José C. Díaz-Maqueo

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.

Is Surgery Necessary in the Treatment of Primary Gastric Non-Hodgkin Lymphoma?

Fifty-two patients with primary gastric lymphoma were randomly assigned to two different surgical approaches. Twenty-eight cases were diagnosed by endoscopy and treated with chemotherapy CHOP-Bleo (cyclophosphamide, adriamycin, vincristine, prednisone and bleomycin) alternating with CMED (cyclophosphamide, metothexate, etoposide and dexamethasone). Twenty four cases underwent debulking surgery (partial or total gastrectomy) followed by the same chemotherapy. No differences were observed in relapse free disease or survival in resected or unresected patients. Complications were more frequent and severe in patients who underwent surgery. We believe that surgery is not necessary in the treatment of patients with primary gastric lymphoma.

Maintenance therapy with interferon alfa 2b in patients with diffuse large cell lymphoma

SummaryForty-eight consecutive patients with diffuse large cell lymphoma (DLCL) in complete remission (CR) after conventional chemotherapy were enrolled in a prospective clinical trial. The maintenance therapy was a random either nothing or interferon alfa 2b (IFN) 5.0 MU three times a week for one year.The median duration of CR in the patients treated with IFN has not been reached. After five years 60% of patients remain in CR compared to the control group who had a median CR of 40 months (p<0.001). Actuarial five-years survival in the IFN treated patients was 88% compared to 42% in the control group (p <0.001).Maintenance therapy with IFN has been beneficial in patients with DLCL with improvement of duration of CR and survival without the excessive toxicity of most common third generation regimen chemotherapy. We felt that IFN could be explored in most controlled clinical trials in patients with DLCL in CR after conventional chemotherapy.

Beta 2 Microglobulin Level as an Indicator of Prognosis in Diffuse Large Cell Lymphoma

We report results of our investigation of prognostic factors for patients with diffuse large cell lymphoma (DLCL) who were entered on the same treatment protocol and who had known pretreatment serum beta 2 microglobulin levels. Serum beta 2 microglobulin, bone marrow involvement, performance status and lactic dehydrogenase (LDH) levels were associated with a poor prognosis in univariate analysis. However, only beta 2 microglobulin remained of prognostic significance in a multivariate analysis with statistical differences at different cut off levels. We believe that beta 2 microglobulin levels accurately separate patients into low-, intermediate- and high-risk patients. It is concluded that serum beta 2 microglobulin is the most significant prognostic factor currently available for DLCL and should be incorporated in the initial staging in order to provide a basis for designing the therapeutic approach in these cases.

Effect of Granulocyte Colony-Stimulating Factor in Patients with Diffuse Large Cell Lymphoma Treated with Intensive Chemotherapy

We investigated whether Granulocyte colony-stimulating factor (G-CSF) could prevent myelotoxicity or accelerate hematopoietic recovery after intensive chemotherapy in previously untreated patients with diffuse large cell lymphoma (DLCL). Forty-two patients were included in a prospective clinical trial in which alternating chemotherapy ESAP (etoposide, Solu-Medrol, cytosine arabinoside, cis-platinum), m-BECOD (low doses methotrexate, bleomycin, epirubicin, cyclophosphamide, vincristine, dexamethasone), MVPP-Bleo (mitoxantrone, vincristine, prednisone, procarbazine, bleomycin) were administered by 9 cycles. Each cycle was followed by 10 days of G-CSF (5 micrograms/kg/day) started five days after chemotherapy compared to a control group which received chemotherapy without G-CSF support. Leucocytes and granulocytes were significantly higher in patients receiving G-CSF compared to the control group. The total number of days of leukopenia (WBC counts below 2.0 x 10(9)/L and absolute granulocytes below 1.0 x 10(9)/L) were longer in the patients without G-CSF compared to those who received G-CSF (14.1 days versus 1.9 days). Delays in treatment were most frequent in the control group: 38% versus 4% in all cycles. Infection episodes occurred in 41 out of 168 cycles (25%) in the control group compared to 7 out of 172 (4%) in the G-CSF arm. Complete response was achieved in 12 out of 22 (54%) in the control group compared to 16 out 20 (80%) in the patients who received G-CSF. Toxicity secondary to G-CSF was mild. G-CSF can be administered safely to patients with DLCL and results in improved hematologic recovery after intensive chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Intensive brief chemotherapy with hematopoietic growth factors as hematological support and adjuvant radiotherapy improve the prognosis in aggressive malignant lymphoma.

An intensive brief chemotherapy and radiotherapy regimen including high doses of cyclophosphamide (5 g/m2), etoposide (1 g/m2), epirubicin (180 mg/m2), and ifosfamide (5 g/m2) administered in a period of 30 days followed by involved field radiotherapy to sites of initial bulky disease was administered to 46 untreated patients with high‐intermedium and high‐risk malignant lymphoma. G‐ or GM‐CSF were used as hematological support instead of bone marrow transplantation. All patients had more than 3 adverse prognostic factors at diagnosis.

Value of Serum Beta 2 Microglobulin as an Indicator of Early Relapse in Diffuse Large Cell Lymphoma

In patients with diffuse large cell lymphoma treated with chemotherapy the presence of high levels of serum beta 2 microglobulin has been considered as a bad prognostic factor. Until now, attempts to detect early relapse in patients with diffuse large cell lymphoma have been sparse. To address this issue we began a prospective clinical trial to evaluate the role of different clinical, laboratory and radiographic tests in the detection of early relapse in non-Hodgkins lymphoma (NHL). Only serum beta 2 microglobulin levels had clinical significance and 26 of 53 patients (49%) had abnormal levels, 3 to 23.1 months (mean 8.5 months) before evident relapse. Elevated serum lactic dehydrogenase (LDH) levels and beta 2 microglobulin were observed in six patients and all relapsed, suggesting that the combination of these two tests should be considered in future prospective clinical trials in order to define the utility of both tests to detect early relapse. This information may allow us to begin chemotherapy when the tumor mass is still low thereby making the probability of achieving a long second remission more likely.

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.

Rituximab in the treatment of refractory follicular lymphoma -- six doses are better than four.

Seventeen patients with refractory follicular lymphoma heavily treated with chemotherapy (>2 regimens), radiotherapy, and biological modifiers were enrolled in a pilot study to receive six weekly doses, instead of the more frequent four doses, of monoclonal anti CD20, at a standard dose of 375 mg/m(2). In an intent-to-treat analysis, overall response was 76%, of which 47% (8 patients) were a complete response. With a median follow-up of 33.6 months, 7 complete responders remained alive and free of disease, and 2 partial-response patients remained stable without additional treatment. Actuarial curves showed that at 3 years, 53% of patients should be alive and free of disease. The 4 patients who were failures died secondary to tumor progression. Overall survival at 3 years was 76%. Toxicity was mild; all patients completed the schedule on time and doses. The addition of two doses of anti-CD 20 clearly improved the outcome in a group of patients with refractory follicular lymphoma heavily treated and poor prognostic factors. However, the number is too small to drawn definitive conclusions, and more clinical trials are necessary to determine if four of six doses of anti-CD20 therapy are better in this setting of patients.

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.