Abstract

Patients with diffuse large B-cell lymphoma,(DLBCL) have an increased risk to developed a second neoplasm (SN). Multiple factors has been considered at risk : age, familial history, smoking, use of alkylant agents, or etoposide at increased doses, and especially  radiotherapy. Moreover, most  of the studies  has been performed in USA and Europe countries, with a preponderance of white population. The aim of the study is analyze an large number of patients with DLBCL  in a search to define the presence of SN in an Mestizo population.

Electronic files of patients with pathological confirmed diagnosis of DLBCL, treated in our hospital between  August 1988 to December 2020 ; age > 18 years age treated, with combined chemotherapy  that were in complete response for at least 3 years.  Probably factors associated were analyzed. Median follow-u were 22.4 (range 3.1 to 31.8) years.

A total of 9316 patients were evaluated , only 16 cases (0.16% ) developed  SN. Neither of previous mentioned  risks factors  were associated to the development of a SN, only race were different, 98 % of our patients were mestizo race. Until now race has not been considered as factor to be associated with the development of  an  SN. It is the first report of this association, than apparently show that SN  are less frequent in a Mestizo  population.: thus it is appear that Mestizo race would have an protective role.

Keywords

Diffuse large B-cell Lymphoma; Radiotherapy; Second Neoplasms; Race

Introduction

Non-Hodgkin lymphoma (NHL) is the most common hematological malignancy (HM) and considered that annually increase the incidence in most parts of the world ; in United States ,estimated 81560 new cases with 20 720 die secondary to the neoplasm in 2021 (1).Increased world wide from 1990 to 2019, in both sexes and in most geographics regions, as  in East Asia. NHL remain a substantial challenge globally and the incidence rates show marked different variation from country to country (2). Greater improvement has been observed in the treatment of this neoplasm; based in the best knowledge of biology, identification of  prognostic factors and the introduction of new therapeutic approaches. Thus, actually > 60 % of patients may be survivors at > 5-years, but longer survival has been associated with the appearance with later adverse events: cardiac disfunction, infertility , but the most disturbing  late complication is the development of a  (SN); that is associated with a poor response to treatment and poor prognosis. Seemingly, the risk remain for many decades after treatment of NHL.

These adverse event has been associated to various factors: age at treatment of NHL, familiar history of cancer, type and doses of cytotoxic agents, specially alkylant agents, use of radiotherapy, also other factors has been mentioned; as immunosuppressive status (not specified), family history, use of rituximab, and smoking. Moreover, most has been reported in sites of white populations: Europe and USA (3-10); and some studies has been reported in East Asia (12-15); and none in Latin America, or Africa that have a different ethnic population, Thus, we conducted and observational study in a Mestizo population, with homogenous histology and treatments schedules.

Patients and Methods:

From August 1988 to December 2020, patients with DLBCL who were diagnosed  and treated in our institution , with at least a 3-years of follow were including according with the following criteria: age > 18 years with no upper limit, no gender differences, previously untreated, negatives for presence of  acquired immunodeficiency ,hepatitis B and C, treated with combined anthracycline regimen, in complete response were including. The factors that were considered were age, stage, cumulative doses of cyclophosphamide and  doxorubicin, use of rituximab and radiotherapy ( fields and doses), positive history of familiar cancer and smoking.

According to the rules of our Department, the patients we evaluated every 3 months, from the first three years, every 6 months to 3 to 5 years, and annually until the last follow-up (December 2020).. The patients were evaluated with clinical examination, complete blood counts, serum chemistry, serum determinations of lactic dehydrogenase and beta 2 microglobulin, X ray of thorax, abdominal and pelvic ultrasound, if the patient report any specific sings or alteration in laboratory test, they were conducted for specific studies, to determine relapse, or SN including biopsy of the possible affected anatomic site. If SN was confirmed, they were send   to the Oncology service according to the pathological diagnosis to received specific treatment. If the patient die, autopsy was mandatory to establish the cause of death: secondary to second neoplasm or no cancer cause.

Results

We found 9316 patients that fulfilled the criteria entry. Demographic at diagnosis and at the time of appearance of SN are show in Table1, that is similar to the population all were in advanced stages (III and IV), no gender differences, 5075 (54.4%) were > 60 years old; 69.1 % had higher clinical risks, no history of familiar cancer was documented and 2622 (25.8%) were smokers. They were treated with standard CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone (1988-2002); R-CHOP: CHOP + rituximab, 2002-2008) and dose-dense CHOP (2008-2017). Radiotherapy was administer to 4025(40,4%) patients, most (3123 ,77.5 %) adjuvant treatment in patients with initial bulky disease at diagnosis. The doses ranged between 25 to 36 Gy.

Table 1: Demografhics and clinical characteristics.

A.-At diagnosis	No (%)
Number	9316 (100)
Sex:
Male	5001 (53.6)
Female	4315 (46.3)
Age (years: median	58.9
Range	27 – 77
<60	4241 (42.4)
>60	5075 (54.4)
Stage
III	3038 (32.6)
IV	6278 (67.3)
Familial history of cancer	0
Smokers	2622 (26.2)
Performed status
0,1	1230 (13.2)
2	3728 (40.0)
> 2	4358 (46.7)
IPI *
0,1	2765 ( 29.6)
2	4088 (42.7)
> 2	2463 (26.4)
Bulky disease (tumor mass > 10 cm)	3992 (42.8)
Treatment
CHOP-21	2916 (31.0)
R-CHOP-21	1970 (21.0)
CHOP-14	3011 (32.3)
R-CHOP-14	1419 (15.2)
Radiotherapy
Yes	4025 (40.4)
Total doses mg/m2
Cyclophosphamide
4500	5711 (61.03)
4501 – 6000	3605 (38.64)
Doxorubicine
300	6064 (65.10)
301 –450	3252 ( 34.09)

 Table 2 show the characteristics at the time of diagnosis of second neoplasms. Only 16 patients (0.17%) developed a SN, all were diagnosed in early stage, thus response was better that patients of general population Treatment for second neoplasmwas well tolerated and complete response was achieved in 7 cases (49%), at the last follow-up, 6 patients remain in complete response, 10 patients died secondary to tumor progression, at death no dates of DLBCL were observed. As expected outcome did no show any statistical differences between patients that developed second neoplasm or not (Table 3).

Table 2:  Second neoplasms. Characteristics.

Number	16 (0.17%)
Site	Lung	Prostate	Breast	Colon
	6	4	4	2
Male	3	4	0	1
Female	3	0	4	1
Age (years) at diagnosis of second neoplasm
<60	3	1	2	1
>60	3	3	2	1
Time to developed a second neoplasm (years):
5 – 10	2	0	1	0
5.1 – 10	0	1	2	0
10.1-20	1	0	1	1
20.1-30	2	0	0	1
> 30	1	3	0	0
Smoking	1	4	3	1
Cyclophosphamide  **
4500	6	4	4	2
>4500	0	0	0	0
Radiotherapy	1	0	1	0

Abbreviations: IPI: International Project Index; CHOP (cyclophosphamide, doxorubicine, vincristine and prednisone, administered every 21 days) CHOP-21 (CHOP administered every 14 days), R-CHOP (rituximab + CHOP) every 21 days); R_CHOP-14 (RCHOP administered every 14 days) ** dosis total of 6 cycles.

Table 3.

Univariaty análisis
	No(%)	p
Gender
Male	5001 (53.6)	0.565
Female	4315 (46.3)
Age (years)
<60	4241 (45.5)	0.601
>60	5075 (54.4)
Radiotherapy
Yes	4025 (43.2)	0.550
Not	5291 (56.7)
Performance status
0 – 2	4958 (51.3)	0.425
≥ 2	4358 (46.7
IPI *
Low	2765 (29.6)	0.020
Higher	6851 (72.2)
Treatment
Standard	4886 (52.4)	0.344
Dose-dense	4430 (46.9)
Total doses /m2
Cyclophosphamide
4500 mg	4946 (52.4 )	0.410
>4500 mg	4320 (46.5)
Doxorubicin:
300 mg	6064 (65.0)	0.889
>300 mg	3242 (35.3)

Discussion

We present the first report of patients with DLBCL in Latin America, with a prevalence of Mestizo population, that have a longer follow-up. We found only 16 cases (0.16%) were diagnosed. Multiple factors has been suggested to can influence on the development of second neoplasm. Chattopadhyay suggested that a familial history of previous cancers, could be associated to the risk of second neoplasms (4), in another report, they found that immune suppressed state is a key underlying mechanisms in the context of second neoplasms (5); Tao et al, observed an increased cases of second neoplasm in patients that received rituximab as induction treatment (6), and the same results were observed by Cho et al (11). Lee et al considered that second neoplasms are more frequent in adolescents and young adults with cancer, because response and longer survival, are common in most cancers in those age (7); Baras et al mentioned that the use of aggressive chemotherapy can be influence the development of this late adverse event (8). Yin et found that primary sites of DLBCL, can be associated to a second neoplasm in the same anatomic site (9). Recently, Major et suggested that stage and time interval since diagnostic will be considered as prognosis factor (10). Studies performed in East Asia considered that the increase of second neoplasms are associated with the increase number of cases (12-15).

We conducted an analysis of the mentioned prognostic factors associated to the development of second neoplasms, and we did not found any statistical differences, inclusive in patients that received higher doses of alkylant agents, and extensive radiotherapy. The unique difference that we considered that influence the development of this adverse events, was race.

Our population is a mixture of Spanish and aborigenal  people. Unfortunately, we did not found any reports   in Latin America. We consult with hematologist of El Salvador, Guatemala, Peru, Colombia, Ecuador and they did not have any study about this association. In the other hand, diagnosis of SN: because in all cases follow-up is performed in the same hospital when these were in early stage, because in our institution, all patients the follow-up is performed in the same hospital, and when any early abnormality (clinical or laboratory), more studies are performed, and treatment began immediately if a second neoplasm is confirmed.

It is evident than several bias were observed, first, it was conducted in a single people, not central pathology was performed, but the strength is that the treatment were uniform, they were an homogenous population, and a longer follow-up was observed. It is evident that studies with the same race will be available, to compare our results: thus we hope these study may induce to other hematological center performed an analysis of this disturbing complication in the treatment of DLBCL.

Conclusion

We present the first study that analyzes the possibility of developed a second neoplasms in patients with DLBCL, in a Mestizo population, with a large number of cases and longer follow-up.

We can no confirm that the mentioned risks factors to developed a second neoplasms were similar in our cases the only difference that can considered, is that our race population is Mestizo. Most of the studies has been reported in countries (USA and Europe) with a Caucasian population. Other studies has been performed in East Asia countries (Japan and Taiwan), with different races, and the rate of second neoplasms is minor that those reports. We contact colleagues in Peru, Colombia, Ecuador, Guatemala, El Salvador, with apopulation similar to our country, and they mentioned that the presence of second neoplasms treated for NHL, is rare.

References

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