Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma.

BACKGROUND: The combination of vincristine and doxorubicin administered as a continuous infusion via an indwelling catheter together with intermittent high-dose dexamethasone (VAD) is an effective primary treatment for patients with symptomatic multiple myeloma. In order to avoid the need for an indwelling catheter, which imposes logistic problems for outpatient administration, several phase II studies have explored the feasibility and efficacy of VAD-like outpatient regimens. We designed a prospective randomized study to compare the objective response rates of two VAD-like outpatient regimens as primary treatment for symptomatic patients with multiple myeloma. PATIENTS AND METHODS: Patients were entered in a randomized study regardless of age, performance status and renal function. One hundred and twenty-seven patients received VAD bolus, which consisted of vincristine 0.4 mg i.v., doxorubicin 9 mg/m(2) i.v. and dexamethasone 40 mg p.o. daily for four consecutive days and 132 patients received VAD doxil, which consisted of vincristine 2 mg i.v. and liposomal doxorubicin 40 mg/m(2) i.v. on day 1 and dexamethasone 40 mg p.o. daily for 4 days. The two regimens were administered every 28 days for four courses and in courses 1 and 3, in both arms, dexamethasone was also given on days 9-12 and 17-20. RESULTS: An objective response was documented in 61.4% and 61.3% of patients treated with VAD bolus and VAD doxil, respectively. Hematological and non-hematological toxicities were mild or moderate and equally distributed between the two treatment arms with the exception of alopecia, which was more common after VAD bolus, and of palmar-plantar erythrodysesthesia, which was more common after VAD doxil. CONCLUSIONS: Our multicenter trial, which included an unselected patient population, indicated that both VAD bolus and VAD doxil can be administered to outpatients and can provide an equal opportunity of rapid response in many patients with multiple myeloma.     

Phase II study of CLAD (cyclophosphamide, liposomal doxorubicin and dexamethasone) in patients with advanced multiple myeloma and historical comparison to CAD (cyclophosphamide, doxorubicin and dexamethasone)

The purpose of this study was to assess the efficacy and safety of pegylated liposomal doxorubicin in combination with cyclophosphamide and dexamethasone (CLAD). In this prospective open-label phase II study, 60 patients with advanced multiple myeloma (MM) received three weekly cycles of CLAD, consisting of cyclophosphamide 200 mg/m2 i.v. d1-4, pegylated liposomal doxorubicin 20 mg/m2 i.v. d1 and dexamethasone 40 mg p.o. d1-4 for a maximum of six cycles in absence of disease progression. Efficacy and toxicity was compared to our immediate historical cohort of 46 patients treated with cyclophosphamide, dexamethasone and conventional doxorubicin (CAD). A total of 239 cycles of CLAD and 209 cycles of CAD, respectively, were given. The objective response rate was 71% (CLAD) and 74% (CAD). Non-cumulative hematological toxicity was predominant in both regimens. It was found that CLAD is an active and well-tolerated treatment regimen for MM. Response rate is comparable to other anthracycline containing regimens like CAD with an advantage in hematological toxicity and lower infectious complications, and a presumed advantage of lower cardiotoxicity.     

Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy

BACKGROUND: Recently, the authors reported improved time to disease progression (TTP) with a combination of pegylated liposomal doxorubicin (PLD) and bortezomib compared with bortezomib alone in a phase 3 randomized trial in patients with recurrent/refractory multiple myeloma (MM). In the current analysis, they determined 1) the efficacy of PLD plus bortezomib versus bortezomib alone in patients with MM who had failed on prior thalidomide/lenalidomide (immunomodulatory drug [IMiD]) treatment and 2) the efficacy and safety profile of PLD plus bortezomib in IMiD-exposed and IMiD-naive patients. METHODS: This prespecified analysis included 646 patients who were randomized to receive either PLD with bortezomib (n=324; 194 IMiD-naive patients and 130 IMiD-exposed patients) or bortezomib alone (n=322; 184 IMiD-naive patients and 138 IMiD-exposed patients). The primary efficacy endpoint was TTP, and secondary endpoints included overall survival, response rate, and safety. RESULTS: The median TTP was significantly longer with PLD plus bortezomib compared with bortezomib alone in IMiD-exposed patients (270 days vs 205 days). No statistical difference was noted with respect to TTP between IMiD-naive (295 days) versus IMiD-exposed (270 days) subgroups who received PLD plus bortezomib. A sustained trend favoring combination therapy was observed in analyses of overall survival. In patients who achieved a response, the response duration was comparable for IMiD-naive patients and IMiD-exposed patients in the combination treatment group and lasted a median of 310 days and 319 days, respectively. The incidence of grade 3/4 adverse events was similar with PLD plus bortezomib regardless of prior IMiD exposure. CONCLUSIONS: A significantly prolonged TTP was observed with combined PLD plus bortezomib combination therapy compared with bortezomib alone despite prior IMiD exposure. For the combination treatment arm in the IMiD-naive and IMiD-exposed subgroups, TTP was comparable. Similarly, the safety profile of the PLD plus bortezomib combination was unaltered by prior IMiD exposure.     

例IgD多发性骨髓瘤患者多柔比星脂质体化疗后胸腔积液消退

IgD myelomas account for only 2% of all myelomas. This kind of hematological malignancy is severe and carries a bleak prognosis. Pleural effusion is very rare in multiple myeloma. We reported a case in which pleural effusion appeared at the end of the illness of IgD myeloma and treated with liposomal doxorubicin.     

Combination regimens using doxorubicin and pegylated liposomal doxorubicin prior to autologous transplantation in multiple myeloma

Doxorubicin and pegylated liposomal doxorubicin are key compounds of several induction regimens used prior to autologous stem cell transplantation in patients with de novo multiple myeloma, such as vincristine, doxorubicin, dexamethasone (VAD), vincristine, pegylated liposomal doxorubicin/Doxil^®, dexamethasone (DVd) or PS-341/bortezomib, doxorubicin, dexamethasone (PAD). The aim of this article is to summarize the more recent data available on the efficacy of these combinations and to discuss their role as part of initial therapy.     

沙利度胺治疗难治性复发性多发性骨髓瘤的临床研究

目的：观察沙利度胺(Thalidomide，国内商品名：反应停)单药或联合地塞米松治疗多发性骨髓瘤(Multiple Myeloma，MM)的疗效及副作用。方法：单药组：男性13例，女性2例，中位年龄58岁。其中2例为初发的MM；1例为原发性浆细胞白血病(PCL)；12例为难治性MM，其中3例为自体外周血干细胞移植(AutoPBSCT)术后复发。反应停治疗起始剂量为100mg／d，根据患者耐受情况，逐渐加量，最高达800mg／d。联合组：男性20例，女性7例，中位年龄56岁。其中初发1例；1例为原发性PCL；25例为难治MM，其中2例为自体外周血干细胞移植(AutoPBSCT)术后复发。反应停剂量为400mg／d左右加用地塞米松40mg／天，第1～4天，第9～12天，第17～20天，1个月为一个疗程。结果：单药组42．9％(6／14)的患者对治疗有效，其中3例为完全缓解(CR)或接近完全缓解(Near-CR)，1例有明显治疗反应(Major response)，1例为部分缓解(PR)。12例难治性MM中4例有效(33．3％)；联合组有效率为57．7％(15／26)，其中4例为CR或Near-CR，2例有明显治疗反应，9例为PR。25例难治性MM中11例有效(44．0％)。两组间在总有效率及难治病例的有效率方面均无显著差异。两组患者均出现不同程度的便秘、皮疹等副作用，但均可耐受。结论：沙利度胺单药或联合地塞米松对难治性复发性MM均有效。     

Pegylated liposomal doxorubicin, melphalan and prednisone therapy for elderly patients with multiple myeloma

Melphalan & Prednisone (MP) is considered as the standard therapy for Multiple Myeloma (MM) patients not eligible for high-dose therapy. Here, we report the results of a phase I-II study to evaluate the feasibility and efficacy of the association of PLD to the conventional MP regimen during the first six cycles of the front-line therapy for untreated MM patients older than 70. Thirty patients were included in the study with a median age of 77 years (71-84) and a M/F ratio of 17/13. The phase I of the study demonstrated that the maximum tolerable dose of PLD in this setting was 30 mg/m(2), so it was the final dose evaluated in the study. Twenty-nine patients were valuable for response, which was: complete in 4 (14%) partial in 15 (52%) minor/no changes in 7 (24%) and progressive in 3 (10%). The median progression free survival (PFS) was 24 months. The median overall survival (OS) has not been reached yet, with a 3-year probability for OS and PFS of 52 and 37%, respectively. Haematological toxicity was frequent but usually weak/moderate (grades 1 & 2 of the WHO scale) and it was resolved only with dose delays. Infection was a relatively frequent event (30% of patients), but only in 4 cases it was of grade 3. No cases of palmar-plantar erythrodysesthesia were observed. In conclusion, pegylated liposomal doxorubicin can be safely added to the other chemotherapeutic drugs in the treatment of elderly MM patients, which can be very useful for patients in whom novel agents are not tolerated or inefficient.     

酞咪哌啶酮联合化疗初治多发性骨髓瘤疗效观察

目的:探讨酞咪哌啶酮(thalidomide,商品名反应停)联合化疗初治多发性骨髓瘤(multiplemyeloma,MM)的初步疗效。方法:治疗组14例初治多发性骨髓瘤应用反应停起始剂量100mg/d~200mg/d,每2周增加100mg~200mg直到患者能够耐受,最大剂量不超过600mg/d,同时联合以马法兰为主的MP或M2方案化疗;对照组20例初治多发性骨髓瘤单用MP或M2方案化疗。观察比较两组的3个月有效率、1年无事件生存率(EFS)和2年总生存率(OS)。结果:有效(部分缓解加进步)率治疗组为85.7%,对照组为50%。1年EFS治疗组为71.4%,对照组为35%。2年OS治疗组为57.1%,对照组为25%。反应停治疗组副作用可以耐受,便秘最常见。结论:反应停联合化疗可提高初治MM的疗效和1年EFS、2年OS。     

Treatment of inoperable hepatocellular carcinoma with pegylated liposomal doxorubicin (PLD): results of a phase II study

Monthly intravenous pegylated liposomal doxorubicin (PLD) 50 mg m(-2), although well tolerated, showed almost no activity in this phase II study of 16 patients with advanced hepatocellular carcinoma with a response rate of 0%, stable disease 19%, median time to progression of 2.4 months, 1-year survival of 25% and median survival of 6.5 months.     

Bortezomib,thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma

BACKGROUND:

This single‐center retrospective study determined the efficacy of bortezomib, thalidomide, and dexamethasone (BTD) as induction for patients with multiple myeloma (MM) who were eligible for autologous stem cell transplantation (ASCT).

METHODS:

Patients with symptomatic MM who had received BTD induction before stem cell collection at Winship Cancer Institute were included. BTD induction comprised up to 8 3‐week cycles of bortezomib 1.3 mg/m² on Days 1, 4, 8, and 11; thalidomide 100 mg daily; and dexamethasone 40 mg on Days 1 through 4 and Days 9 through 12. Stem cell mobilization involved granulocyte‐colony–stimulating factor and/or cyclophosphamide. Response was assessed according to European Group for Blood and Marrow Transplantation criteria.

RESULTS:

Review of medical records identified 44 eligible patients (34 patients who were treated in the front‐line setting and 10 patients who were treated for recurrent disease) who received a median of 4 BTD cycles. The overall response rate (ORR) was 91%, which included a greater than or equal to very good partial response (≥VGPR) rate of 57% (including 20% stringent complete responses/complete response [sCR/CR] rate). In front‐line patients, the ORR was 94%, which included a 56% ≥VGPR rate (24% sCR/CR). The median CD34‐positive stem cell collection was 10.67 × 10⁶/kg. The ORR after ASCT in 34 patients who were evaluable for response was 100%, including a 76% ≥VGPR rate (53% sCR/CR). Among all 44 patients, the median progression‐free survival (PFS) was 27.4 months. The median overall survival (OS) was not reached after a median follow‐up of 25 months, and the 2‐year OS rate was 82%. There were no significant differences in PFS (27.4 months vs 23.5 months) or in 2‐year survival (80% vs 90%) between patients who did and did not undergo ASCT, respectively. Twenty patients (45%) developed neuropathy, including 4 (9%) with grade 3 neuropathy episodes, and 1 patient developed deep vein thrombosis.

CONCLUSIONS:

BTD was highly effective and well tolerated as induction for MM patients who were eligible for ASCT. Long‐term outcomes appeared to be similar with or without ASCT consolidation. Cancer 2010. © 2010 American Cancer Society.     

Phase II clinical trial of arsenic trioxide with liposomal doxorubicin, vincristine, and dexamethasone in newly diagnosed multiple myeloma

In patients with multiple myeloma, there is preclinical justification to combine arsenic trioxide (ATO and As₂O₃) with DVd (Doxil™, vincristine, and dexamethasone) for newly diagnosed patients. Eleven patients on this phase II trial received 0.15 mg/kg of ATO for five consecutive days followed by four cycles of DVd plus ATO with the ATO at 0.25 mg/kg IV twice per week. The most common grade 3 toxicities were hyperglycemia, hyponatremia, and hypocalcemia. There were four partial and no complete responses. We could not demonstrate that the addition of ATO with this schedule improved the response rate of MM to DVd.     

A phase II study of Doxil (liposomal doxorubicin): Lack of activity in poor prognosis soft tissue sarcomas

Background: Liposomal doxorubicin (Caelyx, Doxil) delivers doxorubicin to a tumor, but has a vastly altered pharmacology and attenuated acute and chronic toxicities. Therefore, its efficacy in soft tissue sarcomas is worth exploring.Patients and methods: Sixteen patients with recurrent or metastatic soft tissue sarcomas who had not failed prior doxorubicin were accrued into this phase II study. Patients were treated with Doxil at a dose of 50 mg/m2 every four weeks.Results: No responses were seen but three patients were removed from study after only one cycle of treatment. Moreover, leiomyosarcoma was the most common histology and most patients had low grade, and bulky, disseminated tumors. Treatment was well tolerated with no episodes of grade 4 toxicity and only five episodes of grade 3 toxicities: two episodes of neutropenia and one each of stomatitis, dermatologic toxicity and nausea and vomiting.Conclusions: Doxil's lack of activity in this study of patients with adult soft tissue sarcoma may be related to the poor prognostic features of our population. We confirm its favorable toxicity profile and suggest that additional studies be done in patients with other characteristics.     

A phase II study of pegylated liposomal doxorubicin for treatment of advanced hepatocellular carcinoma

Background:Pegylated liposomal doxorubicin has an enhancedefficacy and reduced toxicity compared with free doxorubicin. The efficacy andtoxicity of pegylated liposomal doxorubicin was investigated in patients withhepatocellular carcinoma. Patients and methods:Patients with histologically confirmed,locally advanced or metastatic hepatocellular carcinoma and a Karnofsky index>60% were included in this prospective single-arm study. Exclusioncriteria were liver cirrhosis stage Child–Pugh C, previous chemotherapy,or chemoembolization. Pegylated liposomal doxorubicin was given in a dose of30 mg/m² every three weeks until progression of disease. Afterinclusion of five patients the dose could be escalated to 40 mg/m²in absence of toxicity grade 3 and 4. Results:Sixteen patients were evaluable for response. Noobjective response was achieved. The median survival time was 140 days(95% confidence interval: 126–154 days). Treatment toxicitiesgrade 3 comprised increased liver enzymes in patients with preexistinggrade 1 or 2 elevation (n = 6), hematologic toxicity (n =5), and hypersensitivity (n = 2). Conclusions:Pegylated liposomal doxorubicin is not effective fortreatment of advanced hepatocellular carcinoma. The favorable toxicity profilewas confirmed even in patients with underlying liver disease.     

硼替佐米、地塞米松及沙利度胺方案治疗多发性骨髓瘤的成本与疗效分析

目的:探讨硼替佐米、地塞米松、沙利度胺方案（BDT）治疗多发性骨髓瘤（MM）的近期疗效、安全性及成本分析。方法:选取我院收治的初治及复发难治的MM患者40例,给予BDT方案化疗3周期,观察患者的治疗疗效、成本、不良反应的发生情况。结果:40例MM患者治疗后的骨髓瘤细胞、M蛋白、β2-MG下降及血红蛋白上升的指标均差异显著(P＜0.05);治疗后的总缓解率为75.0%,其中5例完全缓解,10例非常好的部分缓解,15例部分缓解,7例疾病稳定,3例疾病进展。治疗过程中未发生严重不良反应。BDT方案成本-效果比是867.3元,敏感度分析后成本-效果比是310.4元。结论:硼替佐米、地塞米松及沙利度胺方案治疗MM疗效优异,安全性可,价格适中,具有较好的临床应用价值。     

Thalidomide and dexamethasone combination for refractory multiple?myeloma

Background:Thalidomide is effective in approximately 30%of patients with refractory multiple myeloma. Dexamethasone is active in25% of patients with disease resistant to alkylating agents. Weinvestigated the combination of thalidomide with dexamethasone as salvagetreatment for heavily pretreated patients with multiple myeloma, in order toassess its efficacy and toxicity. Patients and methods:Forty-four patients with refractory myelomawere treated with thalidomide, 200 mg p.o. daily at bedtime, with doseescalation to 400 mg after 14 days, and dexamethasone, which was administeredintermittently at a dose of 20 mg/m² p.o. daily for four days onday 1–4, 9–12, 17–20, followed by monthly dexamethasone forfour days. Patients' median age was 67 years. All patients wereresistant to standard chemotherapy, 77% were resistant todexamethasone-based regimens and 32% had previously received high-dosetherapy. Results:On an intention-to-treat basis twenty-four patients(55%) achieved a partial response with a median time to response of 1.3months. The thalidomide and dexamethasone combination was equally effectivein patients with or without prior resistance to dexamethasone-based regimensand in patients with or without prior high-dose therapy. Toxicities were mildor moderate and consisted primarily of constipation, morning somnolence,tremor, xerostomia and peripheral neuropathy. The median time to progressionfor responding patients is expected to exceed 10 months and the mediansurvival for all patients is 12.6 months. Conclusion:The combination of thalidomide with dexamethasoneappears active in patients with refractory multiple myeloma. If this activityis confirmed, further studies of this combination as second-line treatment forpatients resistant to conventional chemotherapy, and as primary treatment forpatients with active myeloma, should be considered.     

Pegylated liposomal doxorubicin and gemcitabine in the front-line treatment of recurrent/metastatic breast cancer: a multicentre phase II study

This multicentre phase II study was aimed at investigating the activity and safety of pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) as front-line therapy in a large series of chemotherapy-naïve recurrent/metastatic breast cancer patients. From June 2003 to December 2006, a total of 71 recurrent/metastatic breast cancer patients were enrolled. Median age was 63 years (range=37–79), and 31 patients (43.7%) were ⩾65 years old. Patients received PLD, 25 mg m⁻², day 1, followed by GEM, 800 mg m⁻², days 1 and 8, q21. Response was evaluable in 64 cases. Eight complete (12.5%) and 17 partial responses (26.6%) were registered, with an overall response rate of 39.1%. Thirty patients (46.9%) experienced stable disease, with an overall clinical benefit of 85.9%. Median time to progression (TTP) was 11 months, whereas median overall survival (OS) was not reached. The rate of 1- and 2-year OS was 79 and 61%, respectively. A total of 443 courses were evaluable for toxicity: grade 3 and 4 neutropaenia affected 14 patients (20.3%) and 3 patients (4.3%), respectively. Grade 3 and 4 palmar-plantar erythrodysesthesia syndrome was documented in five cases (7.2%) and one case (1.4%), whereas grade 3 and 4 mucositis occurred in six cases (8.7%) and two cases (2.9%), respectively. Grade 2 cardiac toxicity was observed in only one case. Interestingly enough, there was no difference in the percentage and severity of either haematological or non-haematological toxicity according to the age of the patients (<65 vs ⩾65 years). We confirmed in a large, very homogenous study sample of chemotherapy-naïve recurrent/metastatic breast cancer patients the efficacy and safety of PLD/GEM combination, providing response rates, median TTP and OS values comparable with those achieved with more toxic combinations.     

Phase II study of pegylated liposomal doxorubicin (Caelyx) and docetaxel as first-line treatment in metastatic breast cancer.

BACKGROUND: The aim of this study was to determine the activity and safety of pegylated liposomal doxorubicin (PLD; Caelyx) and docetaxel combination as first-line treatment in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-four patients with a median age of 63 years were treated with PLD 30 mg/m(2) (day 1) and docetaxel 75 mg/m(2) (day 2) every 3 weeks for six cycles. Recombinant human Granulocyte Colony-Stimulating Factor (rhG-CSF) could be used in patients with grade > or =3 neutropenia after the first cycle. RESULTS: Forty-two of 44 patients were assessable for response. The response rate (RR) was 64.3% (95% confidence interval 49.8% to 78.8%). Six patients (14.3%) achieved complete response (complete disappearance of all measurable and assessable disease lasting at least 4 weeks, no new lesions, no disease-related symptoms), partial response was observed in 21 patients (50%) > or =50% decrease of measureable disease lasting at least 4 weeks, no progression of assessable disease, no new lesions, no disease-related symptoms), eight patients had stable disease and seven patients progressive disease. Median disease-free and overall survival were not reached, but were in excess of 17 months (range 6-17 months). Twenty of the patients had received previous adjuvant chemotherapy (10 with epirubicin-containing regimen with a median cumulative dose of 400 mg/m(2)). Grade > or =3 neutropenia occurred in 18.4% and neutropenic fever in 9% of patients. Palmar-plantar erythrodysesthesia was observed in four patients. Dose reduction was necessary in seven patients. Two patients discontinued treatment: one due to prolonged grade 3-4 neutropenia and one due to neurotoxicity. No treatment-related deaths occurred. CONCLUSIONS: The combination of PLD and docetaxel achieved high RRs with acceptable toxicity as first-line treatment in MBC.     

Phase II study of liposomal doxorubicin and gemcitabine in the salvage treatment of ovarian cancer

In total, 70 patients were enrolled into this phase II study, to evaluate the activity of the pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) combination in recurrent ovarian cancer patients. PLD, 30 mg m(-2), was administered on day 1 by 60' i.v. infusion, followed by GEM, 1000 mg m(-2), given by 30' i.v. on days 1 and 8; cycles were repeated every 21 days. In all, 67 patients are so far evaluable for response. Seven complete responses (10.4%, 95% CI: 3.1-17.7), 16 partial responses (23.9%, 95% CI: 13.7-34.1), 26 disease stabilisations (38.8%, 95% CI: 27.1-50.5) and 18 progressions (26.9%, 95% CI: 16.3-37.5) have been registered. Within the resistant population (n=36), the response rate was 25% (95% CI: 10.9-39.1). Within the group of platinum-sensitive patients (n=31), the response rate was 45.2% (95% CI: 27.7-62.7). A total of 443 courses are evaluable for toxicity. Grade 3-4 hematological toxicity was registered in 30 patients (42.8%), mainly represented by neutropenia (35.6%); palmar-plantar erythrodysesthesia affected 24 patients (34.2%), but it was of grade 3 in only seven of them (10%).