The treatment of multiple myeloma using vincristine,carmustine, melphalan,cyclophosphamide, and prednisone (VBMCP) alternating with high‐dose cyclophosphamide and α2β interferon versus VBMCP

BACKGROUND:

A randomized controlled trial tested the hypothesis that aggressive initial therapy using high‐dose cyclophosphamide (HiCy) and α₂β interferon (IFN) may be superior to standard combination alkylating agent regimens in the treatment of newly diagnosed myeloma.

METHODS:

This Eastern Cooperative Oncology Group trial evaluated 268 previously untreated patients with active multiple myeloma randomized to vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) or VBMCP plus HiCy and recombinant IFN.

RESULTS:

The overall objective response was 62% in the VBMCP regimen and 68% in the VBMCP + HiCy + IFN group. The near complete response and complete response rates were 8.1% and 8.9%, respectively. Progression‐free survival was 22.1 and 25.3 months, respectively. The median overall survival was 37.1 months for patients treated with VBMCP and 41.3 months for those treated with VBMCP + HiCy + IFN (P = .38). The 5‐year overall survival rates were not significantly different between the 2 arms: 26.4% and 33%, respectively. Lethal toxicities occurred in 15 patients, including 10 from infection, but there was no significant difference in lethal toxicities between the 2 regimens.

CONCLUSIONS:

The study showed no significant benefit with the addition of HiCy and IFN to VBMCP. Cancer 2009. © 2009 American Cancer Society.     

Complete response in multiple myeloma: clinical trial E9486, an Eastern Cooperative Oncology Group study not involving stem cell transplantation

BACKGROUND: The importance of obtaining a complete response (CR) in multiple myeloma (MM) treated with chemotherapy is unclear. METHODS: The Eastern Cooperative Oncology Group evaluated 653 previously untreated patients with active MM randomized to vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone (VBMCP), to VBMCP and recombinant interferon alfa-2 (INFalpha-2), or to VBMCP and high-dose cyclophosphamide. RESULTS: Objective response was achieved in 420 (67%) of the 628 eligible patients, and 85 (14%) achieved a CR. Patients receiving VBMCP and recombinant INFalpha-2 had a significantly higher CR (18%) than those receiving VBMCP alone (10%) (P = .02). The CR rate for VBMCP and high-dose cyclophosphamide was 12%. Median duration of survival was 3.5 years for all eligible patients, and the estimated 5-year survival rate was 31%. The median duration of survival from the date of objective response was 5.1 years for those who achieved a CR and 3.3 years for those with a partial response (P < .0001). The median postresponse survival was 6.6 years in the 21 patients in CR with nonclonal disease and 4.4 years in the 11 patients in CR who had persistent clonal disease. All patients with negative immunofixation results and nonclonal plasma cells in whom polymerase chain reaction was performed had a positive result (presence of tumor DNA). CONCLUSION: Patients in whom a CR was achieved had a longer survival than those who had a partial response.     

Fludarabine phosphate-CVP in patients over 60 years of age with advanced, low-grade and follicular lymphoma: a dose-finding study

The aim of this study was to establish a safe and effective regimen of fludarabine phosphate, cyclophosphamide, vincristine and prednisone (F-CVP) as first-line treatment for elderly patients with advanced, low-grade non-Hodgkin's lymphoma. Twenty-three patients >60 years were assigned successively to eight treatment cycles (Dose level 1: low F, low CV [n=4]; 2A: high F, low CV [n=8]; 2B: low F, high CV [n=4]; 3: high F, high CV [n=7]). High and low levels were: F, 25 and 20mg/m(2), respectively (Days 1-5); C, 750 and 500 mg/m(2), respectively (Day 1); and V, 1.4 and 1mg/m(2), respectively (Day 1). Patients received P at 40 mg/m(2) on Days 1-5. Response was assessed after Cycles 2, 4, 6 and 8. At level 3, dose-limiting toxicity (opportunistic infections and neutropenia) became evident, particularly after Cycle 6. Further patients were recruited at Dose level 2A. All regimens proved effective, with an OR rate of 78% (65% CR), and 3-year survival of 65% (+/-10%). Among 18 responders, 51% were still in response at 3 and 5 years. The study shows that this combination therapy is highly effective. The addition of F to CVP at Dose level 2A was feasible and increased the CR rate, with good tolerability in elderly patients.     

Randomized trial of treatment with cisplatin and interleukin-2 either alone or in combination with interferon-alpha-2a in patients with metastatic melanoma: a Federation Nationale des Centres de Lutte Contre le Cancer Multicenter, parallel study

BACKGROUND: The objective of the current study was to evaluate the response rate, survival, and toxicity of treatment with cisplatin and high dose intravenous continuous infusion interleukin-2 (IL-2) with or without interferon-alpha-2a (IFN) in patients with metastatic melanoma. METHODS: One hundred and seventeen patients with metastatic melanoma randomly were assigned to receive cisplatin, 100 mg/m2, followed after a 3-day rest period by IL-2, 18 x 10(6) IU/m2, on Days 3-6 and Days 17-21 (Arm 1) or cisplatin and IL-2 using an identical schedule plus subcutaneous IFN, 9 x 10(6) U, 3 times a week during IL-2 administration (Arm 2). In the absence of disease progression or undue toxicity, the cycle could be repeated on Day 29. Patients who responded after two cycles eventually could receive a third cycle. One hundred and one patients were evaluable for toxicity and efficacy. RESULTS: On treatment Arm 1, 3 patients (6%) achieved a complete response (CR) and 5 patients (10%) achieved a partial response (PR) with a median response duration of 3.8 months for the CRs and 8.7 months for the PRs. On treatment Arm 2, 2 patients (3%) achieved a CR (durations of 5.9 and 33.1 months, respectively) and 11 patients (21%) a PR with a median response duration of 8.3 months. The median durations of overall survival were 10.4 months (range, 1.1-39.7+ months) and 10.9 months (range, 0.5-38.1+ months) for treatment Arms 1 and 2, respectively. The toxicity profile was consistent with the known side effects of this IL-2 intravenous regimen combined with cisplatin chemotherapy and IFN. Toxicity was more pronounced in treatment Arm 2 compared with treatment Arm 1. There were 2 and 4 patients, respectively, in treatment Arms 1 and 2 who died within 28 days after completion of treatment. CONCLUSIONS: The observed overall response rates of 16% and 25% in treatment Arms 1 and 2, respectively, is lower than that expected with biochemotherapy; despite the fact that the objective of the trial was not to show any difference between the 2 treatment arms, our results indicate that the addition of IFN, at the dose and schedule used in this trial, fails to improve the activity of a cisplatin/IL-2 regimen significantly in patients with metastatic melanoma. Although response rates were relatively low, the median overall survival was nearly 1 year in both groups.     

An open-label pilot study of pentostatin, mitoxantrone, and rituximab in patients with previously untreated, Stage III or IV, low-grade non-Hodgkin lymphoma

BACKGROUND: In a previous study, the authors demonstrated that the combination of pentostatin (P) and rituximab (R) was well tolerated and was active in patients with low-grade non-Hodgkin lymphoma (NHL). In the current study, mitoxantrone (M) was added to P + R to evaluate the toxicity and efficacy of this three-drug combination (PMR). METHODS: Twenty-four previously untreated patients with histologically proven, Stage III or IV, low-grade NHL were registered between April and September, 2002. Patients received P (4 mg/m2), M (10 mg/m2), and R (375 mg/m2) every 28 days (M on Day 1; P and R on Days 1 and 8; in Cycle 1, R was given on Day 8 only). Eighty-three percent of patients had Stage IV disease, the median patient age was 62 years (range, 4-81 years), and the performance status was 0-2. RESULTS: Responses included 9 patients who achieved complete remission (CR) (38%), 3 patients with unconfirmed CR (CRu) (12%), 8 patients who achieved partial remission (33%), and 4 patients who achieved stable disease (17%); the overall response rate (CR + CRu + PR) was 83%. PMR appeared to result in comparable activity in all histologies. The median response duration was 10.0 months (range, 3.5-15.1 months). Patients received a median of 5 cycles (range, 1-10 cycles). Eighteen patients (75%) required dose reduction or delay due to toxicity, mainly neutropenia (the administration of growth factors was not permitted). Three patients died (two patients died of disease progression, and one patient died from unrelated cardiopulmonary arrest). Grade > or = 3 drug-related toxicities included neutropenia (67%), leukopenia and febrile neutropenia (17% each), and sepsis (8%), and 38% of neutropenic episodes occurred in Cycles 1 and 2. CONCLUSIONS: In this study, PMR was active and well-tolerated in patients with low-grade NHL, and the combination is deserving of further study.     

Sequential Phenotyping of Myeloma Patients on Chemotherapy: Persistence of Activated T-cells and Natural Killer Cells

To better detail the status of functional T cell subsets and natural killer cells in multiple myeloma, we undertook a detailed immunophenotypic study of circulating mononuclear cells in myeloma. We studied myeloma patients entered on a large prospective, randomized ECOG chemotherapy trial EST 9486 for patients with newly diagnosed multiple myeloma. All patients were studied prior to entry and then two months after initiation of therapy (e.g. post two cycles of Vincristine, BCNU, melphalan, cyclophosphamide and prednisone (VBMCP)). The chemotherapy protocol was a three-arm protocol utilizing either VBMCP, VBMCP alternating with interferon, or VBMCP with intermittent high dose cyclophosphamide. The major findings in this analysis include significant reductions in the white blood cell count, total lymphocytes, T cell (CD3 +), T helper (CD4+), and T suppressor (CD8+) cells, after 2 cycles of VBMCP. However, there was a relative sparing of Natural killer (CD16+) and activated T cell (CD2+, HLADR+) reduction in these same patients. In summary, only two cycles of combination chemotherapy resulted in significant reductions in white blood cell and lymphocyte counts in multiple myeloma patients. All cell types appear to have been reduced by chemotherapy except for activated T cells and natural killer cells. The impact of selective modulation of functional T cells subsets during therapy for patients with multiple myeloma is an important parameter which needs to be addressed in the overall approach to these patients.     

Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy

BACKGROUND: An aprepitant (APR) regimen was evaluated for prevention of nausea and emesis due to moderately emetogenic chemotherapy (MEC) over multiple cycles. METHODS: The authors performed a randomized, double-blind study. Eligible patients with breast carcinoma were na?ve to emetogenic chemotherapy and treated with cyclophosphamide alone or with doxorubicin or epirubicin. Patients were randomized to receive either an APR regimen (Day 1: APR 125 mg, ondansetron [OND] 8 mg, and dexamethasone [DEX] 12 mg before chemotherapy and OND 8 mg 8 hrs later; Days 2-3: APR 80 mg every day) or a control regimen (Day 1: OND 8 mg and DEX 20 mg before chemotherapy and OND 8 mg 8 hrs later; Days 2-3: OND 8 mg twice per day). Data on nausea, emesis, and use of rescue medication were collected. The primary end point was the proportion of patients with a complete response (CR; no emesis or use of rescue therapy) in Cycle 1. Efficacy end points for the multiple-cycle extension were the probabilities of a CR in Cycles 2-4 and a sustained CR rate across multiple cycles. RESULTS: Of 866 patients randomized, 744 (85.9%) entered the multiple-cycle extension, and 650 (75.1%) completed all 4 cycles. Overall, the CR was greater with the APR regimen over the 4 cycles: 53.8% versus 39.4% for Cycle 2, 54.1% versus 39.3% for Cycle 3, and 55.0% versus 38.4% for Cycle 4. The cumulative percentage of patients with a sustained CR over all 4 cycles was greater with the APR regimen (P = 0.017). CONCLUSIONS: The APR regimen was more effective than a control regimen for the prevention of nausea and emesis induced by MEC over multiple chemotherapy cycles.     

以博安霉素为主的新方案治疗难治性非霍奇金淋巴瘤的疗效观察

 目的　观察以博安霉素为主的新方案治疗化疗后肿瘤反弹较快而骨髓造血功能较差的复发难治性非霍奇金淋巴瘤（NHL）患者的疗效和不良反应。方法　采用新组合的B-VIP方案[博安霉素8.73 mg静脉滴注第1、4、8、12、15天,长春新碱（VCR）2 mg静脉滴注第1、8、15天,异环磷酰胺（IFO）每天1.2 g／m2静脉滴注第1天至第3天、第15天至第17天,泼尼松50 mg口服第1天至第10天,21 d为1个疗程]治疗常规方案治疗无效或难以耐受的复发难治性NHL 6例,该组患者此前已用其他方案化疗平均8.3个周期。结果　6例均可评价疗效和不良反应,总有效4例,完全缓解（CR）1例,部分缓解（PR）3例。主要不良反应为骨髓抑制,其他不良反应较少。结论　B-VIP方案是常规方案治疗无效或难以耐受标准化疗而肿瘤进展较快的复发难治性NHL的有效方案,毒性较低,较为经济。     

Flexible chemotherapy regimen with gemcitabine and vinorelbine for metastatic nonsmall cell lung carcinoma: a phase II multicenter trial

BACKGROUND: This Phase II study evaluated a flexible 3- or 4-week dosing schedule of gemcitabine and vinorelbine to determine its effect on response rate and survival of patients with metastatic nonsmall cell lung carcinoma (NSCLC). METHODS: Thirty-four response-evaluable patients, 24 with performance status (PS) 0-1 and 10 with a PS of 2, 30 with Stage IV, and 4 with Stage IIIB NSCLC were treated with gemcitabine 1000 mg/m(2) intravenously and vinorelbine 25 mg/m(2) intravenously (first 15 patients) or 30 mg/m(2) intravenously (next 19 patients) on Days 1, 8, and 15 of a 4-week cycle, if on Day 15 neutrophils were > or = 1500/uL and platelets > or = 100,000/uL. If chemotherapy could not be administered on Day 15, then Day 22 became Day 1 of the next cycle. RESULTS: When vinorelbine 25 mg/m(2) was given with gemcitabine 1000 mg/m(2), 11 patients received 4-week cycles, 3 patients 3-week cycles, and 1 patient both 3- and 4-week cycles. With vinorelbine 30 mg/m(2) and gemcitabine 1000 mg/m(2), 7 patients received 4-week cycles, 2 patients 3-week cycles, and 10 patients both 3- and 4-week cycles. The partial response rate for 34 patients was 53% (18 patients). Median survival (MS) was 11.1 months, and 1-year survival 50% (17 patients). Patients with PS 0+1 had a MS of 17.5 months compared with patients with PS 2, who had MS of 3.3 months. Patients < 70 years of age had a MS of 18 months, and those >/= 70 years had a MS of 5.5 months. CONCLUSION: This flexible schedule with gemcitabine and vinorelbine enabled optimal dose delivery and suggested excellent efficacy but less toxicity than treatment with platinum regimens.     

Short-term outcome of neoadjuvant gemcitabine-carboplatin therapy for muscle-invasive bladder cancer

Twenty-three patients with muscle-invasive bladder cancer were treated with combination chemotherapy of gemcitabine and carboplatin. Gemcitabine at a dose of 800 mg/m2 by intravenous infusion for 30 minutes on Days 1, 8 and 15. Carboplatin at an AUC of 4, according to the Calvert formula, was administered by intravenous infusion for 3 hours on Day 2. The treatment was repeated every 21 days without drug-free-weeks for a total of 2 cycles. Six patients achieved a complete response(CR)and 8 patients achieved a partial response(PR). Overall response rate(CR+PR) was 60.8%. In addition, 7 patients achieved stable disease(SD), whereas 2 were found to have progressive disease (PD). Although Grade 3 or 4 leukocytopenia was seen in 10 patients(43.4%), low-grade toxicities of anemia, thrombocytopenia and nausea were seen in several patients, so it was possible to complete the treatment on schedule in all patients. Five SD patients died(4 by cancer and 1 by another cause), 2 PD patients were found to have disease progression, and 16 patients were alive without recurrence with a mean follow-up period of 12.6 months(range: 8-19).     

FND与CHOP方案治疗进展期惰性淋巴瘤的疗效比较

目的比较FND(氟达拉滨 米托蒽醌 地塞米松)与CHOP方案治疗进展期惰性淋巴瘤的疗效与安全性。方法临床观察的终点包括缓解率(总有效率OR和完全缓解率CR),无失败生存(FFS),总体生存(OS)及毒性。40例病人随机分组,FND和CHOP组各20例。两种治疗方案均为每28天1次,共3个疗程,之后,二组病人均采用CHOP方案巩固3个疗程。FND方案为氟达拉滨25mg/m2,ivd1~5;米托蒽醌10mg/m2,ivd1;地塞米松20mg/d,ivd1~5。CHOP方案为环磷酰胺600mg/m2,ivd1;阿霉素25mg/m2,ivd1;长春新碱1.4mg/m2,ivd1和强的松50mg/m2,pod1~5。结果FND方案的完全缓解率和总有效率显著优于CHOP(OR83%vs40%,CR50%vs15%;P<0.01)。FND组的中位FFS是32个月,而CHOP组仅为15个月。两种治疗方案的耐受性均较好,只有少量的感染并发症发生。结论FND方案的完全缓解率、总有效率均显著优于CHOP,并可有效改善预后。     

Cisplatin, dacarbazine, and fotemustine plus interferon alpha in patients with advanced malignant melanoma. A multicenter phase II study of the Italian Cooperative Oncology Group

BACKGROUND: In a previous study, the authors tested the combination of fotemustine (FM) 100 mg/m(2) intravenously (i.v.) on Day 1, dacarbazine (DTIC) 250 mg/m(2) i.v. on Days 2-5, and interferon alpha (IFNalpha) 3 MIU intramuscularly three times per week in 43 patients with advanced melanoma. An overall response rate of 40% and a median survival of 40 weeks were obtained. To evaluate whether the addition of cisplatin (CDDP) to this regimen could improve these results, the authors conducted a preliminary Phase I study and concluded that CDDP 25 mg/m(2) i.v. for 2 days can be combined safely with DTIC, FM, and IFNalpha. Herein, the authors report the results of a Phase II trial with this regimen. METHODS: From June 1996 to February 1999, 64 patients with metastatic melanoma who were not amenable to surgery were enrolled in this study. Sixty eligible patients (32 males and 28 females; median age, 53 years) were treated with a combination of FM 100 mg/m(2) i.v. on Day 1, DTIC 300 mg/m(2) i.v. on Days 2-4, and CDDP 25 mg/m(2) i.v. on Days 3 and 4 recycled every 3 weeks. IFN alpha2b was administered at a dose of 3 MIU intramuscularly 3 times per week until disease progression. RESULTS: A total of 189 courses were administered, with a median number of 3 courses per patient (range, 1-8 courses per patient). Eleven complete responses and 12 partial responses were observed, for an overall response rate of 38.3% (95% exact confidence interval, 26.1-51.8%). The median survival was 36 weeks. Neutropenia and thrombocytopenia affected 85% of patients and 68% patients and was World Health Organization Grade 3-4 in 40% and 50%, respectively. The side effects attributable to IFN alpha2b were mild and manageable. The other side effects were moderate and well controlled by supportive therapy. CONCLUSIONS: The schedule used in this study demonstrated significant activity in patients with advanced, untreated melanoma. The addition of CDDP in the management of the patients in this series seemed to increase significantly both the proportion of patients who achieved a complete response and the probability of long term survival compared with a previous series of patients who were treated by the authors. However, considering the currently available therapies, this regimen does not seem to offer a special advantage in the treatment of patients with this disease. New agents and new protocols are needed.     

Dose-escalated cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) chemotherapy for patients with diffuse lymphoma: Cancer and Leukemia Group B studies 8852 and 8854

BACKGROUND: To address the feasibility and outcome of moderate dose intensification with granulocyte-colony stimulating factor (G-CSF) for patients with aggressive non-Hodgkin lymphoma (NHL), the Cancer and Leukemia Group B (CALGB) conducted two studies evaluating dose-escalated cyclophosphamide and etoposide in the cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide (CHOPE) regimen. METHODS: Eligibility criteria included histologically documented, diffuse small cleaved, diffuse mixed, diffuse large cell, or immunoblastic lymphoma, Stage III--IV or bulky Stage II disease, and an ECOG performance status of 0--1. CALGB 8852, a group-wide study, accrued 227 patients: 120 patients in the pilot study to determine the maximum tolerated dose (MTD) without G-CSF and 107 in the pilot study of dose-escalated CHOPE with G-CSF. CALGB 8854, a limited-institution, Phase I study, enrolled 38 patients and determined the MTD of CHOPE with G-CSF to be used in CALGB 8852. The MTD in both studies was defined as the dose at which 50% of patients had 1) Grade 4 neutropenia or thrombocytopenia lasting 7 days or more, or 2) Grade 3--4 hemorrhage or nonhematologic toxicity (excluding alopecia, nausea, and emesis), or 3) were prevented from receiving 100% of drug on Day 22. RESULTS: The MTD of CHOPE without G-CSF was cyclophosphamide 1000 mg/m(2) on Day 1 and etoposide 100 mg/m(2) on Days 1--3 with doxorubicin 50 mg/m(2) on Day 1, vincristine 1.4 mg/m(2) (maximum, 2 mg) on Day 1, and prednisone 100 mg on Days 1--5. With the addition of G-CSF at 200 microg/m(2) on Days 5--19, the MTD was cyclophosphamide 1500 mg/m(2) and etoposide 160 mg/m(2) on Days 1-3 with standard doses of doxorubicin, vincristine, and prednisone. Increasing the dose of G-CSF from 200 microg/m(2) to 400 microg/m(2) did not allow for further dose escalation. The primary toxicity in all cohorts was neutropenia. Four toxic deaths occurred on CALGB 8852. The 5-year failure free survival (FFS) and overall survival (OS) rates for eligible patients on CALGB 8852 were 31% (95% confidence interval [95%CI], 23--39) and 48% (95%CI, 40--57), respectively. The 5-year FFS and OS rates for eligible patients on CALGB 8854 were 34% (95%CI, 17--52) and 51% (95%CI, 33--70), respectively. CONCLUSIONS: Moderate dose escalation with G-CSF is feasible. However, response and survival rates of patients who receive dose-escalated CHOPE, even with the addition of G-CSF, appear similar to the rates reported with standard-dose CHOP.     

Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas

BACKGROUND: Methotrexate-based and alkylator-based chemotherapy regimens are associated with renal and bone marrow toxicities, which limit their use in patients with central nervous system (CNS) lymphomas. The authors report their experience with an immunochemotherapy regimen consisting of rituximab and temozolomide in patients with primary or metastatic CNS lymphoma. METHODS: Seven patients who had received rituximab and temozolomide were identified from the database of the brain tumor clinic at the authors' institution: three patients had developed recurrent primary CNS lymphoma (PCNSL), one patient had newly diagnosed PCNSL but had poor renal function, and three other patients with systemic non-Hodgkin lymphoma developed recurrent lymphoma in the brain only. Patients were scheduled to receive 4 cycles of induction rituximab on Day 1 and temozolomide on Days 1-5 of a 28-day cycle. Thereafter, their treatment included a total of up to 8 maintenance cycles of temozolomide alone on Days 1-5 of a 28-day cycle. A gadolinium-enhanced magnetic resonance image of the head was obtained after every two cycles of treatment. RESULTS: All patients received rituximab without toxicity. Of the 4 patients who received induction temozolomide at doses > 150 mg/m(2) daily on Days 1-5, 2 experienced Grade 2 leukopenia and thrombocytopenia. Five patients achieved a radiographic complete response, and two patients had partial responses after induction treatment. The median response duration was 6 months (range 3-12+ months), and the median survival was 8 months (range 3+-12+ months). CONCLUSIONS: Although median survival was short, immunochemotherapy with rituximab and temozolomide was well tolerated and exhibited efficacy in this elderly and heavily pretreated cohort. The data obtained in the current study suggest that the optimal induction dose combination consists of rituximab 375 mg/m(2) on Day 1 and temozolomide 150 mg/m(2) daily on Days 1-5.     

A multicenter, randomized, Phase II study of cisplatin, etoposide, and gemcitabine or cisplatin plus gemcitabine as first-line treatment in patients with poor-prognosis small cell lung carcinoma

BACKGROUND: The objective of this study was to evaluate the activity and toxicity of combined cisplatin, etoposide, and gemcitabine (PEG) and combined cisplatin plus gemcitabine (PG) in previously untreated patients with extensive-stage and poor-prognosis limited-stage small-cell lung carcinoma. METHODS: One hundred forty patients (70 patients in two arms) were randomized to receive either cisplatin 70 mg/m2 on Day 1, etoposide 50 mg/m2 on Days 1-3, and gemcitabine 1000 mg/m2 on Days 1 and 8 or cisplatin 70 mg/m2 on Day 1 plus gemcitabine 1250 mg/m2 on Days 1 and 8. Both regimens were recycled every 21 days. RESULTS: In total, 626 cycles were delivered (303 cycles of PEG and 323 cycles of PG), with a median of 4 cycles per patient in both arms. The objective response rate was 63% (95% confidence interval [95%CI], 49-71%) for PEG and 57% (95%CI, 43-67%) for PG, with the suggestion of a higher complete response rate in the PEG arm (18.6% and 4.3%, respectively). A similar time to disease progression (6 months in the PEG arm and 7 months in the PG arm) and a similar median survival (9.5 months in the PEG arm and 10 months in the PG arm) were observed in both arms. The PEG regimen was associated with more severe hematologic toxicity in terms of neutropenia, febrile neutropenia, and a higher rate of treatment delays and dose reductions, whereas nonhematologic toxicities did not differ between the two arms. CONCLUSIONS: According to the results of this Phase II randomized trial, the PEG regimen produced a higher complete response rate but more toxicity compared with the PG regimen in patients with extensive-stage or poor-prognosis, limited-stage small cell lung carcinoma.     

Long-term follow-up of a randomized trial of fludarabine-mitoxantrone, compared with cyclophosphamide, doxorubicin, vindesine, prednisone (CHVP), as first-line treatment of elderly patients with advanced, low-grade non-Hodgkin's lymphoma before the era of monoclonal antibodies.

BACKGROUND: This randomized study compared the efficacy and safety of fludarabine-mitoxantrone (FM) with mini-CHVP (cyclophosphamide, doxorubicin, vindesine, prednisone) in elderly patients with advanced, low-grade non-Hodgkin's lymphoma. PATIENTS AND METHODS: End points were remission rates [overall response (OR) and complete response (CR)], failure-free survival (FFS), survival and toxicity. One hundred and fifty-five patients were randomized, 144 were evaluable for safety and 142 for response. Each treatment arm was given as six monthly cycles, followed by three bimonthly cycles. FM comprised fludarabine (20 mg/m(2) i.v.), days 1-5, plus mitoxantrone (10 mg/m(2) i.v.), day 1. CHVP cycles comprised cyclophosphamide (750 mg/m(2) i.v. infusion), doxorubicin (25 mg/m(2) i.v.) and vindesine (3 mg/m(2) i.v.) on day 1, and prednisone (50 mg/m(2)) on days 1-5. RESULTS: FM therapy resulted in superior remission rates (OR 81% versus 64%, CR 49% versus 17%; P = 0.0004). Median FFS for FM patients was 36 months, compared with 19 months for CHVP patients, and has not yet been reached for early CR patients at 53 months. Treatment arm was the major risk factor influencing survival. Both treatments were well tolerated, with only few infectious complications. CONCLUSION: FM was more effective than CHVP in achieving OR and CR, and favorably affected the outcome.     

Gemcitabine, dexamethasone, and cisplatin in patients with recurrent or refractory aggressive histology B-cell non-Hodgkin lymphoma: a Phase II study by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG)

BACKGROUND: Gemcitabine has been shown to have activity as a single agent in lymphoma and, when combined with cisplatin, is effective therapy for a number of solid tumors. The authors wished to determine the response rate and toxicity of gemcitabine, dexamethasone, and cisplatin for recurrent or refractory non-Hodgkin lymphoma (NHL). METHODS: Patients with recurrent or refractory diffuse large B-cell NHL or variants (REAL classification), measurable disease, and one previous chemotherapy regimen were eligible. Treatment consisted of gemcitabine 1000 mg/m(2) intravenously (i.v.) on Days 1 and 8, dexamethasone 40 mg orally on Days 1-4, and cisplatin 75 mg/m(2) i.v. on Day 1 (GDP), every 21 days as an outpatient. The primary end point was a response after two cycles. Patients could then proceed to stem cell transplantation (SCT) or receive up to six treatment cycles. RESULTS: Fifty-one eligible patients were evaluable for toxicity and response. The median age of the patients was 57 years (range, 18-84 years) and most had diffuse large-cell lymphoma. After 2 cycles, there were 8 complete responses (CR; 16%) and 17 partial responses (PR; 33%). There was an overall response rate (RR) of 49% (95% confidence interval = 37-63%). The RR afer completion of all protocol chemotherapy (including those who received > 2 cycles of GDP) was 53% (11 CR, 16 PR). Grade 3 and 4 neutropenia occurred in 33% and 39% of patients, respectively. Grade 3 and 4 thrombocytopenia occurred in 24% and 4% of patients, respectively. Seven patients (14%) experienced febrile neutropenia. Of the 35 patients < 66 years, 22 (63%) proceeded to SCT. CONCLUSIONS: GDP is an active regimen in B-cell NHL and can be administered with acceptable toxicity to outpatients. A Phase III trial comparing GDP with standard cisplatin-based chemotherapy is now ongoing through the National Cancer Institute of Canada Clinical Trials Group.     

Antitumor activity of recombinant-derived interferon alpha in metastatic renal cell carcinoma

Fifty-six patients with metastatic renal cell carcinoma (RCC) were treated with recombinant DNA-derived interferon alpha (rIFN alpha A). The first 30 patients were randomized between doses of 2 X 10(6) U/m2 and 20 X 10(6) U/m2 intramuscularly daily. No complete (CR) or partial (PR) remissions were achieved in 15 patients receiving the low dose. In contrast, 27% of those receiving the high dose achieved CR or PR. Subsequently, 26 additional patients were given the high dose and achieved a 31% response rate. Remissions lasted from 1 to more than 12 months (median, 3 months). Responses occurred predominantly in lung parenchyma or mediastinal node metastases. Toxicity of the high dose required dose reduction in 50% of the patients. Neutralizing antibodies to rIFN alpha A developed in seven of 12 responsive (58%) and nine of 29 (31%) nonresponsive patients (P = greater than .5). The median duration of remission among the antibody-positive and antibody-negative patients were 2 and 10 months, respectively (P = .009). The clinical significance of the antibodies to rIFN alpha A remains unclear, but the coincidence between the detection of antibodies and the early relapse of the disease in some responsive patients suggests that these antibodies may abrogate the biologic activity of rIFN alpha A. This effect, however, was not associated with adverse clinical sequelae.     

Combination therapy with methotrexate, vincristine, polyethylene-glycol conjugated-asparaginase, and prednisone in the treatment of patients with refractory or recurrent acute lymphoblastic leukemia.

BACKGROUND: L-asparaginase in combination with methotrexate has synergistic antileukemic activity in a schedule-dependent fashion. A new preparation of L-asparaginase, polyethylene-glycol conjugated (PEG)-asparaginase, is a pharmacologically different formulation of L-asparaginase with distinct properties including a longer half-life and less immunogenic properties. METHODS: Patients with refractory or recurrent acute lymphoblastic leukemia (ALL) were treated with a combination of methotrexate (MTX), vincristine, PEG-asparaginase, and prednisone (MOAP). The treatment was comprised of MTX, 100 mg/m(2) intravenously (i.v.), over 15 minutes on Days 1 and 14; PEG-asparaginase, 2500 IU/m(2), with a maximum dose of 3750 IU i.v. approximately 4-6 hours after MTX on Days 1 and 14; vincristine, 1.4 mg/m(2) (maximum dose, 2 mg) i.v., over 15 minutes on Days 1, 7, and 14; and prednisone, 200 mg daily orally, on Days 1-5 and 14-19. RESULTS: Thirty-two patients with a median age of 34 years (range, 20-74 years) were treated. Eight patients (25%) had ALL that was refractory to prior therapy and 24 patients (75%) had recurrent disease. Seven patients (22%) achieved a complete remission (CR). Five patients (16%) died early due to infections. Features associated with a poor response were high pretreatment lactate dehydrogenase levels and Philadelphia chromosome positive disease. The median duration of CR was 16 weeks and the overall median survival after MOAP therapy was 12 weeks. Anaphylactic reactions were not observed during MOAP combination therapy. CONCLUSIONS: MOAP is an active regimen in patients with refractory or recurrent ALL. This regimen is well tolerated and is not associated with allergic reactions. However, further studies regarding the pharmacologic interaction of MTX with PEG-asparaginase are needed to optimize this regimen.     

Phase II trial of irinotecan and cisplatin with early concurrent radiotherapy in limited-disease small-cell lung cancer

BACKGROUND: A Phase II trial of irinotecan and cisplatin (IP) with early concurrent radiotherapy was performed in limited-disease small-cell lung cancer (LD-SCLC) to evaluate the efficacy and toxicity. METHODS: For untreated LD-SCLC patients, irinotecan (60 mg/m2, Days 1, 8, and 15) and cisplatin (40 mg/m2, Days 1 and 8) were repeated every 4 weeks for a maximum of 6 cycles. Thoracic radiotherapy of 1.8 Gy/day was begun on Day 1 of the second chemotherapy cycle, up to a total of 45 to 54 Gy. Prophylactic cranial irradiation (30 Gy in 10 fractions) was performed on patients with a complete response (CR). RESULTS: Thirty-three LD-SCLC patients were enrolled. The median age was 60 years and 31 patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Twelve (36.4%) patients had N3 disease. The response rate was 87.9%, with a CR rate of 45.5%. At a median follow-up period of 27 months the median progression-free survival (PFS) and overall survival (OS) were 14.4 and 26.1 months, respectively, with 2-year PFS and OS rates of 26.8% and 54.9%. The dominating toxicity was neutropenia, with grade 3-5 of 81.8%. The most common grade 3-5 nonhematologic toxicities were diarrhea (21.2%), anorexia (21.2%), and fatigue (21.2%). Grade 3-5 radiation esophagitis and pneumonitis occurred in 18.2% and 9.1% of patients, respectively. There were 2 treatment-related deaths from sepsis and radiation pneumonitis. CONCLUSIONS: IP with early concurrent radiotherapy was effective and tolerable in untreated LD-SCLC.