María J. Nambo

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.

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.

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.

CMED in the treatment of nasal natural killer cell lymphoma with distant metastases

Abstract Introduction: Nasal natural killer (NK) cell lymphoma that showed distant metastases generally showed an poor prognosis. We described a group of patients with these atypical presentation and that were treated with an intensive, short chemotherapy/radiotherapy regimen. Methods: Sixty-one patients fulfilled the criteria for NK cell lymphoma with distant metastases and all have very poor prognostic factors: high clinical risk, multiple extranodal presentation and bulky disease (tumor mass >10 cm). They were treated with CMED (cyclophosphamide 2000 mg/m2, iv, day 1, methotrexate 400 mg/m2, iv, day 1(with leucovorin rescue), etoposide 400 mg/m2 twice and dexametasone 40 mg daily for 4 days). If complete response (CR) was observed, they were received adjuvant radiotherapy (50 Gy) to nasal region. Patients with failure were treated with different salvage treatments. Results: Forty nine patients achieved CR and 12 were considered failure, all patients that were failure and nine that relapse die secondary to tumor progression. Median follow-up were 46 months (range 34-68 months). Median has not been observed in relapse-free survival (RFS) and overall survival (OS). Actuarial curves at 5 years showed that RFS was 81% and OS was 65%. Treatment was well tolerated. Conclusions: Nasal NK cell lymphoma with distant metastases is considered an rare clinical entity, probably is under diagnosis because it has been included as stage III and IV in previous reports, that showed an very poor RFS and OS. The treatment herein report could achieve good response and outcome, but it is evident that more specific and aggressive therapy is necessary in these setting of patients.

ESHAP Versus Rituximab-ESHAP in Frail Patients With Refractory Diffuse Large B-Cell Lymphoma

BACKGROUND Treatment for refractory lymphoma in frail patients (older, poor performance status, or concomitant diseases) has not been defined. PATIENTS AND METHODS A total of 100 frail patients naive to rituximab therapy were allocated to be treated with ESHAP (etoposide, methylprednisolone, cytosine arabinoside, and platinum; 53 patients) or RESHAP (rituximab plus ESHAP; 47 patients). Granulocyte colony-stimulating factor was used to ameliorate the presence of severe granulocytopenia. RESULTS Overall response rate (ORR) and complete response (CR) were similar among ESHAP and R-ESHAP (ORR, 33 patients [62%] and 28 patients [60%], respectively; CR, 20 patients [37%] and 18 patients [36%], respectively). Actuarial curves at 5 years showed that progression-free survival (PFS) and overall survival (OS) were similar: 51% and 31% in the ESHAP arm and 50% and 26%, respectively, in R-ESHAP. Toxicity was severe in both groups; grade 4 granulocytopenia was observed in 30% and 32% of ESHAP and R-ESHAP arms, respectively. Viral infections were more frequent in R-ESHAP (52 cases) than in ESHAP (3 cases). CONCLUSION Frail patients, who generally have not been accepted in controlled clinical trials, can be treated with aggressive chemotherapy because tolerance is well and improvement in outcome is feasible. Although ESHAP retains the clinical efficacy previously reported in nonfrail patients, the addition of rituximab did not improve response rate, PFS, or OS.

Rituximab in the treatment of diffuse large B-cell lymphoma primary of the lung

Abstract Diffuse large B-cell lymphoma primary of lung (DLBCL-PL) is a rare presentation of extranodal lymphoma, in most cases chemotherapy-based anthracyclines: CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the treatment, with excellent outcome. The addition of rituximab to CHOP (R-CHOP) has been considered the gold standard in the treatment of nodal DLBCL. Thus, we assess in a large number of cases of DLBCL-PL whether the use of R-CHOP could improve survival in this setting of patients. Forty-two patients with DLBCL-PL, stage IE, age 65 years or younger, were treated with standard R-CHOP, no consolidation radiotherapy or maintenance therapy were considered. They were matched with patients who received CHOP alone to assess efficacy and toxicity. Complete response was observed in 35 patients (83%), and 7 patients were considered failure (16%). The study has a median follow-up of 42.8 months. Actuarial curves at 5 years showed that progression-free survival was 88 % and overall survival was 70 %. The results were not statistically different when compared retrospectively with patients who received CHOP alone. Treatment was well tolerated. The addition of rituximab to chemotherapy did not improve outcome in patients with DLBCL-PL.

RETRACTED: Randomized Clinical Trial to Assess the Efficacy of Radiotherapy in Primary Mediastinal Large B-Lymphoma

PURPOSE We developed a controlled clinical trial to assess the efficacy and toxicity of adjuvant-involved field radiotherapy (IFRT) in patients with primary mediastinal B-cell lymphoma that achieved complete response after the patients were treated with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP-14). METHODS AND MATERIALS Between January 2001 and June 2004, 124 consecutive patients who were in complete remission after dose dense chemotherapy and rituximab administration (R-CHOP14) were randomly assigned to received IFRT (30 Gy). Sixty-three patients received IFR, and 61 patients did not (control group). RESULTS The study aimed to include 182 patients in each arm but was closed prematurely because in a security analysis (June 2004), progression and early relapse were more frequent in patients that did not received IFRT. Patients were followed until March 2009, at which point actuarial curves at 10 years showed that progression free-survival was 72% in patients who received IFR and 20% in the control group (p < 0.001), overall survival was 72% and 31%, respectively (p < 0.001). Acute toxicity was mild and well tolerated. DISCUSSION Adjuvant radiotherapy to sites of bulky disease was the only difference to have an improvement in outcome in our patients; the use of rituximab during induction did not improve complete response rates and did affect overall survival; patients who received rituximab but not IFRT had a worse prognosis. CONCLUSIONS The use of IFRT in patients with primary mediastinal B-cell lymphoma who achieved complete response remain as the best treatment available, even in patients that received rituximab during induction.