The aim of the study was to determine if the use of an intensive regimen (dose-dense) of chemotherapy may improve the response rate and outcome in patients with primary breast lymphoma (PBL), which is considered as lymphoma presentation with a poor prognosis.
Methods: Patients with pathologically confirmed diagnosis of diffuse large B-cell lymphoma with clinical presentation in the breast (PBL), > 18 years old, stage I and II, negative for immunodeficient syndrome, hepatitis A and B, previously untreated, and having non-germinal center cells were included in an open label clinical trial. Phase II patients received a dose dense regimen of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone).
Results: Between July 2006 and December 2016, seventy-eight patients were enrolled in the study. Complete response was achieved in 76 (94.4%) patients. Five patients relapsed, so progression free survival at 5 years was 94.0% (95% confidence interval (CI: 87% to 98%%): three patients achieved a second response and are alive; the overall survival at 5-years was 95.3 (96% CI: 89% to 102%). Relapse at central nervous system has not been observed. Severe granulocytopenia was observed in 42.8 (93.0%) cycles, but no death associated with treatment was observed.
Conclusion: The use of a dose-dense regimen of chemotherapy improved the outcome in these patients; although severe acute toxicities were frequent, they were well-controlled. Relapse in central nervous system was not observed. Thus, we considered that dose-dense chemotherapy should be employed for this group of patients.
Primary breast lymphoma (PBL) is a rare lymphoma, arising in the breast without evidence of systemic disease. The most common histology is diffuse large B-cell lymphoma. This represents 0.5% of malignant breast tumors and 2% of all extranodal lymphomas. Until now, no clear treatment has been defined, probably due to the small number of cases
Dense-dose schedules have been employed in some cancers
Between July 2006 and December 2016, we studied patients with pathological diagnosis of diffuse large B-cell lymphoma, which was confined to the breast, in early stages I or II, previously untreated, age >18 years old without previous treatment, with pathological diagnoses including a battery of monoclonal and polyclonal antibodies: CD45, CD20, CD19, CD5, CD10, bcl-2, bcl-6, and MUM1, performance status <2, negative for immunodeficiency human syndrome, hepatitis B and C and associated with poor prognosis with elevated LDH and non-GCB genotype. Patients with stage III and IV, or a history of CNS disease were excluded. Staging included complete physical examination, measuring the two dimensions of tumor, complete blood counts, and serum chemistry. We also considered serum determinations LDH, and B2M, Immunodeficiency, hepatitis B and C virus, bilateral mammography and ultrasound, computed tomography of neck, thorax, abdomen and pelvis. International Project Index (IPI) was employed to determine clinical risks.
Chemotherapy Cyclophosphamide, 1500mg/m 2, , IV, day 1 Doxorubicin 75mg/m 2, , IV, day 1 Vincristine 2mg, standard dose, IV, day 1 Prednisone 60mg/m 2 , oral, days 1 to 5, in each cycle.
They were programed to receive 6 cycles, every 14 days, if hemoglobin>12 g/dL, granulocytes>1x 10 9 , platelets>100x10
Progression free survival (PFS) was considered from the beginning of the treatment to the date of failure, relapse, progression, toxic death or death from any cause; Overall survival (OS) was considered from diagnosis to death from any cause. Prognostic factors were age, stage, performance status, International Project Index (IPI) score, tumor size, genotype, use of hormonal therapy, smoking, marital status and previous pregnancies. In regards to PFS and OS, we used the Kaplan-Meir methods and comparison between groups, we used the log-rank test: Univariate analysis was carried out using Cox proportional hazards model; variables with a P<0.01 in univariate analysis were included in the multivariable analysis and the results were reported with a hazards ratio.
Eighty patients were considered, but two were excluded because they were at stage IV, so 78 patients were included in the study.
All patients were considered for treatment. The overall response rate was 97.4% and the complete response also was 97.4%. In both cases, the 95% confidence interval was 91.6 % to 106.4%. Relapse was observed in five patients, who were treated with salvage chemotherapy without stem cell transplant and three patients achieved a second longer response. With a median follow-up of 9.8 (range 5.8 to 14.7) years, the actuarial curves at 5 years showed that PFS was 93.45 %, and OS was 94.6%.
The most frequent adverse event was neutropenia: 428 (93.0%) cycles. The delay in treatment was observed in 107 (22.8 %), and hematological recovery was observed at a median of 6.8 (5 to 13) days. No death related to treatment was observed. At a longer follow-up, cardiac toxicity, second neoplasm and acute leukemia have not been observed.
The present study aimed to determine whether a dose-dense anthracycline-based regimen can improve the CR and outcome. The findings showed that six cycles of CHOP were beneficial in these patients, although they had adverse prognostic factors, such as non-GCB genotype, tumor size>5cm, elevated levels of LDH and beta-2-microglobulin, with more that 90% of patients alive, disease-free at more than 5 years. On the other hand, the central nervous system relapses are frequent in this neoplasm, but in the present study, we did not observe this adverse event.
Multiple studies have been performed, but no definitive results have been observed. The CHOP regimen is the standard therapy for diffuse large Bcell lymphoma. The addition of rituximab to CHOP remains controversial and some studies have reported improved outcomes while most did not observe any benefit.
The present study was biased regarding the evidence: the number of patients was small, and the study was performed in a single center. Our hospital is a tertiary reference cancer center, to which about 20,000 new cases of cancer refer, including a median of 455 new patients with malignant lymphoma. It is evident that these results should be validated in other studies, but the small number of patients prevented us from performing controlled clinical trials. The results showed that the use of a dose dense regimen of chemotherapy improves complete response rate and the outcome.
The study was conducted according the Declaration of Helsinki, and was approved by the Ethical and Scientific Committee of our Hospital (2006-HO-07). All patients signed informed consent to participate in the study.
The authors declare no conflict of interests.
This work did not receive any financial support and was performed with the resources of the Instituto Mexicano del Seguro Social.