Agustin Avilés

The role of surgery in primary gastric lymphoma: results of a controlled clinical trial.

Objective:We began a controlled clinical trial to assess efficacy and toxicity of surgery (S), surgery + radiotherapy (SRT), surgery + chemotherapy (SCT), and chemotherapy (CT) in the treatment of primary gastric diffuse large cell lymphoma in early stages: IE and II1. Summary Background Data:Management of primary gastric lymphoma remains controversial. No controlled clinical trials have evaluated the different therapeutic schedules, and prognostic factors have not been identified in a uniform population. Patients and Methods:Five hundred eighty-nine patients were randomized to be treated with S (148 patients), SR (138 patients), SCT (153 patients), and CT (150 patients). Radiotherapy was delivered at doses of 40 Gy; chemotherapy was CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) at standard doses. International Prognostic Index (IPI) and modified IPI (MIPI) were assessed to determine outcome. Results:Complete response rates were similar in the 4 arms. Actuarial curves at 10 years of event-free survival (EFS) were as follows: S: 28% (95% confidence interval [CI], 22% to 41%); SRT: 23% (95% CI, 16% to 29%); that were statistically significant when compared with SCT: 82% (95% CI, 73% to 89%); and CT: 92% (95% CI, 84% to 99%) (P < 0.001). Actuarial curves at 10 years showed that overall survivals (OS) were as follows: S: 54% (95% CI, 46% to 64%); SRT: 53% (95% CI, 45% to 68%); that were statistically significant to SCT: 91% (95% CI, 85% to 99%); CT: 96% (95% CI, 90% to 103%)(P < 0.001). Late toxicity was more frequent and severe in patients who undergoing surgery. IPI and MIPI were not useful in determining outcome and multivariate analysis failed to identify other prognostic factors. Conclusion:In patients with primary gastric diffuse large cell lymphoma and aggressive histology, diffuse large cell lymphoma in early stage SCT achieved good results, but surgery was associated with some cases of lethal complications. Thus it appears that CT should be considered the treatment of choice in this patient setting. Current clinical classifications of risk are not useful in defining treatment.

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.

Adjuvant radiotherapy to sites of previous bulky disease in patients stage IV diffuse large cell lymphoma.

PURPOSE To evaluate the usefulness of adjuvant radiotherapy to sites of previous bulky disease in patients with advanced diffuse large cell lymphoma (DLCL) who were in complete remission after chemotherapy. METHODS AND MATERIAL Two-hundred and eighteen patients were initially treated with combined chemotherapy CEOP-bleo (cyclophosphamide, epirubicin, vincristine, prednisone, bleomycin) alternating with DAC (dexamethasone, cytosine arabinoside, and cisplatinum). One hundred and fifty-five patients achieved complete remission. Eighty-eight patients with initial bulky disease were randomly assigned to either received (43 patients) or not received radiotherapy (45 patients). Dose ranged from 40-50 Gy. RESULTS The median time to treatment failure has not been reached in patients who received radiotherapy. At 5 years 72% of the patients treated with the combined therapy remain alive disease in free compared to only 35% in the control group. Projected survival at 5 years was better in the patients with adjuvant radiotherapy: 81% compared to 55% in the patients who received no radiotherapy. Toxicity was mild and manageable. No lethal toxicities were observed. CONCLUSION This treatment sequence produced durable control disease in patients with disseminated DLCL and bulky disease with acceptable toxicity. The role of radiation therapy in patients with disseminated DLCL will be confirmed in large clinical trials, but we felt that this sequence of treatment could be useful in patients with this clinical condition.

Treatment of non-Hodgkin's lymphoma of waldeyer's ring: Radiotherapy versus chemotherapy versus combined therapy

Treatment of stage IA non-Hodgkins lymphoma (NHL) of Waldeyers ring remains controversial, probably because of the small number of patients and the scarcity of controlled studies. Between 1981 and 1991, 316 patients with stage I NHL of Waldeyers ring were randomised for treatment with radiotherapy alone (extended fields), 101 patients; combined chemotherapy with a regimen of CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) or CHOP-like (epirubicin instead of doxorubicin), 106 patients; and combined therapy (radiotherapy followed by the same combination chemotherapy), 109 patients. Median follow-up was 6.8 years. Complete response was achieved in 93, 87 and 97%, respectively. Relapses were least frequent in patients treated with combination therapy. The 5-year rate for failure-free survival was 48% for radiation therapy, 45% for the patients who were treated with chemotherapy, which was statistically significantly less than the 83% for patients treated with combined therapy (P < 0.001). Overall survival was also better in the combined therapy arm: 90%, statistically different to 58% for the patients treated with chemotherapy alone and 56% for patients treated with radiation therapy (P < 0.001). Toxicity was mild and late side-effects were not observed in any patients. From these results combined therapy should be considered as the best therapeutic approach in patients with localised NHL of Waldeyers ring.

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.

Interferon alpha 2b as maintenance therapy in low grade malignant lymphoma improves duration of remission and survival.

We assessed the efficacy and toxicity of interferon alpha 2b (IFN) as maintenance therapy in patients with low grade malignant lymphoma. Between March 1986 and December 1989, 98 patients with low-grade malignant lymphoma in complete remission after conventional chemotherapy were randomly assigned to received IFN, 5.0 MU three times a week for one year, as maintenance therapy (n = 48), or to receive no treatment (control group, n = 50). In March 1994, the median duration of response had not yet been reached in the patients treated with IFN compared to 46 months in the control group. At 9-years 62% of the patients in the IFN arm remain in first complete remission compared to only 25% in the control group (p <.001). In addition, the median duration of survival has not yet been reached in either the IFN arm compared to 74 months in the control group (p <.001). Quality of life was excellent in both groups and severe side effects secondary to IFN treatment were not observed. All patients completed the planned dose of IFN. We conclude that IFN as maintenance therapy in low-grade malignant lymphoma is an excellent therapeutic option because it improves the duration of remission and survival without producing severe side effects or reducing the quality of life.

Non-Hodgkin's lymphomas and pregnancy: Presentation of 16 cases

Chemotherapy and obstetric care of 16 pregnant patients with non-Hodgkins lymphoma are reported in this paper. All patients received chemotherapy during the various trimesters of pregnancy, including 8 cases during the first trimester, and there was no evidence of congenital malformations in any offspring. Fifteen babies are alive, healthy, and at a normal level of growth 3 to 11 years after birth. Eight mothers who achieved complete remission are alive and free of disease, 4 to 9 years after delivery, without maintenance treatment and would be considered cured. On the basis of the present study it was concluded that pregnancy is not a contraindication for treatment of non-Hodgkins lymphomas, cytotoxic drugs do not necessarily cause congenital malformations, and long-term remission can be achieved in these mothers.

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.