Sergio Cleto

Antitumor effect of zoledronic acid in previously untreated patients with multiple myeloma

Bisphophonates are the treatment of choice to prevent skeletal events in patients with multiple myeloma. Some preclinical studies suggested that bisphophonates can be useful as antitumor drugs in some malignancies. We conducted a controlled clinical trial to assess if zoledronic acid can have this clinical activity. Ninetyfour patients with previously untreated multiple myeloma were treated with a conventional chemotherapy program: cyclophosphamide, vincristine, melphalan, and prednisone (CVMP) and were randomized to received either zoledronic acid (4 mg, iv, every 28 d) or not (control group). The end-point of the present study was to assess improvement in outcome, measured by event-free survival (EFS) and overall survival (OS), and the second-end point was to confirm the efficacy in preventing skeletal events. In an intent-to-treat analysis, all patients were available for efficacy and toxicity. Median follow up was 49.6 mo (range: 34–72 mo). Five year actuarial curves showed that EFS was 80% in the zoledronic acid group, which was statistically different from 52% in the control group (p < 0.01). Actuarial 5 yr OS was 80% in the zoledronic acid arm, and 46% in the control group (p < 0.01). Sketeletal events were more frequent in the control group when compared to zoledronic acid. Toxicity was mild. We confirm the efficacy of zoledronic acid to prevent skeletal events, but we felt that we can demonstrate that zoledronic acid has a clinical antitumor effect measured from a increase in complete response rate and EFS and OS that were better when compared with the control group. We began a controlled clinical trial with modern treatment (including transplant procedures) in combination with zoledronic acid to define the role of zoledonic acid in this setting of patients.

Primary breast lymphoma: results of a controlled clinical trial.

Objectives: To assess the efficacy and toxicity of the most employed therapeutic approaches in the treatment of primary breast lymphoma (PBL). Methods: Ninety-six patients with PBL in the early stage (I or II) were enrolled to receive radiotherapy (45 Gy); chemotherapy (six cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), every 21 days), or combined therapy. Results: Complete response was achieved in 20 of 30 patients treated with radiotherapy, 19 of 32 who were treated with chemotherapy and 30 of 34 in the combined arm (p < 0.01). Actuarial curves at 10 years showed that event-free survival was 50, 57 and 83%, respectively (p < 0.01). Actuarial curves for overall survival were 50, 50 and 76% (p < 0.01), respectively. The most common site of relapse was the central nervous system. Acute toxicity was mild. Until now, no second neoplasm or acute leukemia has been observed. Conclusions: In our study combined therapy is the best treatment in this special setting of patients; with improvement in event-free survival and overall survival without acute or severe late side effects. Prophylaxis to the central nervous system will be considered in the initial treatment to improve outcome.

Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach: results of a controlled clinical trial.

Treatment of patients with early stage gastric mucosa-associated lymphoid tissue (MALT) remains undefined. We began a controlled clinical trial to evaluate efficacy and toxicity of the most common therapies. Two hundred and forty-one patients with gastric low-grade MALT lymphoma in early stage (IE and IIE) were randomized to surgery (80 cases), radiotherapy (78 cases), and chemotherapy (83 cases). With a median follow-up of 7.5 yr, actuarial curves at 10 yr showed that event-free survival was 52% in patients treated with surgery, 52% in radiotherapy arm, and 87% in the chemotherapy group (p<0.01). However, overall survival did not showed any statistical differences: 80%, 75% and 87%, respectively (p=0.4). Acute and late toxicities were mild. No death-related treatments were observed. No clear differences were observed between the most common therapies in patients with primary gastric MALT lymphoma in early stages, probably because this type of lymphoma has an high response rate to salvage treatment after failure to local treatment (surgery and radiotherapy). Thus considered, chemotherapy alone is an effective and safe therapeutic approach in this setting of patients. Surgery or radiotherapy will be reserved to patients that are not candidates for chemotherapy.

Late cardiac toxicity secondary to treatment in Hodgkin's disease. A study comparing doxorubicin, epirubicin and mitoxantrone in combined therapy

Anthracyclines are a group of drugs that are useful in the treatment of Hodgkins disease, but have been associated with severe, and in some cases lethal, cardiac toxicity. Apparently, cardiac toxicity is more frequent after 10 years of anthracycline therapy, but no longer studies of cardiac toxicity have been reported. Four hundred and seventy-six patients with Hodgkins disease, stages III and IV, were randomly assigned to receive ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) compared with EBVD (epirubicin instead of doxorubicin) and MBVD (mitoxantrone instead of doxorubicin) at standard doses. The endpoint was the presence of a clinical cardiac event (CCE) or abnormalities in equilibrium radionuclide angiocardiography (ERNA) and echocardiogram. The patients did not receive radiation therapy and when relapsed they were censored from cardiac toxicity. The median follow-up was 11.5 years (range 7.5 - 14.8 years). CCE was observed in 17% in the MBVD arm, 9% in the ABVD arm and 6% in the EBVD arm (P < 0.001). Mortality associated with CCE was 12% with MBVD, 7% with ABVD and 2% with EBVD. Abnormalities in ERNA and echocardiogram were observed 6 - 36 months before the presence of a CCE. An excess in the standard mortality ratio was observed with the 3 regimens when compared with the general population: 19.4 for EBVD, 46.0 for ABVD and 67.8 for MBVD, which was confirmed with an increase in absolute excess risk/10,000 person-years of 15.6, 39.0 and 58.7, respectively. Overall survival was better in patients treated with EBVD because less cardiac events were observed. The use of mitoxantrone was associated with a high rate of relapse and cardiac events. Thus, we would not recommend use of the drug in Hodgkins disease. ERNA and echocardiogram are early detection tests for cardiac toxicity and can be employed in surveillance studies.

Retracted: Adjuvant Radiotherapy in Stage IV Diffuse Large Cell Lymphoma Improve Outcome

RETRACTED

Residual disease after chemotherapy in aggressive malignant lymphoma: the role of radiotherapy.

Residual disease in patients with diffuse large B-cell lymphoma after intensive chemotherapy remains a problem. Radiotherapy has been used in some retrospective studies without definitive conclusions. We report the first controlled clinical trial to define the role of radiotherapy in this setting of patients. One hundred and sixty-six patients with diagnosis of diffuse large B-cell lymphoma, high- or high-intermediate clinical risk, with residual disease (defined as tumor mass <5 cm) were randomly assigned to received radiotherapy at the involved field, with 30 Gy delivered in 20 sessions or no radiation (control group). Median follow-up was 135 mo; patients who received radiotherapy have an better outcome. Actuarial curves at 10 yr showed that progressive-free disease was 86% and overall survival was 89%; those were statistical significant when compared to patients who did no received radiotherapy: 32% and 58% respectively, (p<0.001). Toxicity was mild and well tolerated. We concluded that presence of residual mass after chemotherapy in patients with aggressive malignant lymphoma has a worse prognosis, and salvage radiotherapy improves outcome with mild toxicity. We feel that radiotherapy will be considered as necessary treatment in this special group of patients.

Rituximab and Chemotherapy in Primary Gastric Lymphoma

PURPOSE We performed a phase II clinical trial to assess the efficacy and toxicity of the addition of rituximab and conventional chemotherapy in primary gastric lymphoma (PGL). METHODS Forty-two (42) patients with PGL, stage IE and IIE, and with low- or low-intermediate clinical risk were treated in a prospective longitudinal study with standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy and rituximab (375 mg/m2, intravenously) on day 1 of each cycle administered every 21 days, for 6 cycles. The endpoint was to assess improvement in outcome measured by prolongation in event-free survival (EFS) and overall survival (OS). Complete response was achieved in 40 cases (95%) (95% confidence interval [CI]: 88%-102%). Relapse was observed in 2 cases. Two (2) patients died secondary to tumor progression. Thus, actuarial 5-year EFS was 95% (95 % CI: 87%-104%) and OS was 95% (95% CI: 88%-101%), which was not statistically different to historic controls. Acute toxicity was minimal and well tolerated, 4 cases developed late toxicity, 2 cases of herpes zoster infection, and 2 cases with granulocytopenia; in 1 case, the patient continued with mild granulocytopenia 3 years after treatment. CONCLUSIONS The addition of rituximab to CHOP chemotherapy did not improve outcome in early-stage PGL.

Addition of a Short Course of Chemotherapy Did Not Improve Outcome in Patients with Localized Marginal B-Cell Lymphoma of the Orbit

Objectives: Primary orbital malignant lymphoma (POML) is a rare malignancy, thus treatment remains to be defined. The present study was designed to define if the use of radiotherapy is sufficient in these patients or if the use of adjuvant chemotherapy would improve the outcome. Methods: Between 1983 and 1995, 98 previously untreated patients diagnosed with POML, stage IE, were randomly allocated to receive either radiotherapy (34–40 Gy) or the same radiotherapy combined with chemotherapy including anthracycline. The median follow-up was 11.4 years (range 9.8–10.8 years). Results: Complete response was similar in both arms: 98% (95% confidence interval, CI: 89–100%) in the radiotherapy arm, and 100% (95% CI: 89–100%) in the combined therapy group. At a median follow-up of 16.4 years, event-free survival was 94% (95% CI: 87–100%) and 85% (95% CI: 88–100%), respectively. Overall survivals were: 96% (95% CI: 89–99%) and 91% (95% CI: 83–98%). No statistical differences were found. Acute and late toxicities were mild. Conclusions: The addition of chemotherapy is of no further benefit, since the results did not differ, thus, radiotherapy will be considered as the treatment of choice in POML patients.

Dose dense (CEOP-14) vs dose dense and rituximab (CEOP-14 +R) in high-risk diffuse large cell lymphoma.

To assess efficacy and toxicity of rituximab and dose chemotherapy in high-risk diffuse large cell lymphoma, we conducted a controlled clinical trial to assess efficacy and toxicity of a dose-dense regimen CEOP-14 (cyclophosphamide, epirubicin, vincristine, and prednisone every 14 d) compared to CEOP-14 plus rituximab. One hundred and ninety-six patients were randomized to received CEOP-rituximab (cyclophosphamide 1500mg/m2, epirubicin 120 mg/m2, vincristine, and prednisone at standard dose and rituximab at 375 mg/m2) compared with the same chemotherapy administered every 14 d (CEOP-14). In an intent-to-treat analysis all patients were available for efficacy and toxicity. Complete response in CEOP-14 was observed in 73 cases (74%) and in 75 patients (76%) in the CEOP-R regimen (76%) (p=0.8). With a median follow-up of 53.4 mo, median has not been reached in time to tumor-progression (TTP) and overall survival (OS). Actuarial curves at 5 yr showed that TTP and OS in patients treated with CEOP-R were 74% and 67%, respectively, that were not statistical different when compared to CEOP-14, 72% and 65%, respectively (p=0.8). Acute toxicity was mild and well tolerated. The use of a dense-dose regimen is useful and well tolerated in patients with very high risk diffuse large cell lymphoma. The addition of rituximab did not improve outcome in these setting of patients.

Second Lethal Events Associated with Treatment for Hodgkin's Disease: A Review of 2980 Patients Treated in a Single Mexican Institute

Presence of second neoplasms and cardiac toxicity has been recognized as potential late lethal second events in patients treated for Hodgkins disease. However, most reports analyze these association independently. We reviewed 2980 cases of patients treated during 1970-1995 with long-term follow-up (> 4 years) in an attempt to identity all late events in Hodgkins disease secondary to the treatment or those which are unrelated. Three hundred and ten patients died, and of these 156 were secondary to relapse and tumor progression. Death associated second tumors and cardiac events were increased 37 fold and 29 fold respectively compared to the general population. The risk factors for this complications did not differ to previous reports and included alkylating agents and/or radiotherapy for second neoplasms and anthracycline therapy and radiotherapy for cardiac toxicity. Moreover, 61 patients died secondary to non-related events. Nevertheless, at 20-years overall survival was 90% (95% confidence interval (CI): 78% to 97%) and event free surviva1 was 88% (95% CI: 76% to 96%) for these patients. Thus, second events, fatal in most cases, should be considered as an expected risk to the treatment in patients with Hodgkins disease; the proposed modifications of therapy may indeed be useful to avoid or diminish these complications in the future.