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.     

Low-grade non-Hodgkin's lymphoma - development of a new effective combination regimen (fludarabine,mitoxantrone and dexamethasone; FND)

Low-grade lymphoma is the commonest form of lymphoma in the USA and Europe with a long natural history with multiple responses and relapses. The tendency has been to use simple oral medication until patients have more advanced aggressive disease but new agents such as the purine analogues, mitoxantrone and monoclonal antibodies has led to re-evaluation of this approach. As purine analogues inhibit DNA repair in lymphoid cells, a new combination of fludarabine, mitoxantrone, and dexamethasone (FND) has been developed that is well tolerated and very effective. In a phase II study, in 51 patients 47% complete remissions and 47% partial remissions were noted. FND is now being used in a randomization comparative trial with alternating triple therapy as frontline treatment for low-grade lymphoma at the M. D. Anderson Cancer Center with monitoring by polymerase chain reaction for rearrangement of the bcl-2 gene in blood and bone marrow cells. The high activity and low morbidity of FND makes it as attractive as initial therapy for patients.     

Subsequent chemotherapy regimens are well tolerated after radioimmunotherapy with yttrium-90 ibritumomab tiuxetan for non-Hodgkin's lymphoma.

PURPOSE: Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin; IDEC Pharmaceutical, San Diego, CA) is an effective therapy for patients with relapsed B-cell non-Hodgkin's lymphoma. The predominant toxicity of 90Y ibritumomab tiuxetan has been myelosuppression, and concern has been expressed about the tolerability of further treatment after this therapy. The goal of this analysis was to evaluate the therapy given to patients who relapsed after 90Y ibritumomab tiuxetan. PATIENTS AND METHODS: A retrospective analysis was performed on 58 patients treated at a single institution on five separate protocols that used 90Y ibritumomab tiuxetan 0.4 mCi/kg. All patients had experienced disease progression after 90Y ibritumomab tiuxetan treatment and received subsequent therapy. The toxicity seen in this cohort of patients with subsequent treatment regimens was analyzed and compared with that of control groups who did not receive 90Y ibritumomab tiuxetan. RESULTS: The median number of subsequent therapies was two (range, one to seven). Sixteen (28%) of the 58 patients received growth factor support with subsequent chemotherapy, and two patients were treated with reduced doses because of persistent pancytopenia. Eight patients subsequently had an autologous stem-cell transplantation with stem cells collected after 90Y ibritumomab tiuxetan therapy. Excluding patients hospitalized at the time of transplantation, 13 patients were hospitalized for neutropenic fever, thrombocytopenia, or both. When compared to patients who did not receive 90Y ibritumomab tiuxetan, there was no significant difference in toxicity. CONCLUSION: We conclude that chemotherapy or autologous stem-cell transplantation after prior therapy with 90Y ibritumomab tiuxetan is feasible and reasonably well tolerated. The toxicity with subsequent therapy seems similar to that in patients not treated with 90Y ibritumomab tiuxetan.     

Fludarabine, cyclophosphamide, and dexamethasone (FluCyD) combination is effective in pretreated low-grade non-Hodgkin's lymphoma

Purpose: Fludarabine phosphate is effective as a single agent in low-grade non-Hodgkin's lymphoma (NHL). Combined with other antineoplastic agents it enhances the antitumor effect. Our aim was to define the therapeutic efficacy and toxicity of a combination of fludarabine, cyclophosphamide and dexamethasone (FluCyD) in patients with advanced low-grade lymphoma.Patients and methods: Twenty-five adults with pretreated advanced-stage low-grade NHL were treated with three-day courses of fludarabine 25 mg/m2/day, cyclophosphamide 350 mg/m2/day, and dexamethasone 20 mg/day, every four weeks for a maximum of six courses.Results: Of the 25 patients, 18 (72%) responded, 8 (32%) achieving CR and 10 (40%) PR. Seven were failures. The median follow-up was 21 months (5–26). Eight CR patients remain in CR after 5–21 months. Of 10 PR patients, 3 are in continuous PR without further treatment after 12, 17 and 18 months. Myelosuppression was the most prevalent toxic effect. Although severe granulocytopenia (granulocyte count nadir <500/µl) and thrombocytopenia (platelet count nadir <50,000/µl) occurred in only 10% and 16% of courses, respectively, slow granulocyte or platelet count recovery caused delay of 40% of the courses. Nine patients (36%) required discontinuation of therapy because of persistent granulocytopenia and/or thrombocytopenia: three after one course, three after 2–4 courses, and three after five courses. Thirteen infectious episodes in 11 patients complicated 11% of courses. Two of 10 patients monitored for the circulating EBV load showed increased viral load. One of these developed aggressive lymphoma. CD4+ lymphocytes declined from a pre-therapy median value of 425/µl to 141/µl post-treatment (P = 0.001). Non-hematologic toxicities were rare and mild.Conclusions: The combination of fludarabine with cyclophosphamide and dexamethasone is effective in pretreated advanced-stage low-grade NHL. It may broaden the range of therapeutic options in the salvage treatment of these patients. The main toxicity of this combination is prolonged myelosuppression that may cause treatment delay or withdrawal. The benefit of adding granulocyte colony-stimulating factor, particularly in patients with poor marrow reserve, needs to be investigated.     

Carboplatin (CBDCA), 5-fluorouracil (5-FU) and mitoxantrone (DHAD): an effective and well tolerated regimen for metastatic breast cancer.

Fifty-five women with metastatic breast cancer were treated with carboplatin (CBDCA), 55 mg/m2 i.v. bolus, daily for 3 days, 5-fluorouracil (5-FU) 900 mg/m2, (max. dose 1,500 mg/day in 24-h infusion (Travenol system) daily for 3 days, and mitoxantrone (DHAD) 8 mg/m2, i.v. bolus on day 1. Cycles were administered every 5 weeks. Objective responses were observed in 25 (44%) patients (95% confidence interval: 28%-60%) with a median duration of remission of 11.5+ months (range 6.5(+)-31+). Toxicity was mild. These results reflect the fact that combination of CBDCA, 5-FU and DHAD is effective and very well tolerated as an outpatient regimen.     

DICE方案治疗难治和复发性非霍奇金淋巴瘤的疗效分析

背景与目的:目前对于难治性和复发性非霍奇金淋巴瘤(non-Hodgkin)slymphoma,NHL)尚无标准解救化疗方案,本文旨在探讨DICE方案(地塞米松,异环磷酰胺,顺铂及VP-16)治疗难治和复发性NHL的疗效和不良反应。方法:80例难治和复发性NHL患者,其中T细胞NHL25例,B细胞NHL55例,既往均接受过6个周期的CHOP化疗方案无缓解。现采用DICE方案对患者进行解救治疗,并对毒副反应加以评估、预防及治疗。结果:80例患者接受6个周期DICE方案化疗后,总体有效率为56.3%,完全缓解率为27.5%;T、B细胞NHL有效率分别为48.0%、60.0%,完全缓解率为16.0%、32.7%(P>0.05);经DICE方案治疗的患者出现骨髓抑制、消化系统反应、脱发以及电解质紊乱发生率增高,经过治疗均恢复,无治疗相关死亡。结论:DICE方案治疗难治和复发性NHL有效。     

Concurrent cyclophosphamide,methotrexate, and 5-fluorouracil chemotherapy and radiotherapy for breast carcinoma: a well tolerated adjuvant regimen

BACKGROUND: The current study was conducted to assess the toxicity of concurrent adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy and radiotherapy (RT) for early breast carcinoma. METHODS: In the current study, the authors reviewed the records of 680 consecutive breast carcinoma patients who received adjuvant CMF at the Princess Margaret Hospital between 1980-1990. Surgery was comprised of mastectomy in 64% of patients, breast conservation in 35% of patients, and was unknown in 1% of patients. Two hundred two patients received concurrent CMF/RT that was defined as an overlap in CMF and RT administration of at least 21 days. Forty-seven patients received sequential CMF/RT (defined as no overlap or an overlap of < 7 days in CMF and RT administration). Other patients received CMF alone. Adverse effects of RT were graded retrospectively using the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) system. Reasons for interruption or failure to complete RT were recorded. The magnitude of chemotherapy dose reductions and delays also were noted. RESULTS: The median age of the patients was 44 years (range, 26-68 years) and 88% of the patients had lymph node-positive disease. RT was interrupted or discontinued due to side effects in 4% of patients (95% confidence interval [95% CI], 1.7-7.7%) and 0% (95% CI, 0-7.6%), respectively, of the concurrent and sequential groups (P = 0.36). The incidence of Grade 3 or Grade 4 RT toxicity was 1.5% (95% CI, 0.3-4.3%) and 2.1% (95% CI, 0.1-11.3%), respectively, for the concurrent and sequential groups (P = 0.57). The median relative dose intensity of chemotherapy for patients receiving concurrent CMF/RT, sequential CMF/RT, and CMF alone was 0.87, 0.84, and 0.85, respectively (P = 0.22). CONCLUSIONS: The results of the current study demonstrate that the concurrent administration of CMF and RT is associated with a low risk of serious toxicity and is an acceptable adjuvant regimen for patients with breast carcinoma.     

Alternating chemotherapy regimen (P-VABEC) for intermediate and high-grade non-Hodgkin's lymphoma of the middle aged and elderly

An intensive third generation regimen (P-VABEC) including adriamycin, etoposide, cyclophosphamide, vincristine, bleomycin and prednisolone was administered to 43 unselected elderly patients with intermediate or high-grade non-Hodgkin's lymphomas (NHL). The median age was 67, 40 per cent were Ann Arbor stage IV, 73 per cent had‘B’ symptoms, 55 per cent had bulky disease, 48 per cent had serum lactate dehydrogenase greater than 450 U/1, 85 per cent had serum thymidine-kinase greater than 4 U/1. Thirty patients were previously untreated. The complete remission (CR) rate was 74 per cent, and the partial remission (PR) rate 23 per cent, with an overall response rate of 97 per cent. The regimen was carried out on an outpatient basis in all patients. No death occurred during therapy. The Kaplan-Meier actuarial survival of all patients at 3-years is 47 per cent, and 50 per cent (16/32) of all patients who attained CR remain alive and in remission at a median of 21+ months (range 6+ to 42+). These results confirm that high remission and failure-free survival rates can be achieved also in elderly unselected patients with aggressive NHL treated with curative intent.     

Ifosfamide, epirubicin and etoposide (IEV) regimen as salvage and mobilization therapy for refractory or early relapsing patients with aggressive non-Hodgkin's lymphoma

The prognosis of early relapsing or refractory aggressive non-Hodgkin's lymphoma (NHL) is still poor. Effective salvage therapy should be able to induce high response rate as well as to mobilize hematopoietic precursors. A combination of ifosfamide, epirubicin and etoposide (IEV) was given to 28 patients with refractory or relapsing high grade NHL (4 lymphoblastic lymphoma and 24 large cell lymphoma). All patients were evaluated for response. After 2 courses of IEV, the overall and complete response rate were 64% and 39%, respectively. All patients were controlled for mobilization of peripheral blood stem cells, which was successful in 26 out of 28 (93%). Overall, 25 out of 26 patients proceeded to autologous stem cell transplantation (ASCT). Toxicity was mild, with no occurrence of severe persisting extra-hematologic side-effects. Following the entire therapeutic program, including IEV and ASCT, median progression free survival has not yet been reached and 21 patients are alive (18 in continuous complete remission) after a median follow-up of 18 months. Our results demonstrate that treatment with IEV regimen is effective in refractory or relapsing aggressive NHL, resulting in a high percentage of successful stem cell mobilization and feasibility of ASCT.     

MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) as a low-dose salvage chemotherapy for recurrent or refractory non-Hodgkin's lymphoma

We conducted a clinical study of MTX-HOPE (day 1, methotrexate 20 mg per os (po); day 2, hydrocortisone 100 mg intravenous (iv), vincristine 1 mg iv; day 3,4 sobuzoxane 400 mg po; etoposide 25 mg po, repeating every 2 or 3 weeks) in 14 relapsed or refractory patients with non-Hodgkin's lymphoma. Ten responders were obtained 5 CR and 5 PR), and heavily treated patients were included in the responders. The median duration of over all survival which was estimated with Kaplan-Meier curve was 11.1 months (range, 2-18+ months), and the median duration of response was 6.9 months (range, 0.8+ -16.4+ months).Out of the 14 patients,eleven were treated with this regimen in an outpatient setting. Grade 4 neutropenia and thrombocytopenia were observed in 4 and 2 patients,and grade 3 GPT-elevation and stomatitis in two and one, respectively. This newly developed MTX-HOPE therapy may be a promising treatment option for such patients as are intolerable for high-dose chemotherapies with PBSC rescue or wish for outpatient therapy.     

Treatment of aggressive non-Hodgkin's lymphoma with dose-intensified epirubicin in combination of cyclophosphamide, vincristine, and prednisone (CEOP-100): a phase II study.

Epirubicin is an agent with a lower incidence of cardiotoxicity and myelotoxicity compared with doxorubicin; and it is active in patients with non-Hodgkin's lymphoma (NHL). Our aim was to define the therapeutic efficacy and toxicity of dose-intensified epirubicin in combination with cyclophosphamide, vincristine, and prednisone (CEOP) in patients with diffuse large-cell NHL. Previously untreated patients aged between 15 and 75 years, with at least one measurable lesion, adequate liver, renal, cardiac functions, and no central nervous system involvement were included in the study. The planned chemotherapy regimen CEOP consisted of cyclophosphamide 750 mg/m2, epirubicin 100 mg/m2, and vincristine 1.4 mg/m2 intravenously on day 1 and 100 mg prednisone taken orally on days 1 to 5. Courses were repeated every 21 days. Patients with stage I and II received four cycles of chemotherapy followed by involved-field radiotherapy, and patients with stage III and IV received six cycles of chemotherapy followed by radiotherapy to bulky lymph node sites. Seventy-five patients were enrolled in the study. The complete response rate was 83.8%, and 72 patients were assessable for toxicity. The most common toxicity was myelosuppression; 13.9% of the patients had grade III-IV neutropenia. Severe mucositis, diarrhea, and emesis were uncommon (<10%). At a median follow-up period of 41 months, the 5-year progression-free survival and overall survival rates were 63.5% and 65.3%, respectively. Increasing the dose intensity of epirubicin can yield a similar complete response rate compared with the regimens used in NHL without significantly increasing the toxicity rate associated with chemotherapy. The role of dose-intensive epirubicin should be investigated further in future randomized trials.     

Combination chemotherapy with pirarubicin (THP), cyclophosphamide, vincristine, and prednisolone (VEP-THP therapy) in the treatment of non-Hodgkin's lymphoma

Twenty-eight patients with non-Hodgkin's lymphoma (NHL) were treated with a combination of (2'-R)-4'-o-tetrahydropyranyladriamycin (pirarubicin, THP), cyclophosphamide, vincristine, and prednisolone (VEP-THP therapy). Eleven (45.8%) of twenty-four evaluable patients achieved complete response (CR). CR rate (52.8%) was higher in the intermediate-grade histology group than in high- or low-grade group. Toxicity was generally acceptable although leukopenia less than 2,000/microliters was observed in 17 (60.7%) of 28 patients. Clinical signs of cardiotoxicity were not observed and alopecia was mild. Therefore, VEP-THP therapy is useful as a first-line chemotherapy in the treatment of NHL, particularly for the patients with intermediate-grade histology. Higher CR rate and longer relapse-free survival can be expected by administering a greater dose of THP or employing a schedule of fractionated low doses.     

Evolution of neuropathy and myopathy during intensive vincristine/corticosteroid chemotherapy for non-Hodgkin's lymphoma.

Neuropathy and myopathy are common sequelae of intensive chemotherapy protocols that contain vincristine and corticosteroids. The authors prospectively monitored the evolution of neuropathy and myopathy during an intensive 12-week chemotherapy program for patients with intermediate and high-grade non-Hodgkin's lymphoma. In this study, vincristine was administered by bolus injection followed by a 3-day continuous intravenous (IV) infusion (total dose of 2.0 mg/m2 every other week); the maximum dose of vincristine was not arbitrarily limited. Cronassial, a mixture of four naturally occurring gangliosides, was administered in a randomized double-blind test to evaluate whether this agent could prevent vincristine-induced neuropathy. High doses of dexamethasone (50 mg/d for 3 days weekly or every other week) were also prescribed. Patients were monitored every 4 weeks with comprehensive physical and neurologic examinations and electrophysiologic studies of peripheral nerve function. Twenty-seven patients were fully evaluable. Weakness was a prominent adverse reaction in this study, and all patients had moderate to severe signs and symptoms of neuropathy and myopathy. Cronassial (100 mg) administered by intramuscular (IM) injection daily provided no protection against the development of neuropathic symptoms. Vincristine typically impaired fine-motor coordination initially, whereas corticosteroids were associated with delayed development of proximal muscle weakness. Results of electrodiagnostic studies did not add to the clinical examination results. The authors conclude that symptomatic weakness due to neuropathy or myopathy appears in a predictable manner during intensive vincristine/corticosteroid-based treatment protocols. Simple clinical tests can be used to rapidly distinguish between toxic effects due either to vincristine or corticosteroids, and routine implementation of these tests can prevent inappropriate dose attenuation of these agents.     

Low dose Velcade, thalidomide and dexamethasone (LD-VTD): an effective regimen for relapsed and refractory multiple myeloma patients

From January 2004, R/R MM cases referred to the Institution received LD-VTD regimen. Patients, irrespective of age, PS and life expectancy, were enrolled in the study once they had a measurable disease. Planned therapy: Velcade 1.0 mg m(-2) i.v. twice weekly for 2 weeks of a 28-day cycle for up to 6 cycles, oral Dexamethasone 24 mg on the day of and the day following each Velcade dose and Thalidomide 100 mg each evening. DVT prophylaxis with warfarin to maintain international normalized ratio between 2.0-3.0 was planned in all patients. As of 1 June 2005, 18 were the treated patients: median age 63 years, median time from diagnosis 5.8 years, a median of 4 previous therapy lines. Seventeen were the valuable patients and 9 (53%) were the responders: 2 CR, 6 PR, 1 MR. Six were the stable disease and 2 the progressive ones. Median time to best response was 2 months. Toxicity was negligible. No case of DVT was recorded. Except for the first cycle, subsequent cycles were delivered on an outpatient basis. After a median follow-up of 11 months, 12 patients were alive and 5 died (3 disease progression, 1 heart failure, 1 intestinal bleeding). Thus, the LD-VTD regimen applied appears feasible and effective in elderly and heavily pre-treated R/R myeloma patients.     

A limited role for VEEP (vincristine, etoposide, epirubicin, prednisolone) chemotherapy in childhood Hodgkin's disease

The VEEP regimen (vincristine, etoposide, epirubicin, prednisolone), with or without involved field radiotherapy, has been shown to be an effective treatment in adult Hodgkin's disease. In an attempt to avoid the late sequelae of both alkylating agents and radiotherapy this regimen has been studied in a series of 54 children and young adults. Early analysis suggested that the relapse rate was higher with VEEP than with standard alkylating agent-based regimens. Sufficient follow-up has now been achieved to evaluate the likelihood of sustained remission following second-line treatment and therefore the overall long term survival with this treatment approach. The 5-year Overall Survival (OS) and 5-year Progression Free Survival (PFS) for patients with stage I-III disease was 93% and 82% respectively. However, the 5-year OS and PFS for stage IV patients was only 44% and 50%, respectively. Of 13 patients who were initial treatment failures on VEEP, 7 of whom had advanced disease, only 6 were salvaged with second-line therapy. 8 of 33 who attained a complete response (CR) relapsed and there were 2 relapses in those achieving a partial response (PR) (n = 8). All those relapsing from CR/PR were salvaged by second-line alkylating agent chemotherapy +/- radiotherapy, +/- high dose chemotherapy. In conclusion, patients with stage I-IIIA, non-bulky disease, the moderately high relapse rate did not adversely affect the overall high cure rate, although VEEP failures were subjected to a high total treatment burden. VEEP alone is inadequate in patients with stage IV disease, bulky mediastinal disease in/or those with B symptoms in whom there is a high primary failure rate and relatively poor results with second line therapy.     

Outpatient regimen rituximab plus ifosfamide, carboplatin and etoposide (R-ICE) for relapsed non-Hodgkin's lymphoma

View this table: [in this window] [in a new window]   Table 1.     

Mitoxantrone, L-leucovorin and 5-fluorouracil: an effective and well tolerated first-line treatment for advanced breast cancer

AIMS AND BACKGROUND: The combination of mitoxantrone plus leucovorin/fluorouracil in heavily pretreated patients with advanced breast cancer has shown significant activity and extremely good tolerability. The aim of this study was to evaluate the activity of this combination in patients not previously submitted to chemotherapy. METHODS: From May 1993 to December 1995 we treated 80 patients with advanced breast cancer with a combination of mitoxantrone, l-leucovorin and 5-fluorouracil. All patients had histologically or cytologically proven breast cancer, WHO performance status 0-3, normal hematological parameters and normal serum bilirubin. Prior chemotherapy for metastatic disease was not allowed, whereas adjuvant CMF (cyclophosphamide, methotrexate and 5-fluorouracil) or adjuvant anthracycline (doxorubicin or epirubicin) therapy was allowed; a single prior hormone treatment was permitted. Chemotherapy consisted of mitoxantrone 12 mg/m2 i.v. day 1, l-leucovorin 150 mg/m2 i.v. days 1, 2 and 3 and 5-fluorouracil 350 mg/m2 i.v. days 1, 2 and 3. The courses were repeated every 3 weeks. RESULTS: Objective response (CR + PR) was observed in 46/80 (57%) patients (95% CI, 46%-68%). Complete response (CR) was observed in 21/80 cases (26%). Response was observed in 14/24 (58%) patients with soft tissues as the dominant site of disease, in 22/34 (65%) patients with visceral involvement and in 10/22 (45%) of those with bone as the dominant site of disease. The median duration of response and survival was 9 months (range, 3-16) and 22 months (range, 2-48+), respectively. Toxicity was very manageable, with grade 4 leukopenia and thrombocytopenia in 6/80 (7.5%) and 1/80 (1.25%) patients, respectively, and negligible non-hematological toxicity. CONCLUSIONS: The combination of mitoxantrone, 5-fluorouracil and high-dose l-leucovorin is a safe and effective regimen for first-line treatment of advanced breast cancer.     

EPIC: an effective low toxicity regimen for relapsing lymphoma.

We have treated 40 patients was relapsed or resistant lymphoma with the combination of Etoposide, Prednisolone, Ifosfamide and Cisplatin (EPIC). Complete response was obtained in 11 patients (28%) with an overall response of 58%. The presence of bulky disease (P < 0.005), elevated LDH serum levels (P < 0.005), response to prior chemotherapy (P < 0.01) and B symptoms (P < 0.005) were significantly associated with response. However on multivariate analysis only the presence of bulky disease and of B symptoms were independent adverse factors for response and for survival. The regimen was well tolerated with myelosuppression being the most common toxicity. Leucopenia < or 1,000 microliters-1 and thrombocytopenia < or = 25,000 microliters-1 developed in 27% and 4% of cycles respectively. There were no treatment related deaths. The EPIC regimen has equivalent activity to other reported cisplatin based regimens used in the treatment of recurrent lymphoma, but is associated with lower treatment related morbidity and mortality.