Randomized clinical trial of zoledronic acid in multiple myeloma patients undergoing high-dose chemotherapy and stem-cell transplantation.

BACKGROUND: A growing body of evidence is demonstrating that the nitrogen-containing bisphosphonate zoledronic acid (zol) improves clinical outcomes in various cancer settings, including multiple myeloma. Those findings provided the rationale for conducting an open-label randomized controlled phase iii trial to evaluate the effect of zol on overall survival (os) and progression-free survival (pfs) in patients with previously untreated high-risk multiple myeloma. METHODS: The trial randomly assigned 308 adult patients less than 65 years of age with previously untreated symptomatic multiple myeloma (1:1) to receive zol 4 mg intravenously once every 28 days for 24 months (n = 151) or no zol (n = 157). Before autologous stem-cell transplantation (asct), all patients received a high-dose noncytotoxic induction regimen of dexamethasone, all-trans-retinoic acid, and interferon alpha 2b. RESULTS: After a median follow-up of 69.8 months (range: 36.5-96 months), the 10-year pfs (66% vs. 52%, p < 0.001) and os (67% vs. 48%, p < 0.001) rates were significantly higher in treated patients than in control patients. Overall response (77% zol vs. 75% control), complete response (52% vs. 46%), and very good partial response (25% vs. 29%) rates were similar between the groups. Treatment was generally well tolerated, with no reports of renal impairment or osteonecrosis of the jaw. CONCLUSIONS: In symptomatic previously untreated multiple myeloma patients, zol combined with high-dose therapy followed by asct improved os and pfs without appreciable toxicity. These findings provide additional evidence of the meaningful anticancer activity of zol in this patient population.

Late lethal events in patients with diffuse large B cell lymphoma: a review of 714 patients treated in a single centre.

Presence of late lethal events has been recognized as a complication in patients with malignant lymphoma. We reviewed 714 cases of patients treated during 1975-1995 with a long term follow-up (>4 years) in an attempt to identify all late events secondary to malignant lymphoma, either to the treatment or those which are unrelated. Forty-three patients died, and of these 21 (2.8%) were secondary to relapse and tumor progression; deaths associated with second neoplasm and cardiac events were increased 9.6 fold and 26.4 fold respectively compared to the general population. The risk factors for these complications did not differ from those in previous reports and included alkylating agents and/or radiotherapy for second neoplasms and anthracycline therapy and radiotherapy for cardiac toxicity. Moreover, 10 patients died secondary to non-related events. Nevertheless, at 10 years overall survival was 94% (95% confidence interval (CI): 82% to 98%) and event free survival was 97.1% (95% CI: 81% to 98%), for these patients. Thus, second events, fatal in most cases, will be considered as an expected risk in the treatment of patients with malignant lymphoma. The proposed modifications of therapy many indeed be useful to avoid or diminish these complications in the future.

Interferon alfa 2b as maintenance therapy in poor risk diffuse large B-cell lymphoma in complete remission after intensive CHOP-BLEO regimens.

OBJECTIVES: We conducted a randomized clinical trial to evaluate the role of interferon alfa 2b (IFN) as maintenance therapy in patients with diffuse large B-cell lymphoma with high or high-intermediate clinical risk on complete remission (CR) after CHOP-BLEO regimens. METHODS: Patients were initially treated with CHOP-BLEO regimens (which include increased doses of cyclophosphamide and epirubicine, instead of doxorubicin). If the patients achieved CR they were randomly assigned to receive either maintenance therapy with IFN 5.0 MU, three times at week by 1 yr, or no treatment (control group). RESULTS: Two hundred and twenty-three patients were considered as candidates for the study. They were of high (80%) or high-intermediate (20%) clinical risk; additionaly most patients had poor prognostic factors such as high levels of beta 2 microglobulin, lactic dehydrogenase levels, bulky disease (defined as a tumor mass >10 cm) or multiple extranodal involvement. In an intent-to-treat analysis all patients were evaluable to efficacy and toxicity. Median follow-up was 45 months, the estimated 5-yr overall survival and event-free survival (EFS) for patients who received IFN were 71% (95% confidence interval (CI): 61-83%) and 57% (95% CI: 39-69%), respectively, values which were not statistically different from the control group: 69% (95% CI: 63-79%) and 54% (95% CI: 37-63%), respectively (p=0.2). Toxicity was mild. CONCLUSIONS: These results suggest that IFN used as maintenance therapy at these doses and schedules is not useful in aggressive malignant lymphoma when more intensive chemotherapy has been employed during induction treatment. Nevertheless, follow-up is too short, and long-term follow-up would be necessary in order to draw definitive conclusions. Probably, an multicenter study is necessary to define the role of IFN as maintenance therapy in this patient setting.

Randomized Clinical Trial to Evaluate Maintenance Therapy in Diffuse Large Cell Lymphoma Treated with Intensive Chemotherapy.

Although complete response (CR) rate has been increased with the use of more intensive and in some cases myeloblative chemotherapy, long term follow-up has shown that relapse continues to be a major problem in patients with diffuse large cell lymphoma. Maintenance therapy is not considered as standard therapy in this group of patients. In our experience, the use of maintenance therapy either with low-doses of cyclophosphamide and prednisone (C/P) or interferon-α2b (IFN) improves the duration of event free survival (EFS) and overall survival (OS) in patients treated with conventional chemotherapy. The use of more intensive chemotherapy increases the CR rate, but does not effect EFS and OS. We therefore started a controlled clinical trial to assess the efficacy and toxicity of maintenance therapy with C/P or IFN in patients on CR after intensive, non myeloablative, chemotherapy. From January 1994 to December 1996; 269 patients with diffuse large cell lymphoma (defined as patients with high- or high-intermediate clinical risk) were allocated to receive C/P (200mg/m(2), po, daily, by 5 days and 50 mg/m(2), po, daily, by 5 days, respectively, every 6 weeks by 2 years) or IFN: 5 MU three times at week by 1 year compared to a control group. In an intent to treat analysis, 269 patients were eligible for study. All were evaluated for EFS and OS. The median follow-up is 49.6 months. A comparison of the three groups revealed no significant differences on EFS: 72% (95% CI: 60% to 77%) for IFN arm; 71% (95% CI: 62% to 82%) for C/P group and 74% (95% CI: 68% to 85%) in the control group (p =.8). Also OS was not different: 70% (95% CI: 59% to 79%); 68% (95% CI: 60% to 78%) and 72% (95% CI: 63% to 78%) respectively (p =.750). All patients completed the programmed schedule. Toxicity was mild. Previously we demonstrated that maintenance therapy is useful in patients with aggressive malignant lymphoma when they were treated with conventional chemotherapy. However, when more intensive chemotherapy was used to achieve CR, maintenance therapy was not useful. We do not have a convincing explanation. We believe that intensive chemotherapy may eradicate all sensitive cells to drugs, such as IFN or C/P, and for this reason improve survival was not observed. On the other hand, in patients treated with conventional chemotherapy, some residual and sensitive tumor cells must remain and maintenance therapy may eliminate this cells, with improvement in EFS and OS. Long term follow-up is necessary and for the controlled clinical trials to define the role of maintenance therapy in patients with aggressive malignant lymphoma are required.

Results of a Controlled Clinical Trial Radiotherapy versus Combined Therapy in the Management of Stage IE Orbital Marginal Zone B-cell Lymphoma.

The aim of the present study was to compare the usefulness of radiotherapy (34-40 Gy, median 3.8 Gy) versus radiotherapy following by adjuvant chemotherapy in the management of 73 patients with stage I marginal zone B cell lymphoma (MZBCL) of the orbit. Complete response was similar in both arms: 95% (95% confidence interval (CI): 89-99%) in the radiotherapy group and 100% (95% CI: 92-104%) in the combined therapy arm. At a median follow-up of 8 years no median has been reached in event free survival (EFS) and overall survival (OS). At 8-years EFS shown that 87% (95%CI: 82-93%) and 82%, (95%CI: 78-87%), respectively remain in first complete response (p=0.6). OS was very similar 87% (95% CI: 84-89%) and 90%, (95% CI: 84-95%), respectively (p=0.5). Because we use low-radiation therapy (<50Gy) acute and late toxicities were mild. We concluded that combined therapy it is not useful in the treatment of MZBCL primary of the orbit and confirm that radiotherapy is the treatment of choice in this setting of patients.

Dexamethasone, all trans retinoic acid and interferon alpha 2a in patients with refractory multiple myeloma.

Few effective regimen are available for patients with refractory multiple myeloma (RMM). Generally, responses are scarce and disease free survival is very short. We developed a new therapeutic option in these patients using dexamethasone (40 mg/m2, i.v., daily, days 1 to 4), all-trans retinoic acid (45 mg/m2, po, daily, days 5 to 14) and interferon alpha 2a (9.0 MU, daily, subcutaneously, days 5 to 14). The treatment was administered every 21 days for 6 cycles. In a pilot study, 12 patients, heavily treated with chemotherapy and radiotherapy and in some cases with interferon, were allocated to receive the afore mentioned treatment. Response was observed in 10 patients (83%). With a median follow-up of 36.1 months (range 27 to 41), seven patients remain alive and disease-free without any treatment. Two patients were failures and have died due to tumor progression. Toxicity was mild and all patients received treatment according to the planned doses of drugs. The use of biological modifiers in combination with dexamethasone offer a safe and effective therapeutic option in patients with refractory multiple myeloma. More studies are warranted to define the role of this type of treatment.

Dose escalation of epirubicin in the CEOP-BLEO regimen: a controlled clinical trial comparing standard doses for the treatment of diffuse large cell lymphoma.

One hundred and forty-seven consecutive patients with previously untreated high-intermedium and high clinical risk diffuse large cell lymphoma (DLCL) were included in a prospective clinical trial to evaluate the efficacy and toxicity of escalating doses of epirubicin compared to standard doses in the CEOP-Bleo (cyclophosphamide, epirubicin, vincristine and prednisone and bleomycin) regimen, 55% of the patients were > 60 years old and most patients had adverse prognostic factors at diagnosis. Complete response rates were similar in both groups (68% in the standard dose compared to 73% in the escalating arm, (p = 0.5). However, time to treatment failure (TFF) and overall survival were better after escalating doses. At 3-years TTF at a medial follow-up of 33.6 months was 76% in the patients whose received escalating dose statistical different to 37% of the patients whose received standard doses (p < .01). Overall survival was 81% in the escalated therapy arm which is statistical different to 40% of the patients treated with standard doses (p < .01). Toxicity was mild in both arms. Neutropenia, mucositis and cardiotoxicity were mild in the escalated dose arm and no severe complications were observed. All patients received the planned doses of all drugs. Patients > 60 years old had the same CR rate, TTF and overall survival as younger patients. In conclusion it seems that the dose of epirubicin can be increased in combination chemotherapy regimens with safety and only mild toxicity. The CR rate was not superior compared to the standard dose but the TTF and overall survival were better. Longer follow-up periods are required in order to determine if the cure rate can also be improved. Older patients can also benefit because they also tolerated the increase in epirubicin without severe side effects and also improved their outcome. The use of more aggressive regimens with increase in dose intensity may be the treatment of choice for more patients poor prognosis, with DLCL provided there is no increase in toxicity. In this respect the use of epirubicin in higher doses/appears to be useful.

Epirubicin (CEOP-Bleo) versus idaurubicin (CIOP-Bleo) in the treatment of elderly patients with aggressive non-Hodgkin's lymphoma: dose escalation studies.

One hundred and sixty nine untreated elderly patients (median age 69 years old; range 60-89 years old) with high or high-intermediate clinical risk non-Hodgkin's lymphoma were enrolled in a controlled clinical trial to evaluate escalated doses of epirubicin in a CEOP-Bleo regimen (cyclophosphamide, vincristine, epirubicin, prednisone and bleomycin), compared to escalated doses of idaurubicin in an CIOP-Bleo regimen (idaurubicin instead of epirubicin). Overall, 71% of the patients in the CEOP-Bleo arm achieved a complete response compared to only 48% in the CIOP-Bleo regimen (p < 0.01). At actuarial 3 year, 72% of the patients treated with the CEOP-Bleo regimen remained alive and free of disease, compared to 34% in the CIOP-Bleo arm (p < 0.01). Dose intensity was 0.86 in the epirubicin regimen, similar to 0.82 in the idaurubicin arm. Toxicities were more frequent and severe in the CEOP-Bleo regimen; however, no death-related treatment was observed in either groups. Cardiac toxicity was also similar in both arms. We conclude that treatment of elderly paitents with aggressive non-Hodgkin's lymphoma should be considered a curative attempt and not only palliative. The use of full doses of chemotherapy should be contemplated in elderly patients. Epirubicin, in escalating doses, is a drug with mild toxicity and improvement in outcome in this setting is observed. We cannot confirm the usefulness of idaurubicin, including escalating doses, in the treatment of patients with aggressive malignant lymphoma, because the complete response rate and survival were worse than other chemotherapy regimens. We feel that the CEOP-Bleo regimen with escalated doses of epirubicin is a useful option in the treatment of elderly patients with aggressive non-Hodgkin's lymphoma.

Marginal zone B cell lymphoma of the parotid glands: results of a randomised trial comparing radiotherapy to combined therapy.

39 patients with marginal zone B cell lymphoma (MZBCL) of the parotid glands (stages I or II) were studied. They were randomized to be treated with either radiotherapy alone (extended fields, 4500 cGy) or radiotherapy (the same schedule) plus adjuvant chemotherapy (cyclophosphamide, vincristine and prednisone). The end points were survival and time to treatment failure (TTF). Patients who received radiotherapy alone had a complete remission rate of 100%, the TTF was 90% at 5 years and overall survival at 5 years was 90% with no statistical difference when compared with patients who received combined therapy [100, 80 and 95%, respectively (P = 0.5)]. Although adjuvant chemotherapy was well tolerated, the use of this therapeutic approach in patients with early stage MZBCL did not offer any advantage over radiotherapy alone as the initial treatment. Until now, radiotherapy was considered the treatment of choice in this clinical setting of patients.

Improved outcome in solitary bone plasmacytomata with combined therapy.

Solitary bone plasmacytoma (SBP) is a rare presentation of plasma cell dyscrasias. Radiotherapy has been considered the treatment of choice, however, most patients will develop multiple myeloma, 3 to 10 years after initial diagnosis and treatment. No innovations have been introduced in the treatment of SBP in the last 30 years. We began a prospective clinical trial to assess the efficacy and toxicity of adjuvant chemotherapy with low doses of melphalan and prednisone administered to patients with SBP after radiation therapy in an attempt to improve the disease-free survival and overall survival. Between 1982 and 1989, 53 patients with SBP were randomly assigned to be treated with either local radiotherapy with doses ranged from 4000 to 5000 cGy to achieve local control of disease (28 patients) or the same radiotherapy schedule followed by melphalan and prednisone given every 6 weeks for 3 years (25 patients). After a median follow-up of 8.9 years, disease-free survival and overall survival were improved in patients who were treated with combined therapy, 22 patients remain alive and free of disease in the combined treatment group compared to only 13 patients in the radiotherapy group (p < 0.01). Treatment was well tolerated; planned doses were administered in all cases; no delays in treatment or acute side-effects were observed during treatment. Long-term secondary toxicities including secondary neoplasms and acute leukaemia, have not been observed. We felt that the use of adjuvant chemotherapy after adequate doses of radiotherapy in patients with SBP improved duration of remission and survival without severe side-effects. However, as with other studies in SBP, the group was too small to draw definitive conclusions and more controlled clinical trials are necessary to define the role of this therapeutic approach in patients with SBP.