiation as initial treatment. Splenectomy should be considered in patients refractory to these modalities. The course of PL may be more protracted than originally reported.

Four patients who demonstrated unusually prolonged survival with Philadelphia chromosome positive Ph' (+) chronic myeloid leukemia (CML) were analyzed for factors associated with survival. Survival duration from initial diagnosis ranged from 120 to 222 months, with a mean of 170 months. At diagnosis, age, symptoms, liver or spleen size, hematocrit, white blood cell count, absolute peripheral myeloblast plus promyelocyte count, and uric acid did not have unique prognostic significance. At diagnosis all four patients had normal or low-normal platelet counts, (range: 170,000 to 248,000/mm3). Thrombocytopenia occurred during treatment in three patients. None of the four patients, however, developed severe marrow hypoplasia or leukopenia during treatment for the chronic phase. Cytogenic studies performed from 103 to 156 months after diagnosis did not reveal a large subpopulation of marrow cells with a normal karyotype or cells with the XO genotype in the male patients. These observations suggest that prolonged survival in CML 1) is not contingent upon intensive treatment resulting in marrow hypoplasia, and 2) does not require the persistence of a clone of karyotypically-normal bone marrow cells or a clone of marrow cells in males which has lost the Y chromosome. A normal or low-normal platelet count at diagnosis may be a favorable prognostic indicator.

Seven adult patients with advanced lymphoma, resistant to vincristine, prednisone, alkylating agents and Adriamycin were treated with "high dose" methotrexate and citrovorum factor rescue. Therapy consisted of 4 to 6-hour infusions of methotrexate (5--100 mg/kg) every 1 to 2 weeks with citrovorum rescue initiates 2 to 12 hours after termination of the infusion. Objective responses were obtained in three patients but these were short lived. Mucosal and hematologic toxicity occurred when repeat courses of therapy were administered. The results suggest that high dose methotrexate may be effective therapy in lymphoma, particularlly if citrovorum factor rescue is used early and in adequate dosage.

A prospective randomized trial by CALGB examined the relative value of four chemotherapy regimens in 537 patients with stage III B and IV Hodgkin's disease. A new combination BOPP, derived by substitution of BCNU for nitrogen mustard in the MOPP regimen, was compared to MOPP and to two 3-drug regimens, derived by removing the procarbazine in BOPP (BOP) or removing the alkylating agent (OPP). The 4-drug programs gave significantly higher frequency of complete remissions (BOPP 67%, MOPP 63%) than the 3-drug regimens (BOP 40%, OPP 42%), and significantly longer duration of remission and survival. BOPP had a therapeutic activity equal to MOPP, and was accompanied by less toxicity. After 6 cycles of induction chemotherapy, responding patients, both CR and PR, were continued on maintenance chemotherapy for 3 years. No significant difference in relapse rate was demonstrated following maintenance treatment with either vinblastine, chlorambucil, or chlorambucil plus monthly vincristine + prednisone doses. Nor could a reinforcement phase late in the maintenance program be shown to influence the relapse rate. The median survival for all patients entered on the 4-drug programs was 5 years, while the median has not yet been reached at 6 years for those patients, who obtained CR.

Two groups of patients were observed for evidence of acute radiation hepatitis during "high dose" radiation to the liver. The first group of 18 patients with metastatic liver disease received an average of 4,050 rad to the whole liver. Half received anticoagulation with warfarin. One patient on anticoagulation developed evidence of acute radiation hepatitis while 2 patients did so without anticoagulation. Eleven patients with Hodgkin's disease received 4,000 rad to the left lobe of the liver during extended field radiation. Four of these 11 patients were anticoagulated to therapeutic range. Only one of the fully anticoagulated patients showed changes on liver scan consistent with radiation hepatitis whereas three did so without anticoagulation. No serious sequelae from anticoagulation occurred in either group. These preliminary data suggest that anticoagulation may be safely administered with high dose hepatic radiation and that further trials with anticoagulation are warranted.

In a cooperative study of the Cancer and Acute Leukemia Group B, 27 evaluable patients with advanced malignant lymphomas were treated with 70 mg/m2 of cisdichlorodiammineplatinum(II) (cis-platinum) once every three weeks. All patients had received extensive prior therapy. Partial remission was obtained in two of eight patients (25%) with Hodgkin's disease, for six and 40 weeks, and in five of 19 (26%) patients with non-Hodgkin's lymphoma, for a median duration of six weeks. The major toxic effects were profuse vomiting and, to a lesser degree, myelosuppression. Nephrotoxicity was easily controlled. Cis-platinum is an active agent in lymphoma and should merit incorporation into combination therapy for recently diagnosed disease.

Sixteen patients with resistant non-Hodgkin's lymphoma were treated with continuous infusions of vincristine (1-2 mg/m2 daily X 2 days) and bleomycin (0.25 mg/kg bolus dose, then 0.25 mg/kg/daily X 5 days). Responding patients received high dose methotrexate (1500 mg/m2) with citrovorum rescue on days 15, 22, 29, 36. Treatment cycles were repeated every six weeks in responding patients. The response frequency was 50% (three complete and five partial responses). Median response duration was 29 weeks. Major toxicity included stomatitis (63%) and leukopenia (44%). One episode each of possible hypersensitivity pneumonitis and paralytic ileus occurred. Continuous infusions of vincristine and bleomycin should be studied further in less critically ill patients.

A patient with Hodgkin's disease, who at laparotomy had liver involvement with no evidence of Hodgkin's disease in the spleen, is reported. Rare alternate lymphaticovenous anastomoses exist that may lead to liver involvement in the absence of splenic involvement.

A number of common metastatic cancers are associated with marked weight loss at the time of diagnosis. Cancer patients with weight loss at the time of diagnosis have decreased mean survival compared to similar cancer patients without weight loss. Provision of excess calories alone does not appear to change median survival in patients with advanced cancer and many patients either maintain body weight or lose weight while receiving calories which would be predicted to result in weight gain. The authors recently have extended their studies to head and neck cancer patients without detectable metastatic disease in order to detect systemic metabolic effects of a localized tumor. These patients failed to gain weight despite the administration of apparently adequate calories by continuous enteral alimentation. Abnormalities of carbohydrate metabolism with secondary effects on fat and protein metabolism have been identified in several populations of patients with common cancers. These abnormalities offer potential points of intervention which may enhance nutritional therapy as rehabilitation and as a potential biological modifier of the response of specific cancers to chemotherapy, radiation therapy, or surgery.

Twenty-two previously untreated patients with adenocarcinoma of the ovary were treated with 28 day cycles of hexamethylmelamine, Adriamycin (doxorubicin), and cisplatin (HAC) for 9 months followed by three monthly cycles of intense intravenous cyclophosphamide. An overall response frequency of 82% (18/22) was achieved. Complete pathologic responses (CPR) documented by second look operations were found in 50% (11/22); however, patients considered to be free of disease (prolonged complete clinical response refusing "second look" and CPR) totaled 59%. Median survival has not been reached after a median follow-up of 34 months. No major or life threatening toxicity was encountered. HAC followed by cyclophosphamide is a highly effective regimen that may be easily administered on an outpatient basis with comparatively little toxicity.

Two long-term survivors with nodular sclerosing Hodgkin's disease were found to have adenocarcinoma of the breast sixteen and twenty years after limited field radiotherapy. Examination of the axillary nodes at radical mastectomy showed both metastatic adenocarcinoma and clinically inapparent Hodgkin's disease. The occurrence of persistent but clinically inactive Hodgkin's disease as well as the development of secondary malignancies in this disease has important clinical ramifications. Skin testing and in vitro lymphocyte transformation studies in these two patients were also done.