Raúl Ambriz Fernández

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

RETRACTED

Nasal NK/T-cell lymphoma with disseminated disease treated with aggressive combined therapy

Thirty-two patients with nasal NK/T-cell lymphoma and disseminated disease (lung, skin, and bone marrow) were treated with an intensive combined therapy that consisted of three cycles of CMED (cyclophosphamide 2 g/m2, metothrexate 200 mg/m2, etoposide 600 mg/m2, and dexamethasone 80 mg/m2 with leucovorin rescue administered 24 h after) every 14 d, following high-dose radiotherapy: 55 Gy in 20 sesions to centrofacial region and three cycles more of the same chemotherapy regimen. To ameliorate the presence of severe granulocytopenia, granulocyte colony-stimulating factor, 5 µg/kg, daily for 14 d, begun on d 2 after chemotherapy, was administered. Complete response was achieved in 21 cases (65%); failure or progression was observed in 11 cases (35%). With a median follow-up of 69.1 mo, relapse has not been observed; thus, actuarial curves at 5 yr showed that event-free survival (EFS) is 100% in 21 patients and overall survival (OS) is 65%. Granulocytopenia grade IV was observed in 15% cycles, Nonhematological toxicity was mild and well tolerated. Radiotherapy was well tolerated; only mild mucositis was observed. Nasal NK/T-cell lymphoma is an rare presentation of maligant lymphoma (<1% of all cases) with a worse prognosis; less than 5% patients are alive free of disease at 1 yr. The use of intensive more specific chemotherapy and high dose of local radiotherapy, appear to be an excellent therapeutic approach with improvement in EFS and OS.

Combined therapy in advanced stages (III and IV) of follicular lymphoma increases the possibility of cure: results of a large controlled clinical trial.

Abstract: Objectives: We evaluate the long‐term results of a randomized clinical trial in patients with advanced stages (III and IV) of follicular lymphoma using chemotherapy or combined therapy (chemotherapy following by adjuvant radiotherapy in patients with nodal bulky disease). Material and methods: Between 1981 and 1995, patients with follicular lymphoma were treated with combined chemotherapy, mostly anthracycline‐based regimens; patients who achieved complete response were randomly assigned either to receive adjuvant radiotherapy to sites or to nodal bulky disease or not (control group). Results: Four hundred and sixty‐nine patients were randomized; in an intent‐to‐treat analysis all were evaluable for efficacy and toxicity. Actuarial curves at 20 yr showed that event‐free survival (EFS) and overall survival (OS) in the control group were 41% [95% confidence interval (CI) 36–56%) and 71% (95% CI 65–78%), respectively; these were statistically different from results for the patients who received adjuvant radiotherapy: 68% (95% CI 62–72%) and 89% (95% CI 79–96%), respectively (P < 0.01). Acute and late toxicity were minimal; only four patients (< 1%) developed myelodysplastic syndrome/acute leukemia. Cardiac toxicity was 2%, but one case was lethal. Thirty‐six patients (8%) died secondary to unrelated causes, in complete remission. Conclusions: The use of adjuvant radiotherapy in patients with poor‐prognosis follicular lymphoma increases EFS and OS with minimal toxicity. We feel that follicular lymphoma should be treated curatively because < 80% of patients will be in first complete response at < 20 yr. The use of adjuvant radiotherapy will be considered in the first line of treatment in this set of patients.

Testicular Lymphoma: Organ-Specific Treatment Did Not Improve Outcome

Objectives: To assess whether the use of an organ-specific treatment could improve event-free survival (EFS) and overall survival as endpoints in testicular lymphoma in the early stage: IE and IIE. Methods: Thirty-four patients were selected to be treated with orchiectomy following six cycles of anthracycline-based combined chemotherapy and radiotherapy (scrotum and contralateral testis in stage IE, contralateral testis and lymph nodes in stage IIE). Prophylaxis to the central nervous system was administered with four monthly cycles of a high dose of methotrexate: 6 g/m2. Results: Complete response was achieved in 33 cases (97%). However, relapses continue to be the rule; at a median follow-up of 74 months (range 61–120), 21 patients relapsed. Thus, actuarial curves at 5 years were 32% for EFS and 30% for overall survival, because all patients with failure and relapse died of tumor progression. Relapses were observed in uncommon sites: lung, bone marrow and as disseminate disease; no relapses were observed in irradiated sites of the central nervous system. Conclusions: Testicular lymphomas remain a problem as regards defining the optimal treatment. The use of a specific treatment based on organ-involved sites did not show any improvement in outcome. It is evident that more specific therapies need to be explored.

Gemcitabine and Cisplatin in Refractory Malignant Lymphoma

Objective: We performed a pilot study to evaluate the effect of the high-dose gemcitabine-cisplatin combination in a brief weekly regimen in the treatment of primary refractory diffuse large cell lymphoma with high or high-intermediate clinical risk. Methods: Thirty patients refractory to first-line anthracycline-based chemotherapy were treated with a combination of gemcitabine (1.5 g/m2 i.v.) and cisplatin (50 mg/m2 i.v.) on days 1, 8, 22, 29, 42 and 49. No further treatment was administered. Results: Complete response rate was 53%; and only two relapses have been observed at the last follow-up. Thus actuarial disease-free survival at the 3-year follow-up was: 87% (95% confidence interval, CI: 70–93%) and overall survival 53% (95% CI: 44–63%). Toxicity was mild, and treatment was well tolerated. No treatment-related death was observed. Conclusions: The gemcitabine-cisplatin combination appears to be promising in the treatment of refractory lymphoma patients, with a low toxicity. However, a longer follow-up is needed to confirm the results. In our opinion, prolonged chemotherapy (6–8 cycles) did not improve outcome. At present, we are testing if the use of monoclonal antibodies (anti-CD20) employed as maintenance therapy may improve disease-free survival and overall survival.

Spinal Cord Compression as a Primary Manifestation of Aggressive Malignant Lymphomas: Long-term Analysis of Treatments with Radiotherapy, Chemotherapy or Combined Therapy

A controlled clinical trial evaluated the usefulness of three different therapeutic approaches in the treatment of spinal cord compression (SCC) as primary manifestation of malignant lymphoma with the following end-points: neurological function, event free survival (EFS) and overall survival (OS). Forty-eight patients with SCC as unique manifestation (IE) of malignant lymphoma, were randomly assigned to receive either: radiotherapy (16 patients), chemotherapy (11 patients) or combined therapy (radiotherapy followed by chemotherapy, 21 patients). Although neurological recovery was similar in both groups, EFS and OS were better in the combined therapy arm. Actuarial curves at 10 years showed that EFS was 50% for patients treated with radiotherapy, 46% in the chemotherapy arm and 76% in the combined therapy group. Overall survival was 58, 38 and 76%, respectively, however because of the small number of patients, no statistical differences were observed. Although malignant lymphoma with SCC as primary manifestation could be considered as a localized disease, more patients could have microscopic disseminated disease. The use of combined therapy improves the outcome in this group of patients, and so it should be considered the treatment of choice.

Lack of Prognostic Factors in Follicular Lymphoma

We performed a retrospective analysis of prognostic factors in patients with stage III and IV and high-tumor burden follicular lymphoma (FL) treated with uniform schedules and with a long term follow-up. Eight-hundred and ten patients treated with intensive, anthracycline-based, chemotherapy and adjuvant radiotherapy to sites of initial bulky nodal disease were the basis of this analysis. Age >60 years, presence of B symptoms, bulky disease, >2 extranodal sites involved, high levels of LDH and the presence of serous effusions all identified as worse prognostic factors in univariate analysis were subject to multivariate analysis. Three factors remained significant: age >60 years old, presence of B symptoms and >2 extranodal sites involved and these were found to influence overall survival (OS) and progression-free survival (PFS). We developed a score system and only two groups (score 0 and 1 and score 2 and 3) showed statistical significance in OS. When the International Prognostic Index was applied to these patients, no statistical differences were observed in OS and PFS between the four groups. Comparison of our results with multiple previous studies showed a lack of uniform prognostic factors and adequate prognostic classification could not be performed. In conclusion, it is mandatory for multicentric international clinical analysis to define prognostic factors and search for a clinical classification, as in diffuse large B cell lymphoma, so as to define groups of FL for more aggressive or conservative therapy.

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.

Radiotherapy versus combined therapy in early stages with bulky disease aggressive malignant lymphoma.

Abstract The purpose of this study was to evaluate the use of radiotherapy compared with combined therapy (radiotherapy followed by chemotherapy) in early stages (I and II) in patients with diffuse large cell lymphoma and bulky disease. One hundred and thirty patients were randomly assigned to receive either radiotherapy involved field doses range from 40 to 48 Gy (median 44.5 Gy) or the same radiation therapy following chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone, by six cycles. Complete response (CR) was achieved in 58 out of 61 patients (95%) of the patients whose received radiotherapy, that was no different to 91% (63 out of 69 patients) in the combined therapy arm. However, at 10-years event-free survival (EFS) was 68% (95% confidence interval (CI): 61-73%) in the radiotherapy arm that was statistical different to 90% (95% CI: 86-94%) in the combined therapy group (p<0.01). Overall survival (OS) showed statistical differences: 72% (95% CI 67-76%) in the radiotherapy group compared to 89% (95% CI: 84-93%) in the combined therapy arm (p<0.01). Toxicity was mild in both groups, at this time, no second neoplasm or acute leukemia has been observed. We conclude that combined therapy appear to be superior in patients with early stages and bulky disease in patients with aggressive malignant lymphoma.

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.