High-dose chemotherapy with carboplatin, etoposide and ifosfamide followed by autologous stem cell rescue in patients with relapsed or refractory malignant lymphomas: a phase I/II study

Patients with relapsed or refractory non-Hodgkin's lymphomas (NHL) and Hodgkin's disease (HD) with recurrences after an anthracyclin-containing regimen only have a chance of cure of below 10% with conventional chemotherapy. In order to improve their prognosis, we started a phase I/II trial using high-dose therapy comprising carboplatin, together with etoposide and ifosfamide (CEI), followed by autologous stem cell rescue (ASCR) as consolidation after salvage treatment. Since September 1990, 40 patients with intensively pretreated advanced NHL (n = 24) or HD (n = 16) received one cycle of high-dose therapy (HDT) consisting of carboplatin 1500 mg/m2, ifosfamide 10 g/m2 and etoposide in escalating doses from 1200 mg/m2 to 2400 mg/m2 followed by ASCR. Thirty-nine patients were assessable for toxicity and response. The following doses appeared to be safe: carboplatin 1500 mg/m2, etoposide 2400 mg/m2 and ifosfamide 10 g/m2. All patients developed grade 3 nausea and grade 3 or 4 mucositis. Granulocytopenic fever occurred in 100% with grade 4 infections in 15%. Mild transient kidney toxicity was noted in 36% and liver toxicity in 20% of patients. One toxic death occurred (2.5%). Objective responses were obtained in 36 of 39 patients (92%) with complete remissions (CR) in 24 patients (61.5%) and partial remissions (PR) in 12 (30.7%). Median observation time for surviving patients was 23.3 months (range 3.4-52.3). The probabilities of overall, event-free and relapse-free survival at 2 years are 62, 39 and 55%, respectively. Patients with primary refractory disease or resistant relapse had a poor prognosis. High-dose carboplatin, etoposide and ifosfamide plus autologous stem cell rescue represents an effective, potentially curative salvage treatment with acceptable toxicities.     

DIZE (dexamethasone, idarubicin, and continuous infusion of ifosfamide and etoposide): an effective and well-tolerated new regimen for patients with relapsed lymphoma

We performed a phase II study of dexamethasone, ifosfamide, idarubicin and etoposide (DIZE) in patients with relapsed or refractory Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL). The regimen consisted of dexamethasone (20 mg i.v. days 1-4), idarubicin (8 mg/m2 i.v. days 1+2), continuous infusion (c.i.) of ifosfamide (1,000 mg/m2 days 1-4), and c.i. etoposide (60 mg/m2 days 1-4). G-CSF (5 microg/kg) was used to support neutrophil recovery from day 5. In older patients (> 60 years) the dosage of idarubicin and ifosfamide was reduced to 75% in the initial cycle. Fourty six patients (pts) were treated with a total of 131 cycles. Sixteen pts were primary resistant and 30 were relapsed. Median age was 54.3 years (range 22-75). The median number of different prior chemotherapies was 1.7 (range 1 to 5). 31/46 (67.4%) pts had advanced disease (stage III or IV); 19/46 had B symptoms. Of 43 evaluable pts the response rate was 58.1% including 11 complete remissions (CR) and 14 partial remissions (PR). Mean duration of response was 8 months (1-30+). DIZE was more effective in relapsed than in refractory high-grade NHL (74 % vs 16.6%; p < 0.001). Of four heavily pretreated pts with HL, one obtained CR and two PR (response rate 75%). Myelosuppression was generally moderate with a mean duration of leukocytopenia < 1,000/microl of 2.5 days (range 0-18) and of thrombocytopenia < 25,000/microl 1.5 days (range 0-17). One patient died of uncontrollable infection in treatment related neutropenia. No other serious toxicities apart from alopecia were observed. We conclude that DIZE is safe and effective in heavily pretreated pts with relapsed lymphoma. The continuous infusion of cytostatic drugs such as that used in the new DIZE protocol might reduce hematotoxicity.     

Laparoscopic needle colposuspension for genuine stress incontinence

Twenty patients with relapsed or refractory non-Hodgkin's lymphoma were treated with high-dose chlorambucil (14 mg/m2 every 6 hours for 6 doses) and dexamethasone (40 mg/day for 5 days). There was a 45% response rate with 17% complete responses. The median duration of complete response was 7 months. The regimen was well tolerated and had minimal toxicity.     

Thought control strategies in acute stress disorder

Relapse after transplant for malignant lymphomas remains the main cause of treatment failure. Most conditioning regimens contain total body irradiation (TBI). We investigated the toxicity and efficacy of an intensified chemotherapy conditioning regimen without TBI in patients with relapsed or high-risk malignant lymphoma who had received prior radiation therapy and were therefore not eligible for TBI. Twenty patients with a median age of 38 (18-56) and relapsed or high-risk malignant non-Hodgkin's lymphoma (NHL, n = 16) or Hodgkin's disease (HD, n = 4) underwent high-dose chemotherapy consisting of busulfan (16 mg/kg), cyclophosphamide (120 mg/kg) and etoposide 30 mg/kg (n = 8) or 45 mg/kg (n = 12) followed by peripheral stem cell support (n = 14), autologous bone marrow (n = 3), allogeneic (n = 2) or syngeneic (n = 1) transplantation. All but two had chemosensitive disease before high-dose chemotherapy. The main toxicity -- according to the Bearman score -- was mucositis II in 18 (90%) patients; five patients (25%) suffered a grade I hepatic toxicity. GI toxicity I occurred in three (15%) and renal toxicity I in two patients (10%). Sixty percent of the patients developed transient dermatitis with erythema and three of them (15%) had skin desquamation; one patient experienced asymptomatic pancreatitis. Toxicity was slightly higher in patients treated with 45 mg/kg etoposide. One patient (5%) died of treatment-related venoocclusive disease. After a median follow-up of 50 months (24-84) the disease-free and overall survival were 50% and 55%. One of the nine relapsing patients developed secondary AML 18 months after transplant. High-dose busulfan, cyclophosphamide and etoposide is an effective regimen resulting in long-term disease-free survival in 50% of patients with relapsed malignant lymphoma and prior radiation therapy. The toxicity is moderate with a low treatment-related mortality (5%).     

Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide, and autologous hematopoietic stem cell support

Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7. Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Granulocyte colony-stimulating factor was administered following reinfusion until the granulocytes recovered to > 1000/microliter. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients. Four dose levels of etanidazole between 3 and 5.5 g/m2/day (12, 16, 20, and 22 g/m2 total doses) and two doses of carboplatin (1600 and 1800 mg/m2 total doses) were evaluated. Seven patients died of organ toxicity (13%); two each from veno-occlusive disease of liver and sepsis; and one each from sudden death, renal failure, and refractory thrombocytopenic hemorrhage. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated. Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: severe cramping myalgic/neuralgic pain, predominantly in stocking glove distribution, occurring between day -3 and day 0, and a sensory peripheral neuropathy with similar distribution peaking around day +60. The maximal achievable dose of etanidazole (16 g/m2 dose level) resulted in a mean serum level of 38 micrograms/ml (25-55 micrograms/ml). Etanidazole significantly enhanced host toxicity of high-dose ICE. Effective modulatory doses of etanidazole could not be given with acceptable toxicity using this schedule.     

Paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of small-cell lung cancer: comparison of sequential phase II trials using different dose-intensities

PURPOSE: In two sequential phase II studies, we evaluate the feasibility and efficacy of adding paclitaxel to a standard platinum/etoposide regimen in the first-line treatment of small-cell lung cancer. PATIENTS AND METHODS: One hundred seventeen patients with small-cell lung cancer were treated between June 1993 and July 1996. The first 38 patients received a lower-dose regimen: paclitaxel 135 mg/m2 by 1-hour infusion, carboplatin at an area under the concentration-time curve (AUC) of 5.0, and etoposide 50 mg alternating with 100 mg orally on days 1 to 10. When only mild myelosuppression was observed, doses of paclitaxel and carboplatin were increased in the subsequent 79 patients (paclitaxel 200 mg/m2 by 1-hour infusion and carboplatin at an AUC of 6.0). All patients received four courses of treatment, administered at 21-day intervals. Patients with limited-stage small-cell lung cancer also received thoracic radiation therapy (1.8 Gy/d; total dose, 45 Gy) administered concurrently with courses 3 and 4 of chemotherapy. RESULTS: Seventy-two of 79 patients (91%) who receive the higher-dose regimen had major responses. Thirty-two of 38 (84%) with extensive-stage disease responded (21% complete response rate); median survival was 10 months for this group. With limited-stage disease, the overall response rate was 98%, with 71% complete responses; the median survival time has not been reached at 16 months. Median survival in extensive-stage patients was longer in patients who received the higher-dose regimen (10 months) than in the previous group treated with lower doses (7 months; P = .008). The higher-dose regimen was well tolerated, with myelosuppression being the major toxicity. Compared with the lower-dose regimen, grade 3/4 neutropenia increased from 8% to 38% of courses, but the incidence of hospitalization for neutropenia and fever did not increase. Other nonhematologic toxicities were uncommon, and did not increase substantially with the higher-dose regimen. CONCLUSION: Paclitaxel can be added at full dose (200 mg/m2) to a carboplatin/etoposide combination while maintaining a tolerable toxicity profile. Median survival times in both extensive- and limited-stage patients compare favorably with other reported regimens. This regimen merits further investigation, and a randomized trial to compare this regimen with a standard carboplatin/etoposide combination is underway.     

High dose chemotherapy in metastatic carcinoma of the breast

PURPOSE: To verify tolerance and clinical efficacy of high-dose chemotherapy (HDCT) in metastatic breast cancer (MBC). PATIENTS AND METHODS: We submitted to HDCT with autologous peripheral blood cells transplant 66 patients, with MBC responding to induction chemotherapy. The condizioning regimen was ICE: iphosphamide 3.3 g/m2 dd. -8/-6, carboplatin 450 mg/m2 plus etoposide 400 mg/m2 dd. -5/-3 (21 patients = 78%); CTM: cyclophosphamide 100 mg/kg dd. -4/-3, tyothepa 500 mg:m2 d.-5, mytoxantrone 40 mg/m2 d. -6 (6 patients, 22%). RESULTS: Median number of aphereses was 2 (range 1-5), median amount of CD34+ cells/kg bw of 10 x 10E6 (range 3.5-38.2). Median recovery time was 10th day for PMN (range 8-37) while for platelets it was 9th day (range 8-37): total hospital stay was of 24 days (range 22-48). After induction therapy we had PR in 13/27 metastatic patients (48%) and CR in 14/27 (52%). After conditioning treatment we had PR in 12/27 (44%) and CR in 15/27 (56%). Median time to progression was 19 months (range 7-38) and median survival 52 months (range 7-59+), with 30% surviving beyond 4 years. CONCLUSIONS: Feasibility of HDCT in advanced breast cancer seems verified. The promising results need to be confirmed.     

Combined irradiation and chemotherapy using ifosfamide, cisplatin, and etoposide for children with medulloblastoma/posterior fossa primitive neuroectodermal tumor--results of a pilot study

Ten children with newly diagnosed medulloblastoma/primitive neuroectodermal tumor of the posterior fossa were treated with total surgical resection, radiation therapy, and ICE chemotherapy regimen with ifosfamide (900 mg/m2, days 1-5), cisplatin (20 mg/m2, days 1-5), and etoposide (60 mg/m2, days 1-5) every 4 weeks for eight cycles. Four children under 2 years old were at first treated with eight cycles of ICE chemotherapy, and then irradiated. The ICE regimen was well tolerated by all children, with no irreversible adverse effects. However, dose reductions during the eight cycles were inevitable mainly due to myelosuppression. Complete remissions were achieved in eight of 10 patients at 1 month after completion of the treatment. One child showed recurrence 21 months after complete remission. The disease-free survival rate was 70% with a mean observation period of 24 months after surgery. The ICE regimen is a useful treatment modality for children with medulloblastoma. Further study is warranted to clarify long-term outcome in a number of patients.     

Peripheral blood progenitor cell mobilization with Dexa-Beam/G-CSF, ether lipid purging, and autologous transplantation after high-dose CBV treatment: a safe and effective regimen in patients with poor risk malignant lymphomas

High-dose chemotherapy followed by autologous peripheral blood progenitor cell transplantation (PBPCT) is increasingly applied in patients with relapsed, poor risk malignant lymphomas. Different strategies for progenitor cell mobilization using cytoreductive chemotherapy, hematopoietic growth factors, or both have been described. We studied the safety and efficacy of a modified DexaBEAM regimen (dexamethasone, BCNU [carmustine], etoposide, ara-C, melphalan) followed by granulocyte-colony stimulating factor (G-CSF) that was administered in order to minimize any residual disease and to obtain a sufficient amount of progenitor cells in the autografts. Until now, 16 patients at poor risk (8 with Hodgkin's disease, 8 with non-Hodgkin's lymphoma) entered the study. All the 12 patients with measurable disease at study entry responded to DexaBEAM. Median time of subsequent leukopenia (leukocytes < 1.000/microL) was 6 days (range 5-8 days). Peak numbers of CD34+ hematopoietic progenitor cells appeared in the peripheral blood after a median of 20 days (range 18-22 days) after onset of therapy. At that time, peripheral mononuclear cells were collected for autografting. Thereafter, the leukapheresis products were frozen until the day of transplantation, either unpurged in the case of Hodgkin's disease or purged with the ether lipid edelfosine in cases of non-Hodgkin's lymphoma. After high-dose chemotherapy with the CBV regimen (cyclophosphamide, BCNU, etoposide) the patients received their autografts, followed again by G-CSF treatment. A stable hematopoietic recovery was reached with granulocytes > 2.000/muL within 11 days (range 8-17 days), and platelets > 50.000/microL within 15 days (range 10-31 days), respectively, without significant differences between the purged and unpurged transplants. After a median follow-up of 28 months (range 1-40 months) 7 patients are alive without signs of recurrent disease, while 1 patient has died due to acute treatment related toxicity. Three patients had refractory disease, and 5 have relapsed of whom 4 have died. In summary, the DexaBEAM/G-CSF/CBV strategy appears to be safe and effective for salvage treatment in patients with poor risk malignant lymphomas.     

Combination phase I/II study of irinotecan hydrochloride (CPT-11) and carboplatin in relapsed or refractory non-Hodgkin's lymphoma. CPT-11/Lymphoma Study Group

Irinotecan hydrochloride (CPT-11) is a new derivative of camptothecin which inhibits topoisomerase I. Phase II studies have demonstrated that CPT-11 is active against a broad spectrum of neoplasms including intractable non-Hodgkin's lymphoma. An early phase II study in lymphoma suggested that a schedule of daily infusions of 40 mg/m2/day for three or five consecutive days is more effective than a single infusion of 200 mg/m2 every three to four weeks. Carboplatin is also an active agent against lymphoma, and preclinical studies have shown that CPT-11 and its active metabolite have a synergistic effect with platinum compounds. To evaluate the maximal tolerated dose (MTD) and the therapeutic efficacy of CPT-11 in combination with carboplatin in relapsed or refractory non-Hodgkin's lymphoma, we conducted a combination phase I/II study. The starting dose of CPT-11 was 20 mg/m2/day (days 1 through 3 and 8 through 10), and dose escalations of 5 mg/m2/day increments were planned, with a fixed dose of carboplatin (300 mg/m2, day 1). Six of the eight patients receiving both agents at the starting dose level developed critical toxicities such as grade 4 hematologic (neutropenia 6/8, thrombocytopenia 1/8) and grade 3 non-hematologic toxicities (diarrhea 2/8, transaminase elevation 1/8). Further dose escalation of CPT-11 was halted, and the starting doses were judged to be the MTDs. The response rate (25%, 2/8) to the combination of the MTDs was not superior to that of CPT-11 alone in a previous phase II study (38%, 26/69), and the MTD of CPT-11 in combination with carboplatin was less than half the single-agent dose. We conclude that carboplatin is not recommendable for combination with CPT-11 in lymphoma patients. Other suitable agents for such a combination should be sought.     

Methylguazone, vindesine and cisplatin for the treatment of patients with relapsed or refractory malignant lymphoma: an Eastern Cooperative Oncology Group Study (PA482)

A new regimen not cross-resistant with standard regimens was developed for patients with relapsed or refractory Hodgkin's disease and non-Hodgkin's lymphoma. The regimen consisted of cisplatin, 70 mg/M2 given intravenously on day 1, vindesine, 3 mg/M2 given intravenously on days 1 and 8 (and also on day 15 of the first cycle only), and methylguazone, 600 mg/M2 given intravenously on days 8 and 15. Courses were repeated every 21 days. Thirty-nine patients (35 with non-Hodgkin's and 4 with Hodgkin's lymphoma) were treated and all were evaluable for response and toxicity. There were 5 complete and 14 partial responses for a total response rate of 49% (C.I. = 35%-63%). The median durations of partial and complete response were only 2.8 and 4.2 months, respectively. Only one patient remained in complete response for more than a year. There was one treatment-related death from renal failure on the study. Although this regimen was, in general. well tolerated the results are disappointing and seem no better than those obtained with many other salvage regimens for lymphoma.     

Advances in antiviral therapy

The maximum tolerated dose (MTD) of etoposide and carboplatin without growth factor support was previously defined by Cancer and Leukemia Group B (CALGB) as 200 and 125 mg/m2/day x 3, respectively, given every 28 days to previously untreated patients who have extensive, small-cell lung cancer (SCLC). Myelosuppression was dose-limiting. The purpose of this phase I trial was to determine if granulocyte macrophage colony-stimulating factor (GM-CSF) support allows the dosage of the combination of etoposide and carboplatin to be increased above the previously determined MTD. In this CALGB study of 44 evaluable patients with performance status 0-2, cohorts were treated with etoposide and carboplatin given intravenously on days 1-3 followed by GM-CSF (molgramostim) given subcutaneously on days 4-18. Four dose levels of bacteria-derived recombinant GM-CSF (5, 10, 20 microg/kg/day and 5 microg/kg every 12 h), three dose levels of etoposide (200, 250, and 300 mg/m2/day x 3), and two dose levels of carboplatin (125 and 150 mg/m2/day x 3) were evaluated. There was no chemotherapy dose escalation in individual patients. With 5 microg/kg/d GM-CSF, the first etoposide and carboplatin cycle of 300 and 150 mg/m2/day x 3, respectively, could be administered with acceptable toxicity. However, GM-CSF did not allow repeated administration of this dose-escalated regimen every 21 days, since delayed platelet and/or neutrophil recovery was dose limiting in later cycles. These results demonstrate that GM-CSF alone has limited capability to support the repeated administration of high doses of etoposide and carboplatin. CALGB currently is testing the ability of interleukin (IL)-6 given with GM-CSF to ameliorate the cumulative myelosuppression of this intense regimen.     

Drug resistance patterns among tuberculosis patients in Rome, 1990-1992

PURPOSE: A Phase II study to evaluate the effect of a five-drug regimen, VP-16, ifosfamide, cisplatin, vinblastine, and bleomycin (VIP/VB) on complete response rate, continuous disease-free survival, and toxicity in patients with advanced germ-cell tumor. PATIENTS AND METHODS: Twenty male patients with a histologic diagnosis of advanced-stage germ-cell cancer, previously untreated with chemotherapy, received the following: etoposide 75 mg/m2 i.v. days 1-5; ifosfamide (with mesna uroprotection) 1.2 g/m2 i.v. days 1-5; cisplatin 20 mg/m2 i.v. days 1-5; vinblastine 0.18 mg/kg i.v. day 1; bleomycin 30 units i.v. day 1; filgrastim 5 micrograms/kg days 7-16. Chemotherapy was given every 3 weeks (bleomycin weekly x 12) for four courses. RESULTS: All patients entered were evaluable for toxicity, response, and survival. Eleven of 20 (55%) achieved complete remissions with chemotherapy alone and an additional 5 (25%) were rendered disease-free with surgical resection of teratoma (3) or viable cancer (2). Two patients relapsed at 4 and 5 months from complete remission (CR). There was one treatment-related death, from bleomycin lung toxicity after thoracotomy. Thirteen patients (65%) are alive and continuously free of disease, with a median follow-up of 20 months and a minimal follow-up of 12 months. Hematologic toxicity was most common, with 16 patients (80%) having grade 3 or 4 leukopenia. CONCLUSIONS: VIP/VB appears to be a very active regimen in advanced disseminated germ-cell cancer. Hematological toxicity was severe but manageable.     

Two cases of relapse or refractory germ cell tumor who had been treated with combination chemotherapy of cisplatin and carboplatin

We tried a combination chemotherapy with cisplatin (CDDP) and carboplatin (CBDCA) (CDDP/CBDCA regimen) as salvage therapy for 2 cases with recurrent or refractory Germ Cell Tumor (GCT). Case 1 was a 29-year-old man with 2nd relapsed embryonal carcinoma and seminoma originating from testis. Case 2 was a 23-year-old man with primary refractory embryonal carcinoma and yolk sac tumor originating from mediastinum. CDDP and CBDCA were administered at the dose of 120 mg/m2 and 350 mg/m2 on day 1, and vinblastin was administered at the dose of 10 mg/body on day 2. In one of two cases, a complete response was obtained. Non-hematologic toxicity of CDDP/CBDCA regimen was tolerable. It is suggested that this combination chemotherapy is useful for GCT recurrence.     

Paclitaxel plus high-dose cyclophosphamide with G-CSF support in patients with relapsed and refractory aggressive non-Hodgkin's lymphoma

Based on the single-agent activity of both paclitaxel and cyclophosphamide in the treatment of non-Hodgkin's lymphoma (NHL), we conducted a phase II study to evaluate the efficacy of the combination of the two drugs in patients with refractory and relapsed aggressive NHL. All patients received 900 mg/m2 bolus of cyclophosphamide intravenously daily for 3 consecutive days with a concurrent infusion of 150 mg/m2 of paclitaxel over 72 h (50 mg/m2/d). 24 h after the completion of chemotherapy, patients received subcutaneous injections of 5 microg/kg of granulocyte-colony stimulating factor (G-CSF) daily until white cell count recovery. Treatment was repeated every 3 weeks. Patients who had at least a partial response (PR) after two courses continued to receive a maximum of four courses. Patients with responding disease were allowed to undergo high-dose chemotherapy followed by stem-cell/bone marrow transplantation if they were eligible. Of the 77 patients who were eligible for the study, 74 (96%) were evaluable for toxicity and treatment response. The overall response rate was 45% (95% CI 33-57%). Patients who received treatment after their disease relapsed from a complete response (CR) had an 81% response rate (38% CRs), whereas those with primary refractory disease had a 22% response rate. Toxicities of > grade 2 included alopecia (100%) and stomatitis (25%). Neutropenic fever of grade > 2 occurred after 18% of the courses, and platelet count of < or = 20 x 10(9)/l developed after 20% of the courses. Thus, the combination of paclitaxel plus high-dose cyclophosphamide is an effective new regimen in the treatment of refractory and relapsed NHL.     

Effect of prostaglandin A1 on proliferation and telomerase activity of human melanoma cells in vitro

BACKGROUND AND OBJECTIVE: Idarubicin, an anthracycline analogue, is active in non-Hodgkin's lymphoma. This study evaluates the efficacy and toxicity of a combination of idarubicin, etoposide and intermediate-dose cytarabine (IVA) in unfavorable lymphoma in relapse or resistant to prior doxorubicin- or novantrone-based regimens. DESIGN AND METHODS: Thirty patients with relapsing or resistant unfavorable lymphoma received a combination of idarubicin 12 mg/m2 i.v. on day 1, etoposide 60 mg/m2 i.v. every 12 hours for 3 days, and Ara-C 1 g/m2 i.v. every 12 hours for 3 days (3-hour infusion). Median age was 39 years (range: 22-60). All patients had been given prior doxorubicin or novantrone; 54% of them had received 2 or more chemotherapy regimens; 67% of total were in clinical relapse (30% in their second relapse), and 23% had resistant disease. RESULTS: The overall response rate to IVA was 60% (18 of 30 patients). Complete remission rate was 20% (6 of 30) in the whole group, 45% (5 of 11) among patients in their first relapse. Remission median duration was 9 months (range: 1-18), with a 3-year relapse-free and overall survival of 20% and 15%, respectively. Severe neutropenia occurred in 13 patients (43%) and severe thrombocytopenia in 11 patients (37%), with a median duration of 9 and 13 days, respectively. No cardiac toxicity developed; sepsis during neutropenia was documented in four instances and two patients (7%) died of therapy-related events (septic shock). INTERPRETATION AND CONCLUSIONS: Idarubicin combined with etoposide and intermediate-dose cytarabine proved to be an active salvage therapy in unfavorable lymphoma given prior doxorubicin or novantrone; the best results were obtained among patients in their first relapse, with low tumor burden.     

The value of pre-operative lymphoscintigraphy in breast cancer treatment

Three patients (aged 68-75 years) with histologically confirmed relapsed or refractory high-grade non-Hodgkin's lymphoma were entered in this pilot study in which gemcitabine 800 mg/m2 was given as a 30 min i.v. infusion once a week for 3 weeks. One patient responded with complete remission and the other two with partial remission and stable disease for 2 and 3 months, respectively. Haematological toxicity was modest with grade 4 leucopenia (one cycle) and grade 4 thrombocytopenia (two cycles). The activity and mild toxicity seen with gemcitabine suggest that this agent should be further evaluated in the treatment of high-grade non-Hodgkin's lymphoma.     

Unexpected hepatotoxicities in patients with non-Hodgkin's lymphoma treated with irinotecan (CPT-11) and etoposide

BACKGROUND: Irinotecan (CPT-11) is a topoisomerase I inhibitor that has been confirmed to be active against a broad spectrum of neoplasms including non-Hodgkin's lymphoma (NHL). Because the combination of topoisomerase I and II inhibitors seemed to be an attractive therapeutic strategy owing to their complementary functions, we conducted a combination phase I study of CPT-11 and etoposide, a topoisomerase II inhibitor, in relapsed or refractory non-Hodgkin's lymphoma (NHL). METHODS: The starting doses of CPT-11 and etoposide were 30 mg/m2/day (days 1-3 and 8-10) and 40 mg/m2 (days 1-3), respectively. RESULTS: All three patients who received the starting dose developed dose-limiting toxicities including one case of grade 4 neutropenia lasting for > 7 days, one of grade 3 serum transaminase elevation and one of grade 3 hyperbilirubinemia. All three patients presented hepatotoxicity > or = grade 2. The starting dose level was judged to be the maximum tolerated dose (MTD) and further dose escalation of this combination was halted. The patient who developed grade 3 hyperbilirubinemia presented a second peak of plasma SN-38, an active metabolite of CPT-11, on the concentration-time curve for day 3, suggesting the possibility of the enterohepatic circulation of SN-38 and of a drug-to-drug interaction. No durable objective response was observed in the three patients treated at the starting dose. CONCLUSIONS: We conclude that etoposide is not recommended for combination with CPT-11 in NHL patients because of unexpected frequent hepatotoxicities.     

A better therapeutic profile for the combination of mitomycin-C, ifosfamide and cisplatin (MIC) in advanced non-small-cell lung cancer: a useful dose-schedule modification

BACKGROUND: In our previous experience with chemotherapy for non-small-cell lung cancer (NSCLC) the combination of mitomycin, ifosfamide and cisplatin (MIC) showed the highest activity in a three-arm randomized trial; the MIC regimen also yielded the most toxic effects, with 8% WHO grade 2-4 nephrotoxicity, 21% grade 3-4 leukopenia and 10% grade 3-4 thrombocytopenia. In that study cisplatin (120 mg/m2) was delivered on day 1 and ifosfamide and mitomycin on day 2. In an effort to reduce MIC toxicity a modified regimen was tested in a phase II trial: cisplatin 100 mg/m2 was given on day 2 and ifosfamide on day 1 with mitomycin. PATIENTS AND METHODS: From November 1993 to December 1995, 70 advanced NSCLC patients entered the trial. RESULTS: Twenty-nine of 70 patients achieved major response (41%) with 6 complete (9%) and 23 partial remissions (33%). We recorded 4% of WHO grade 3-4 anemia, and 2% of leukopenia and thrombocytopenia. CONCLUSION: We confirmed the activity of the MIC regimen in NSCLC, and the modified schedule seems to substantially improve the safety of the combination.     

EPOCH方案治疗老年人外周T细胞淋巴瘤的临床研究

目的 评价EPOCH方案治疗老年外周T细胞淋巴瘤( PTCL)患者的临床疗效和不良反应.方法 对经病理确诊为PTCL老年患者28例,采用EPOCH方案治疗:依托泊苷50 mg/m2、表柔比星12mg/m2、长春新碱0.4mg/m2溶解于0.9%NaCl溶液持续静脉滴注,第1天至第4天;环磷酰胺750 mg/m2静脉滴注,第5天;泼尼松60 mg/m2口服,第1天至第5天,每21 d为1个疗程.依据WHO标准进行疗效和安全性分析和评估.结果 28例患者共完成85个疗程EPOCH方案化疗,中位化疗2个疗程,完全缓解(CR)15例,部分缓解(PR)5例,总有效(OR)率71.4%(20/28),总体平均生存时间20个月.初治患者CR率64.7%(11/17),PR率23.5%(4/17),OR率88.2%(15/17),明显高于诱导化疗失败的难治性患者[分别为36.4%(4/11)、9.1%(1/11)和45.5%(5/11)].两组OR率比较差异有统计学意义(λ2=5.99,P＜0.05),且初治患者平均生存时间长于难治性患者(24个月与13个月).EPOCH方案化疗的主要毒副作用为骨髓抑制,其中Ⅲ～Ⅳ度粒细胞和血小板减少的发生率分别为53.6%(15/28)和50.0%(14/28),非血液毒性发生率较低,初治与难治性患者的不良反应发生率差异无统计学意义(P＞0.05).结论 EPOCH方案是治疗老年PTCL患者有效而且耐受性较好的化疗方案.