Phase II study of infusional chemotherapy with doxorubicin, vincristine and etoposide plus cyclophosphamide and prednisone (I-CHOPE) in resistant diffuse aggressive non-Hodgkin's lymphoma: CALGB 9255

Background:Patients with resistant diffuse aggressivenon-Hodgkin's lymphoma (DA-NHL) have a poor prognosis. Studies have suggestedinfusional therapy may be beneficial. Patients and methods:This trial used an infusional regimen calledI-CHOPE in resistant patients who had previously received only bolus CHOPE orCHOP regimen. Resistance was defined as: a) primary refractory disease, b)progression on therapy, c) partial response, d) complete remission lastingless than one year. Eligibility criteria included a diagnosis of DA-NHL (IWFE-H), no prior irradiation and adequate organ function. Results:Thirty-seven patients were entered and twenty-nine wereeligible. Reasons for ineligibility were incorrect histology (5) and other(3). The median age was 57 years (range 29–81) with 21 males. Theperformance status scores were: 0 (12 patients); 1 (9 patients); 2 (8patients). Prior therapy consisted of standard CHOP (26 patients), bolus CHOPE(2 patients), high dose CHOP (1 patient). Therapy consisted of a 120 hourcontinuous intravenous infusion of doxorubicin 10 mg/m²/day,vincristine 0.28 mg/m²/day (maximum 0.4 mg/day), and etoposide 48mg/m²/day. Cyclophosphamide 750 mg/m² was given as aniv bolus day 6 and prednisone was given at 100 mg/day p.o. on days 1–5.G-CSF was allowed for myelosuppression. The overall response rate was48% (CR 17%; PR 31%). Freedom from progression was24% at six months and 8% at one year. Survival was 69%at six months and 40% at one year. In an exploratory analysis a priorCR or PR predicted response to I-CHOPE. Twelve of sixteen patients who had aCR/PR on previous therapy responded while two of thirteen who had no priorresponse, responded to I-CHOPE (P= 0.003). The toxicity wastolerable with grade 3–4 hematologic toxicity being leucopenia94% and thrombocytopenia 41%. The grade 3–4non-hematologic toxicities were infection in 28%, phlebitis in11%, and stomatitis in 15%. Conclusions:I-CHOPE can induce responses in this group ofpatients with a poor prognosis, but most were seen in those who had previouslyhad a response to bolus chemotherapy.     

High-dose intensity cyclophosphamide, epidoxorubicin, vincristine and prednisone by shortened intervals and granulocyte colony-stimulating factor in non-Hodgkin's lymphoma: a phase II study.

Twenty patients with non-Hodgkin''s lymphoma were treated with a combination of cyclophosphamide (750 mg m(-2), day 1), epidoxorubicin (60 mg m(-2), day 1), vincristine (1.4 mg m(-2), day 1) and prednisone (100 mg m(-2), days 1-5) every 14 days. Shortening of intervals was associated with the prophylactic employment of granulocyte colony-stimulating factor (G-CSF; specifically, filgrastim) administered at a dose of 300 microg subcutaneously from day 6 to day 11. The ratio between actually delivered dose intensity and planned dose intensity was 1.0 in 18 out the 20 patients. Toxicity was acceptable; response rate and survival are in the expected range. The present study demonstrated the feasibility of acceleration of chemotherapy cycles to obtain dose intensification in non-Hodgkin''s lymphoma.     

Treatment of aggressive non-Hodgkin's lymphoma in elderly patients with thiotepa, Novantrone (mitoxantrone), vincristine, prednisone (TNOP)

The aging of the population and the increased incidence of non-Hodgkin's lymphoma will result in a large number of elderly patients with this disorder. Newer therapies will be required for this group of patients. This article reports a new therapy for elderly patients with diffuse aggressive non-Hodgkin's lymphoma. Patients were treated with TNOP (thiotepa 20 mg/m(2), mitoxantrone (Novantrone) 10 mg/m(2), vincristine (Oncovin) 1 mg/m(2) all on day 1 and prednisone 60 mg/m(2) on days 1 through 5 of a 21-day course. Twenty-six patients were enrolled on study. The patients' ages ranged from 66 years to 87 years, with a mean age of 75.5 years. Eleven patients had a partial response (42%) and 4 patients had a complete response (15%) for a total response of 57%. Eighty-one percent of patients survived 1 year and 54% survived for 2 years. The median survival was 26 months. Hematologic and nonhematologic toxicity was tolerable. We believe that TNOP is an excellent therapeutic option in this group of elderly patients, particularly in the palliative setting.     

Long-term follow-up of patients with intermediate or high-grade non-Hodgkin lymphoma treated with a combination of cyclophosphamide, epirubicin, vincristine, and prednisone

BACKGROUND: Doxorubicin cardiotoxicity is one of the most serious side effects of the cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, regimen, especially among elderly patients. In the CEOP regimen, epirubicin was substituted for doxorubicin to reduce cardiotoxicity. METHODS: Between March 1984 and September 1998, 186 previously untreated patients with a histologically confirmed diagnosis of intermediate- or high-grade non-Hodgkin lymphoma according to the Working Formulation were treated with CEOP (cyclophosphamide, 750 mg/m(2), epirubicin, 75 mg/m(2), vincristine, 1.4 mg/m(2); and prednisone, 60 mg per day orally on Days 1-5). Of 186 patients, 85 (45.7%) had Stage IV disease, and 60 (32.3%) had an International Prognostic Index score > 2. Comorbidity was present in 36 patients (19.3%). RESULTS: Complete remission (CR) was achieved in 119 patients (64.3%), and partial remission was achieved in 30 patients (16.2%). Among the patients who achieved a CR, 95 (79.8%) were still disease free at a median follow-up time of 86.9 months (range, 14-200 months). The remaining 24 patients experienced disease recurrence, at a median follow-up time of 19 months (range, 3-101 months). The relative dose intensities were 0.69, 0.89, and 0.80 for vincristine, epirubicin, and cyclophosphamide, respectively. Two patients died of toxicity due to infection. Two patients, 59 and 73 years old, respectively, experienced arrhythmia. Another patient, age 64 years, who had a myocardial infarction 10 years earlier, had angina. One patient with hypertension experienced cardiac failure. No patients died of cardiac toxicity. CONCLUSION: Long-term follow-up confirmed that CEOP is an effective and well-tolerated chemotherapy regimen for intermediate- and high-grade lymphoma. The results were promising, especially among elderly patients.     

Combination chemotherapy with cyclophosphamide, vincristine, and prednisone in advanced non-Hodgkin's lymphomas.

From July 1971 to July 1974, 58 patients with advanced non-Hodgkin's lymphomas were treated with cyclophosphamide, vincristine, prednisone (CVP) at Stanford Medical Center. Utilizing the histopathologic criteria of Rappaport el al., response to CVP was found to be significantly better in the nodular (96.6%) and the diffuse lymphocytic (100%) histologies as compared to the diffuse nonlymphocytic lymphomas (47.6%). A pathologically documented complete remission was obtained in 33.9% of patients and all but two remain disease free for periods of 2-28 months. Concurrent bleomycin was administered to 17 patients during CVP therapy and no improvement in response or median survival was noted. Prior radiation therapy delivered to 21 patients did not adversely affect their response to CVP or their survival. Splenectomy in 17 patients prior to CVP did not improve hematologic tolerance to chemotherapy except in those patients with prior radiation therapy, and there was no improvement in response to CVP or survival. CVP is effective in achieving complete remissions and extended disease-free survivals in advanced non-Hodgkin's lymphomas; both a nodular architecture and a diffuse lymphocytic histology are positive determinants for response to chemotherapy and improved median survival.     

Liposome-encapsulated doxorubicin in combination with standard agents (cyclophosphamide, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin's lymphoma: results of therapy and correlates of response.

PURPOSE: To evaluate the safety and efficacy of liposomal doxorubicin (Myocet; Medeus Pharma Ltd, Herts,UK) when substituted for doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin's lymphoma (AIDS-NHL). Secondary objectives were to assess the impact of HIV viral control on response and survival, and to correlate MDR-1 expression with outcome. PATIENTS AND METHODS: Liposomal doxorubicin at doses of 40, 50, 60, and 80 mg/m(2) was given with fixed doses of cyclophosphamide, vincristine, and prednisone every 21 days. All patients received concurrent highly active antiretroviral therapy. NHL tissues were evaluated for multidrug resistance (MDR-1) expression. RESULTS: Twenty-four patients were accrued. 67% had high or high-intermediate International Prognostic Index scores; the median CD4 lymphocyte count was 112/mm(3) (range, 19/mm(3) to 791/mm(3)). No dose-limiting toxicities were observed at any level, with myelosuppression being the most frequent toxicity. Overall response rate was 88%, with 75% complete responses (CRs), and 13% partial responses. The median duration of CR was 15.6+ months (range, 1.7 to 43.5+ months). Effective HIV viral control during chemotherapy was associated with significantly improved survival (P =.027), but CRs were attained independent of HIV viral control. MDR-1 expression did not correlate with response, suggesting that the liposomal doxorubicin may evade this resistance mechanism. CONCLUSION: Liposomal doxorubicin in combination with cyclophosphamide, vincristine, and prednisone is active in AIDS-NHL, with complete remissions achieved in 75% independent of HIV viral control or tissue MDR-1 expression. HIV viral control is associated with a significant improvement in survival. Additional studies are warranted.     

Methotrexate,cyclophosphamide and vincristine (MEV regimen) for non-Hodgkin's lymphoma

Five courses of combination chemotherapy with methotrexate, cyclophosphamide and vincristine (MEV regimen) were given on an outpatient basis to sixteen previously untreated patients with lymphocytic lymphoma (L.L.) and to fourteen previously untreated patients with histiocytic lymphoma (H.L.) Clinical and haematological tolerance was such that the interval between each course was never prolonged, nor was drug dosage reduced (vincristine excepted).Of the 16 cases with L.L., there were 9 complete remissions, 5 of them being continuously unmaintained complete remissions for 5 to 24 months. Of the 14 cases with H.L., there were 13 complete remissions, 7 being continuously unmaintained complete remissions for 10 to 34 months.It is suggested that the combination of cell-cycle phase-specific drugs with an alkylating agent may prove to be more than additive in effect in non-Hodgkin's lymphoma. The very high remission rate in H.L. warrants further investigation.     

A multicenter trial of infusional etoposide, doxorubicin, and vincristine with cyclophosphamide and prednisone (EPOCH) in patients with relapsed non-Hodgkin's lymphoma

A phase II study was performed in a multicenter community setting of EPOCH (etoposide/doxorubicin/vincristine/cyclophosphamide/prednisone) chemotherapy in 93 patients with relapsed non-Hodgkin's lymphoma. Patients included 41 females and 52 males, ranging in age from 31-81 years (median, 63 years). Lymphoma histologies included diffuse large-cell (56), follicular (21), mantle cell (11), peripheral T-cell (3), and small lymphocytic (2) lymphomas. Patients had received a median of two previous chemotherapy combinations (range, 1-9). Most patients had received the drugs in EPOCH with their previous chemotherapy regimens (vincristine 97%, cyclophosphamide 97%, doxorubicin 87%, and etoposide 28%). A total of 350 cycles of EPOCH were administered. EPOCH chemotherapy gave a response rate of 51% in the entire cohort of 93 patients. Among the 83 evaluable patients, a response rate of 57% was observed (24% complete response, 33% partial response). Seven of the 47 responders remain in clinical remission at 3 years after EPOCH chemotherapy alone. Additionally, 11 patients are alive after further salvage chemotherapy (four patients) or bone marrow transplantation (seven patients). Myelosuppression was common, with 36% of all cycles resulting in an absolute neutrophil count nadir < 500/microL. This study confirms the activity of infusional chemotherapy with EPOCH in patients with relapsed non-Hodgkin's lymphoma.     

Long-term results of patients with advanced diffuse, non-Hodgkin's lymphoma treated with cyclophosphamide, doxorubicin, vincristine, prednisone and bleomycin (CHOP-Bleo)

17 patients with diffuse non-Hodgkin's lymphoma with unfavorable histologies were treated with cyclophosphamide, hydroxyldaunorubicin (doxorubicin), vincristine (Oncovin), prednisone and bleomycin (CHOP-Bleo). Of the 16 patients entering a complete remission, 8 remain in remission at 46+, 50+, 51+, 61+, 61+, 61+ and 63+ months. There were 2 treatment deaths in elderly patients, both in remission. 2 of the early relapses (less than 12 months) were later characterized as lymphoblastic lymphoma upon review of the original pathology. All 3 patients with late relapses (32, 37, and 44 months), were able to be successfully retreated. The 2 patients with lymphoblastic lymphoma developed central nervous system disease despite prophylactic intrathecal methotrexate; but central nervous system disease has not developed in the 4 other patients with initial bone marrow involvement who received prophylactic intrathecal therapy.     

Combination chemotherapy with cyclophosphamide, adriamycin, vincristine and prednisolone (VEPA) for non-Hodgkin's lymphoma

Combination Chemotherapy with Adriamycin (VEPA) was applied to 16 patients with non-Hodgkin's lymphoma. The effects of VEPA therapy were compared with those of combination chemotherapy without Adriamycin (non-VEPA). Complete remission rate achieved with VEPA therapy was 37.5% while that with non-VEPA therapy was 27.6%. Histologically, the complete remission rate in cases of large-cell type treated with VEPA therapy was 40%, while that with non-VEPA therapy was 14.3%. No cases of stage IV showed complete remission, whereas the complete remission rate for cases of stage III was 37.5% for VEPA therapy, but 27.6% for non-VEPA therapy. From these results we concluded that VEPA therapy is more effective for non-Hodgkin's lymphoma, especially large-cell type, than non-VEPA therapy.     

The combined modality therapy of diffuse histology non-Hodgkin's lymphoma with cyclophosphamide, adriamycin, vincristine, prednisone (CHOP) and total body irradiation

The combination of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) alternating with total body irradiation (TBI) has been shown earlier to be effective therapy in patients with malignant lymphoma who have received prior chemotherapy and/or radiation therapy. A limited institutional pilot study was therefore done by the Southwest Oncology Group between October 1977, and November 1978 to test the benefit of this program in previously untreated persons with Stages 3 and 4 diffuse histology non-Hodgkin's lymphoma. Eleven evaluable patients with the following histologies were treated: 7 poorly differentiated, 2 with histiocytic, 1 with mixed lymphoma and 1 with well-differentiated morphology. CHOP was given in the following manner: cyclophosphamide 400 mg/M2 IV day 1, adriamycin 40 mg/M2 IV day 1, vincristine 2 mg IV day 1, and Prednisone 100 mg po daily X 5. Forty-five rad total body irradiation was delivered in three fractions on days 21, 23 and 25. Chemotherapy was repeated on day 42, etc., until four cycles of CHOP and three cycles TBI (135R) were delivered. Responses were seen in 8/11 patients (6 CR and 2 PR); 5 persons are currently alive and 6 are dead. Two of the living patients are alive with disease and the remainder are in unmaintained remission. Two persons died with no response and one died in complete remission of an unrelated illness. The median duration of remission is 15 months and the median survival for all patients is 48 months. The therapy was well tolerated with a mean nadir leukocyte count of 3,020 X 10(9)/microliters (range 1.2-5.5) and a mean nadir platelet count of 188 X 10(9)/microliters (range 016-270). As delivered, this program is capable of producing durable remissions and needs to be verified in a larger series of patients.     

Liposomal encapsulated doxorubicin (Caelyx) in the treatment of relapsed aggressive non-Hodgkin's lymphoma: a phase II study

Aggressive non-Hodgkin's lymphoma (NHL), such as diffuse large B-cell lymphoma, can be cured in approximately 50% of cases, but those cases that recur and are not amenable to high-dose chemotherapy rely on palliative chemotherapy to improve symptoms and prolong life. Anthracyclines are associated with a high response rate in aggressive NHL but extended treatment results in cardiotoxicity. Liposomal encapsulated doxorubicin has been shown in other tumor types to allow for extended treatment with doxorubicin, but is associated with a low cardiac risk. The present study aimed to assess the response rate, survival and cardiac risk of patients with relapsed aggressive NHL treated with liposomal encapsulated doxorubicin. Eighteen patients with relapsed aggressive NHL were treated with liposomal encapsulated doxorubicin (40 - 50 mg/m2) for a planned six cycles. Some 83% of patients had diffuse large B-cell or mantle cell NHL. Four patients had a partial response (23%), whereas five patients had stable disease. None had a complete response. Eight patients progressed when receiving the liposomal encapsulated doxorubicin therapy. The median survival time was 34 weeks, and the median progression-free survival was 15.7 weeks. Overall survival was 50% at 6 months and 39% at 12 months. Progression-free survival was 33% at 6 months and was 28% at 12 months. The mean ejection fraction pre- and post-liposomal encapsulated doxorubicin treatment remained the same. Only one patient had a drop in ejection fraction to <50%. Liposomal encapsulated doxorubicin offers another choice to patients seeking palliation from their lymphoma recurrence with a response rate of 23% that was well tolerated and had a minimal cardiotoxic risk.     

Long-term update of a phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma

The present study aimed to determine the long-term safety and efficacy of chimeric anti-CD 20 antibody rituxan (rituximab, Biogen IDEC, San Diego, CA, USA; Genentech, South San Francisco, CA, USA) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in previously untreated patients with aggressive non-Hodgkin's lymphoma (NHL). Thirty-three patients with previously untreated aggressive B-cell NHL received six infusions of rituximab (375 mg/m² per dose) on day 1 of each cycle of CHOP chemotherapy, given on day 3 of each cycle of therapy. Currently, the patients now have a median follow-up of 63 months (range 34 - 82 months). The overall response (OR) rate was 94% and the complete response (CR) rate was 61% at the end of therapy. Of the 33 patients, 2 patients experienced disease progression and subsequently died of their disease, 2 patients experienced disease progression but were alive at last follow-up following additional therapy, and 2 patients died without experiencing disease progression: one due to a cerebral vascular accident at 9 months after therapy and a second patient due to small cell lung carcinoma at 55 months. The 5-year survival rate was 88% (95% confidence interval (CI) 72 - 97) and the 5-year progression-free survival was 82% (95% CI 64 - 93). There were no long-term adverse events noted directly related to the rituximab. The long-term follow-up of patients in this phase II trial of rituximab with CHOP chemotherapy for previously untreated aggressive NHL demonstrates a high response rate, which remains very durable with high 5-year overall and progression-free survivals.     

Phase I and subsequent phase II study of filgrastim (r-met-HuG-CSF) and dose intensified cyclophosphamide plus epirubicin in patients with non-Hodgkin's lymphoma and advanced solid tumors

Background: To define a maximum tolerated dose (MTD) for the combination of epirubicin and cyclophosphamide with filgrastim (r-met-HuG-CSF) in patients with advanced solid tumors and non-Hodgkin's lymphoma (NHL).Patients and methods: Thirty-five patients with advanced solid tumors were enrolled in stages I and II. Twenty-one patients were treated in stage I in sequential cohorts of at least three patients at increasing dosage levels of cyclophosphamide and epirubicin, for up to six cycles every 21 days. At the completion of stage I, a MTD for epirubicin was established. Fourteen patients were treated in stage II, in cohorts of three or more. The epirubicin dose remained constant at the MTD dosage from stage I. Cyclophosphamide was further dose-escalated to establish its MTD. Twenty-one patients with previously untreated non-Hodgkin's lymphoma were treated in stage III with the MTD established in the prior stages.Results: The MTD in stage I was epirubicin 150 mg/m² and cyclophosphamide 1500 mg/m² with cumulative neutropenia as the dose-limiting toxicity (DLT). Cumulative thrombocytopenia prevented further dose-escalation of cyclophosphamide in stage II. The stage III regimen consisted of six, 21-day cycles of epirubicin 150 mg/m², cyclophosphamide 1500 mg/m², vincristine 2 mg, and prednisolone 100 mg for five days with filgrastim support. Nineteen of twenty-one patients (90%) completed six cycles of treatment, eight (38%) without dose reduction. Common toxicity criteria (CTC) grade 4 neutropenia (neutrophil nadir <0.5 × 10⁹/l) was documented in 85 of 118 cycles (72%). Neutropenic fever was documented in 17 of 21 patients (81%) on at least one occasion. Severe thrombocytopenia (<25 × 10⁹/l) was seen in fourteen of 118 cycles (12%) and increased with cycle number. There was no significant non-hematological toxicity.Conclusion: Significant dose-escalation of epirubicin and cyclophosphamide was possible with filgrastim support. The MTD achieved was approximately double that of standard-dose therapy. This study forms the basis of an ongoing randomized study evaluating dose-intensification in intermediate grade NHL.     

Alternating combination chemotherapy COP (cyclophosphamide, vincristine, prednisone) and MP (melphalan, prednisone) in multiple myeloma: a multicenter phase II study (JCOG8906). Lymphoma Study Group of the Japan Clinical Oncology Group

BACKGROUND: The main form of cytotoxic treatment for multiple myeloma (MM) is conventional dose chemotherapy at present. METHOD: Between November 1989 and December 1991, a multicenter phase II study of alternating conventional dose combination chemotherapy (CCT) with COP (cyclophosphamide, vincristine, prednisone) and MP (melphalan and prednisone) to evaluate its clinical usefulness for overt MM patients was conducted by the Lymphoma Study Group of the Japan Clinical Oncology Group (JCOG). RESULTS: Eighty-one previously untreated patients were enrolled in the study. For 69 eligible patients, the response rate was 50.7% [95% confidence interval (CI) 38.4-63.0%]. The median survival time was 38.5 (95% CI 32.0-44.4) months. The survival rate at 3 and 5 years was 50.7 and 27.3%, respectively. Grade 4 toxicity by the criteria of the World Health Organization consisted of anemia in eight patients, leucocytopenia in three, cardiac in one and hepatic in two, but there was no treatment-related death. CONCLUSION: The COP-MP regimen for overt MM is thought to be one of the effective CCTs according to the results of the present phase II study.     

Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's lymphoma previously treated with an alkylating agent or alkylator-containing regimen.

PURPOSE: To compare in a phase III study the safety and efficacy of fludarabine to that of cyclophosphamide, vincristine, and prednisone (CVP) in recurrent, low-grade, non-Hodgkin's lymphoma after previous response to systemic treatment. PATIENTS AND METHODS: Patients were randomized to fludarabine (25 mg/m(2) intravenously on days 1 to 5, every 28 days) or CVP (cyclophosphamide 750 mg/m(2) and vincristine 1.2 mg/m(2) both intravenously on day 1 and prednisone 40 mg/m(2) orally on days 1 to 5, every 21 days). The primary outcome assessed was progression-free survival (PFS); secondary outcomes included treatment-free survival (TFS), overall survival (OS), treatment-related toxicity, and quality of life (QoL) according to the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire C-30 version 1.0 instrument. RESULTS: Ninety-one patients were randomized, 47 to fludarabine and 44 to CVP. There was no difference in response rates, with 64% (complete response [CR], 9%) for fludarabine versus 52% (CR, 7%) for CVP (P =.72). With a median follow-up of 42 months, median PFS (11 months v 9.1 months; P =.03) and TFS (15 months v 11 months; P =.02) were superior in patients receiving fludarabine. No difference in median overall survival was detected (57 months for fludarabine v 44 months for CVP; P =.95). Three patients receiving fludarabine died of treatment-related toxicity compared with none of the patients receiving CVP. Peripheral neuropathy and alopecia were more common with CVP. Patients receiving fludarabine had higher scores for social function (P =.008); no other differences in QoL were detected. CONCLUSION: In recurrent low-grade lymphoma, fludarabine improves PFS, TFS, and social function scores in comparison with CVP but does not improve OS.