Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients

doi:10.1182/blood-2003-04-1124Prepublished online October 23, 2003;

Christian GisselbrechtTilly, Bertrand Coiffier, Andre Bosly, Pierre Morel, Corinne Haioun, Philippe Gaulard, Felix Reyes and Marc P Andre, Nicolas Mounier, Xavier Leleu, Anne Sonet, Pauline Brice, Michel Henry-Amar, Herve on 2837 patientsnon-Hodgkin lymphoma with the ACVBP regimen. A GELA cohort study Second cancers and late toxicities after treatment of aggressive

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1

Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma

with the ACVBP regimen. A GELA cohort study on 2837 patients.

M. André1, N. Mounier2, X. Leleu3, A. Sonet4, P. Brice2, M. Henry-Amar5, H. Tilly6, B.

Coiffier7, A. Bosly4, P. Morel8, C. Haioun9 P. Gaulard9, F. Reyes9 and C. Gisselbrecht2. For

the Groupe des Lymphomes de l’Adulte, Department of Hematology, CHNDRF, Charleroi,

Belgium.

1.Hematology department, Centre Hospitalier Notre Dame et reine Fabiola, 3 Grand Rue, 6000 Charleroi, Belgium.

2. Hematology department, Hôpital Saint-Louis, 1 avenue C. Vellefaux, 75010 Paris, France.

3. Hematology department, Centre Hospitalier Universitaire de Lille, Place de Verdun , 59037 Lille Cedex, France.

4.Hematology department, Cliniques Universitaires Mont Godinne, 1 avenue G. Thérasse, 5530 Yvoir, Belgium.

5. Clinical Research Unit and INSERM CJF 96-03/GRECAN, Centre Régional François Baclesse, route de Lion-sur-Mer, 14076 Caen Cedex 5, France.

6. Hematology department, CENTRE HENRI BECQUEREL, Rue d'Amiens, 76038 ROUEN, France.

7. Hematology Department, Centre Hospitalier Lyon-Sud, 69495 Pierre-Bénite, France.

8. Hematology Department, Centre Hospitalier de Lens, 99, route de la Bassée, 62307 Lens, France.

9 Hematology and pathology department, Hôpital Henri Mondor, Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.

Address for correspondence : Marc ANDRE, MD, CHNDRF, Grand-Rue 3, 6000 Charleroi,

Belgium, Tel & Fax: 00-32-71-281671 E-mail: [email protected].

Word count : Total : 4040 Abstract: 199.

Copyright (c) 2003 American Society of Hematology

Blood First Edition Paper, prepublished online October 23, 2003; DOI 10.1182/blood-2003-04-1124 For personal use only. by guest on June 9, 2013. bloodjournal.hematologylibrary.orgFrom



2

Abstract

The survival of aggressive NHL is increasing but the incidence of secondary cancer and late

toxicities is poorly defined for these patient treated with CHOP-like chemotherapy.

From 02/1984 to 01/1998, 2837 patients with aggressive NHL received the control arm

chemotherapy ACVBP in three consecutive GELA studies.

With a median follow-up of 74 months, the 5 years overall and event-free survival were 60%

and 52%. 202 non-neoplasic late toxicities were reported and this resulted in a 5.35%

cumulative probability of incidence at 7 years. 81 second tumors were observed and the 7-

years cumulative incidence rate was 2.75%. There were 64 solid tumors and 17 hematologic

malignancies. In multivariate analysis, age was the only risk factor for the development of

second cancer. An epidemiological analysis allowed a comparison of this NHL group with the

general population. Considering all tumors, no excess of second cancer was observed. But in

the male population, there was an excess of lung cancer (SIR:2.45, p<0.001) and MDS/AML

(SIR:5.65,p=0.006) and in the female population there was an excess of MDS/AML

(SIR:19.9,p<0.001).

With a long follow-up, ACVB regimen is highly effective for the treatment of aggressive

NHL. An increase of secondary MDS/AML and male lung cancer was observed.

Introduction

The late sequelae, including secondary cancers and major organ dysfunction, have been

extensively studied in Hodgkin’s disease patients as a result of the successful treatment of this




3

disease for many years. Second cancer, including acute non-lymphoblastic leukaemia, caused

either by chemotherapy, radiotherapy or both have been reported by different group [1,2,3].

Much less have been published about non-Hodgkin’s lymphoma (NHL) because the disease

generally occurred at a more advanced age and therapies have been less successful.

Nevertheless, recent advances in the definition of risk groups and in therapies have improved

the prognosis of the disease and an increasing number of patients can now expect relatively

long-term survival. According to the International Prognostic Index, the 5-year survival of

NHL is between 26 to 73% [4] and recent therapeutic improvements including the use of

monoclonal antibodies will probably ameliorate these results [5]. Even in case of relapse,

high-dose chemotherapy with stem cell support will allow patient to be cured and therefore

expose them to the risk of late toxicities [6].

The ACVBP regimen has been used as the control arm by the GELA Group since 1984 in

multi-centric trials to treat aggressive non-Hodgkin lymphoma and have recently shown better

results than conventional CHOP chemotherapy [7,8]. This prompted us to perform a

retrospective cohort study of an homogenous population of 2837 NHL patients included in

three different GELA protocols to evaluate the occurrence of second cancers and late

toxicities. A special attention was drawn on secondary myelodysplasia and acute leukaemia.

Patients and methods

This retrospective analysis was performed on 2837 patients included in three consecutive

GELA trials, namely LNH84, LNH87 and LNH93, between February 1984 and January 1998.

The ACVBP regimen consisted in four cycles of Adriamycine 75 mg/m2 D1,

Cyclophosphamide 1200 mg/m2 D1, Vindesine 2 mg/m2 D1 and 5, Bleomycine 10 mg D1 and

5 followed by 2 cycles of Methotrexate 3000 mg/m2, 4 cycles of Ifosfamide 1500 mg/m2 and




4

VP-16 300 mg/m2 and 2 cycles of Cytarabin 100 mg/m2 D1-4. Prophylactic intrathecal

administration of 15 mg of Methotrexate was performed during the first four cycles.

The first trial, LNH84, was a multicentric non-randomized trial. All the patients of this

protocol were included in the present study [9].

The second trial, LNH87, was a multicentric randomized trial based on prognostic factors

different from those of the International Index because this trial was initiated before the

publication of the International Index. Risk factors were age, ECOG >1, large tumor mass

(>10 cm), extra-nodal localization >2, bone marrow and neurological involvement. Group 1

included patient less than 70 years-old with no risk factors. The reference chemotherapy was

ACVBP and those patients were included in this study [10]. Group 2 included patients less

than 55 years-old with at least one adverse prognostic factor [11]. Only patients who received

the adriamycin-containing chemotherapy and conventional consolidation were included in the

present study. Group 3 included patients >55 and <70 years-old with at least one adverse

prognostic factor. The reference chemotherapy was ACVBP and those patients were included

in the present study [12].

The third trial, LNH93 was a multicentric randomized trial based on the International

Prognostic Index. Groups 1, 2 and 3 included patients <60 years-old. In group 1 patients

without any adverse prognostic factor were randomized between CHOP and radiotherapy vs

ACVBP [9]. The latest were included in this study. In group 2, patients with one adverse

prognostic factor were randomized between ACVBP and an epirubicin-containing regimen.

Patients from the ACVBP arm were included in the present study. In group 3, patients with 2

or more adverse prognostic factors were randomized between ACVBP and an intensive high-

dose chemotherapy with stem cell support. The patients from the ACVBP arm were included

in the present study [13]. Group 5 included patients from 61 to 69 years-old with at least one




5

adverse prognostic factor. They were randomized between CHOP and ACVBP. The patients

from the ACVBP arm were included in the present study [8].

Initial staging procedure included bone marrow biopsy, CSF examination and computed

tomographic scan of chest and abdomen. Patients were classified according to the Ann Arbor

system. Serum lactate dehydrogenase (LDH) was expressed as a percentage of the highest

normal value. Central histological review was performed and B or T phenotype was

determined on deparaffinized tissue section for patient of LNH87 and LNH93. These

protocols were approved by the institutional ethics committee and all patients gave informed

consent.

Using the database of the GELA, patients assigned to the ACVBP regimen in the three

different protocols were identified. HIV positive lymphoma and non-lymphoma patients at

histological review were excluded from the study. Files were reviewed and data about

radiotherapy, occurrence of second cancer, any type of late toxicity (NCI grade II-IV) were

collected by means of a standardized form. Data were reviewed for each individual patient at

the GELA data center, if necessary additional information was requested from the responsible

investigator. Systematical review of all original files was not performed. For women less than

40 years-old occurrence of pregnancy was also recorded.

Second cancer included any tumor occurring after inclusion date. Previous cancer was an

exclusion criteria for the protocol excepted for basal skin carcinoma or non-invasive cervix

cancer. Late toxicities included any new toxicity occurring after chemotherapy completion, as

well as toxicities developing on therapy and continuing after the end of therapy [14].

Statistical methods




6

Follow-up started at the date of the end of the first NHL treatment and ended at the date of

death, date of second cancer or last examination whichever came first. Cancers observed were

classified by site and histological type in accordance with the oncology section of the

International Classification of Diseases [15]. Diagnoses used were those provided by centers

where the patient was followed.

The primary end point of the study was the occurrence of a solid tumour or haematological

cancer. It was calculated both as a cumulative probability or a cumulative incidence of second

cancer. The cumulative probability was calculated with a Kaplan–Meier estimate in which

data of patients who died were censored [16], curves were compared by the log-rank test [17].

Effects of potential risk factors on second cancer rates were examined in a Cox proportional-

hazards model [18]. The cumulative incidence curve, however, explicitly accounted for other

causes of death and was computed by the method of Gooley et al [19]. Demographic and

base-line laboratory data were compared for consistency among subpopulations with 2 tests

for nominal variables and t-tests for ordinal variables. All statistical tests were two-sided.

Analyses were performed with SAS software (version 8.0 , SAS Institute, Cary, N.C.) and S-

Plus (version 2000, Insightful, Seattle).

The incidence of second cancer in the NHL population was compared to the incidence of

cancer in the general population using the 1995 French registry of cancer after matching for

age and gender. In this part of the analysis, synchronous cancer, defined as cancer occurring

during the first year after diagnosis of lymphoma, were excluded and therefore, the time at

risk started 12 months after randomization and ended at the date of occurrence of second

cancer, the date of death, or the date of last known vital status. Basal skin carcinoma is not

reported to the French registry of cancer since 1990 and therefore this cancer was excluded

from this part of the analysis. Standardized incidence ratio (SIR) were calculated as the ratio

of observed to expected numbers based on cancer incidence data in France in 1995. The 95%




7

confidence limits were calculated assuming a binomial distribution of the observed numbers.

Finally, the excess number of cases was reported as the excess number of malignancies per

104 person-years at risk.

RESULTS

Patients characteristics and survival

Eight patients who were HIV positive lymphoma and 42 patients who were not non-

Hodgkin’s lymphoma at histological review were excluded from the analysis. LNH84,

LNH87 and LNH93 contributed respectively for 26%, 34% and 40% of the total cohort. The

main patients characteristics were (Table 1): median age: 54 years (range 8-79), male: 59%,

Stage III-IV: 60%, PS >1: 21%, elevated LDH: 49%, > 1 extra-nodal involvement: 36% and

bone marrow involvement: 22%. The 5 factors of the International Prognostic Index were

distributed as 0 (19%), 1 (24%), 2 (23%), 3 17%), 4 (13%) and 5 (4%). The histology was

diffuse large cell in 55%. Phenotype was not available for the LNH84 group. In the LNH87

and LNH93 groups, 83% were B-cell lymphoma and 17% T-cell lymphoma. Additional

radiotherapy (RT) was allowed by protocols and was administered as part of the initial

treatment to 4.3% of the patient. Refractory or relapsing patients received supportive care (31

%) or additional treatments: chemotherapy alone: 40 %, radiotherapy alone: 2.5 %,

chemotherapy and radiotherapy: 10.2 %, chemotherapy and high-dose chemotherapy with

stem cell support: 10.3 %, chemotherapy, radiotherapy and high-dose chemotherapy with

stem cell support: 6 %. Among the 207 transplanted patients, 195 received an autologous

transplant and 12 an allogenic transplant.




8

With a median follow-up of 74 months (range: 1-203), the 5 years overall survival was 60%

(±2%) and the 5 years event-free survival was 52% (±2%) (Figure 1).

Second cancers

81 second tumors were observed and the 7-years cumulative incidence rate was 2.75%

(Figure 2). Eight (5 solid tumors and 3 MDS/AML) of these 81 second cancers occurred after

an additional treatment for relapse or progression. There were 64 solid tumors (lung 22, skin

8, head and neck 5, uterus 5, colo-rectal 4, breast 4, kidney 2, bladder 1, prostate 1, gastric 1,

biliary tract 1 esophagus 1, ovary 1 and unknown origin 5). Among the 22 lung cancers, 9

were squamous cell carcinoma, 3 were adenocarcinoma, 1 was large-cell carcinoma, 7 were

small cell lung cancer and for 3 cases the histology was not available. Among the 8 skin

tumors there were 2 melanoma end 6 non-melanoma skin cancers. Only 1 tumor, a bladder

cancer, occurred in the field of radiotherapy. Two patients developed a third solid tumor.

These two third solid tumor were not included in the present analysis.

Median time from diagnosis of NHL to solid tumor was 47 months (range 2-183). Thirty-one

patients died from second solid tumor and the median time from diagnosis of solid tumor was

2.1 years (95%CI: 1.18-7.2) (figure 3).

Seventeen hematologic malignancies (AML 7, MDS 4, CML 2, CMML 1, polycythemia vera

1, essential thrombocytemia 1, myeloma 1) were observed. For the 12 cases of AML and

MDS, karyotype was available only in 2 cases of AML, showing either a monosomy 7 or a

t(8;21), and in one MDS showing a monosomy 7 associated to other abnormalities. All

patients presented with pancytopenia at diagnosis. Among them, type 2 and 4 in the FAB

classification were predominant. Of the 12 patients, 5 patients (4 AML, 1 MDS) were in first

complete remission of their NHL, 3 patients were in second complete remission. Eight out of




9

12 patients died from leukemia, one patient died from relapse of NHL while he was in CR

from his secondary AML, and one patient died from MDS without acutisation.

Median time from diagnosis of NHL to leukemia was 40 months (range 18-100), median

survival from diagnosis of MDS/AML was 1 years (95% CI: 0.45-1.62), and only one patient

had a prolonged survival after the diagnosis of his leukemia (figure 3).

During the course of the disease, patients experienced several competing events such as

death, second cancer or late toxicities. Risk factors associated with these different events were

evaluated. For death, prognostic factors were those of the International Prognostic Index (age,

stage, LDH, ECOG and >1 extra-nodal localization, p<0.001). In multivariate analysis, age

was the only significant risk factor for second cancer (p<0.0001). Gender, LDH, stage,

ECOG, extra-nodal involvement, relapse, stem cell transplantation at relapse, radiotherapy at

relapse and chemotherapy at relapse were not shown to have a significant influence.

Comparison to normal population

Among the 81 cases reported, 9 synchronous tumors occurring less than 12 months after the

diagnosis of NHL were excluded as well as 6 cases of basal skin cancer. Forty-nine solid

tumors (21 lung, 3 head and neck, 6 digestive, 4 breast, 7 genito-urinary, 2 melanoma and 6

miscellaneous) and all cases of hematological cancer were analyzed. This allowed us to

analyze 2,267 patients accounting for 9,847 person-year at risk. The observed second

neoplasm, SIR, and excess number are reported for male and female patients in tables 2 and 3

with various grouping of cancers . For all second cancer no excess of risk was detected for the

whole population (male, SIR 0.92; 95% CI, 0.67-1.24 and female, SIR 0.94; 95% CI, 0.59-

1.42, p value non significant for both). A significant excess of risk for secondary MDS/AML

was detected in the male population (SIR 5.65; 95% CI, 1.54-14.46, p=0.006) and was even

stronger in the female population (SIR 19.89; 95% CI, 7.98-40.97, p <0.001). For all solid




10

tumors, no excess of risk was identified (male, SIR 0.77; 95% CI, 0.54-1.07 and female, SIR

0.63; 95% CI, 0.35-1.06, p value non significant for both). But, in the male population only,

we observed a highly significant excess of risk of lung cancer (SIR 2.45; 95% CI, 1.48-3.83, p

<0.001). This resulted in an excess of 19.9 cases of lung cancer per 104 person-years at risk

(table 3).

Late non-neoplastic toxicities

There were 222 reported late non-neoplastic toxicities and this resulted in a 5.35 + 0.76

cumulative probability of incidence at 7 years (figure 4). 8.2 % of this late toxicities occurred

after additional treatment for refractory or relapsing lymphoma. In multivariate analysis, age

(p<0.0001) and relapse (p=0.02) were significant risk factors for late non-neoplastic

toxicities. Gender, LDH, stage, ECOG, extra-nodal involvement, stem cell transplantation at

relapse, radiotherapy at relapse and chemotherapy at relapse were not significant risk factors

in this multivariate analysys. The different causes of toxicities and death are reported in table

4. Late non-neoplastic toxicities resulted in 61 death and were the second cause of death after

NHL recurrence or progression. Late second cancers (31 deaths) were the third cause of

death. 17% of these late non-neoplastic toxic death occurred in patients who received

additional treatments after ACVBP for resistance or relapse after this first-line treatment. The

two major causes of late toxicities and death from late toxicities were infections and

cardiovascular events, resulting in 29 and 14 death respectively.

Hepatitis was the most frequent infectious complication. Because the different studies

recruited patients through the period of discovery of hepatitis C virus and HIV, several cases

of viral transmission through transfusions probably occurred. There were 12 cases of hepatitis

C transmission with one death, 2 cases of hepatitis B transmission and only one case of HIV

transmission. Two other hepatitis of unknown etiology also occurred. Seven late deaths were




11

attributed to aspergillosis and 4 to P. Carinii. Angina pectoris was the most frequently

reported cardiovascular complication (20 cases) but only 3 patients died from myocardial

infarction. Three other patients died from cardiac failure and 3 from arrhythmia. Ten cases of

ischemic stroke were reported resulting in 4 deaths. Eighteen patients reported disabling

peripheral neuropathy attributed to vindesine and two patient deceased from encephalopathy,

one of them after receiving brain radiotherapy. Nineteen patients experienced severe

psychological problems after treatment and this resulted in 3 deaths from suicide while in

complete remission. Three patients developed severe pulmonary fibrosis and two of them

died.

The other most frequently reported late complications were thyroid dysfunction (6 cases),

renal failure (5 cases), alcohol abuse (5 cases), benign tumor (3 cases), cataract (3 cases).

Five patients deceased from toxicity of autologous stem cell transplantation and 6 from

allogenic transplantation.

Pregnancies

Among the 2837 patients, 609 women were less than 40 years-old at the time of diagnosis of

NHL and 344 were in complete remission at the time of analysis. Thirty-one pregnancies were

reported in 26 patients. There were two therapeutic abortion and one death in utero. No

malformation was reported among the 28 children. The mean age at the time of pregnancy

was 26 years old and no pregnancy occurred after the age of 33.

DISCUSSION




12

In this study, the risk of second malignancies and other late toxicities was analyzed in 2837

patients treated with the same ACVBP regimen for NHL. These trials covering almost 20

years were retrospectively analyzed. With 9,847 person-year at risk, this represents one of the

largest studies ever reported on this subject. However, results must be interpreted cautiously

because of the retrospective design of this study. A total of 81 second tumors were observed

and the 7-years cumulative incidence rate was 3.5%. Overall, there was no increased risk of

developing a second cancer compared to the general population but there was a 5.6-fold risk

of developing MDS/AML in male and a 19.9-fold risk in female as compared with the general

population. In the male population, there was a strong 2.45-fold excess of risk of developing

lung cancer. However, with a median follow-up of 74 months, non-neoplastic toxicities are

accountable for much more deaths than second malignancies.

Therapy-related MDS/AML have been extensively described after treatment of Hodgkin’s

[20] disease or after use of high-dose therapy with stem cell support [21,22,23]. However, the

impact of high-dose chemotherapy by itself is unlikely to increase the risk generated by

conventional therapy [3,19]. Several investigations focused on secondary MDS/AML after

conventional chemotherapy for NHL [24, 25, 26, 27, 28, 29, 30]. In the series of Travis,

despite the excess of MDS/AML associated with therapy, secondary leukemia remained rare

events after NHL. Of 10,000 NHL patients treated for 6 months with various chemotherapy

agents and followed for 10 years, an excess of four leukemia could be expected [25]. Various

alkylating agents are used in the treatment of NHL. The increased incidence of MDS/AML

after prednimustine, chlorambucil, mechlorethamine and procarbazine for the treatment of

NHL is well known. Their risk increases with either cumulative dose and duration of therapy.

Cyclophosphamide-based regimens at a median cumulative dose of 12.5 g, were associated

with a non-significant 1.8-fold risk of AML, compared with treatments that did not include

alkylating agents. Increasing cumulative dose or duration of treatment with




13

cyclophosphamide was not associated with increasing risk of AML (P=0.57 and 0.33,

respectively) [25]. This weak association between small cumulative doses of

cyclophosphamide and AML is consistent with the results of other studies [31], and is

reassuring, given the frequent use of this alkylating agent in current therapy of NHL.

Epipodophyllotoxins have clearly demonstrated a leukemogenic potential after treatment of

acute lymphoblastic leukemia. In NHL and also in our studies, they were not administered

without alkylating agents and therefore the individual leukemogenic risk of

cyclophosphamide, ifosfamide and VP-16 could not be evaluated in this study. However, as

suggested by one of our patient showing a t (8;21), a possible contribution of

epipodophyllotoxins to the occurrence of secondary MDS/AML can not be ruled out.

The increased risk of lung cancer associated with radiotherapy is well known[32,33]. A recent

large study on lung cancer after Hodgkin’s disease clearly linked this cancer to alkylating

agent and distinguished this toxicity from that of radiotherapy and tabacco use [34]. Travis et

al. reported that treatment with alkylating agents without radiotherapy was associated with

increased lung cancer risk (RR=4.2). Statistically significant elevated risk was apparent

within 1-4 years after treatment with chemotherapy. In another case-control study, Kaldor et

al showed that Hodgkin’s disease patients treated with chemotherapy alone had about twice

the risk of developing lung cancer than those treated by radiotherapy and both modalities [35].

The finding that the risk of lung cancer following chemotherapy was higher than after

radiotherapy was unexplained and unexpected as it is in our study. Following alkylating agent

therapy, the risk of squamous cell lung cancer and small-cell lung cancer was statistically

significantly elevated [31]. In our series, these two histological type of tumor also represented

most of cases. A major limitation of our study, as well as of previous studies of lung cancer

in Hodgkin’s disease is the uncertainty of risk associated with treatment, in view of the great

risk conferred by tobacco use. While information on radiotherapy and chemotherapy was




14

consistently available in medical records, informations on smoking habits were not

systematically reported in formats used for epidemiological purposes. During the time of this

study (1984-2000), the incidence of smoking ranged between 25% and 36% (male: 30-47%,

female: 19-27%) in our countries [36]. The excess of lung cancers among male patients may

partially be explained by the consistent, 10%-higher incidence of cigarette smoking among

male. However, the difference of lung cancer among male and female population was major

in this study. Therefore, the possibility of a difference between male and female for this

tumor, despite different smoking habits, may not be ruled out. A recent review of the

literature on the association between smoking and NHL found no evidence that tobacco could

increase the risk of NHL [37]. The probability that our large NHL population would have

different smoking habits than the general population is this low and may reflect a true increase

of lung cancer secondary to chemotherapy in the male population.

Only one bladder cancer was reported in this series, although cyclophosphamide is known to

induce this late complication. This low incidence is related to the low cumulative dose (4.8

mg/m2) and short duration of treatment. In the largest study reported on bladder cancer after

cyclophosphamide, the risk was strongly associated with cumulative dose and patients

receiving less than 20 g had only a 2.4-fold increased risk [38].

Among agents used in the treatment of non-Hodgkin’s lymphoma, anthracyclines are the most

important in causing direct injury to the heart. However since the heart has considerable

compensatory reserves, a long time elapse before heart failure becomes manifest. In the study

of Miller [39], left ventricular dysfunction was found in 7 of 201 patients treated with 8 cycles

of CHOP (cumulative dose of doxorubicin 400 mg/m2), while in the group treated with 3

cycles combined with radiotherapy none of 200 patients developed left ventricular

dysfunction. Seven patients treated with the 8 cycles of CHOP but only two treated with 3

CHOP and radiotherapy subsequently died of heart disease. In our study, left ventricular




15

function was not systematically assessed but only 3 patients died from cardiac failure. They

received a cumulative dose of doxorucine of 300 mg/m2.

Injury to ovary by radiation or chemotherapy can cause sterilization and suppressed sexual

hormone production. In woman, the assessment of gonadal function after treatment of

lymphoma is difficult because the ova and ovary are not easily accessible for study.

Therefore, the surrogate markers of woman’s fertility are regular menses, oestrogen levels

greater than 20 pmol/L, and the ability to become pregnant. Bokemeyer [40] reported 10

women with NHL treated with CHOP and radiotherapy. One of them showed elevated level

of serum gonadotrophins and decreased oestradiol as an indicator of gonadal toxicity, with

abnormalities of the menstrual cycle. In the series of Müller, 1 of 7 woman was found to have

gonadal dysfunction after MACOP-B or VACOP-B [41]. In our series, we showed that

fertility may be preserved after 4.8 g/m2 cyclophosphamide, but no pregnancy was observed

for woman aged more than 33 years-old at time of NHL diagnosis. Several reports have

shown preservation of fertility even after high-dose chemotherapy with stem cell support [42].

NHL patients experienced after treatment elevated risks for late toxicities, therapy-related

leukemia and several solid tumors. Although, especially for second cancer occurrence, this is

substantially less frequent than for patients with Hodgkin’s disease. Genetic predisposition to

drug induced second cancers may be in the future a valuable tool to tailor therapy to

individual patients [43], but, in the meantime, a careful continuous follow-up of our

lymphoma patients is recommended to correctly evaluate late toxicities and second cancers

and to allow the design of new less toxic regimens.

Acknowledgments

Supported by grants from the Programme Hospitalier de Recherche Clinique (AOM95061)

from the Ministère de la Santé and from Amgen, Roche, Schering-Plough and Asta Medica..




16

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21

Figure 1: overall survival and event-free survival of the 2837 NHL patients treated with the

ACVBP regimen with a median follow-up of 74 months.

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16Years

% survival

OS

EFS




22

0 2 5 5 0 7 5 1 0 0 1 2 50 .0 0

0 .0 2

0 .0 4

0 .0 6

0 .0 8

0 .1 0

T im e ( m o n th s )

Cum

ulat

ive

inci

denc

e

Figure 2: cumulative probability of incidence of second cancer after the ACVBP regimen in

2837 NHL patients.




23

Figure 3: survival from diagnosis of second solid tumour and secondary MDS/AML.

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10Years

% survival

Solid tumor

MDS/AML




24

0 2 5 5 0 7 5 1 0 0 1 2 50 .0 0

0 .0 2

0 .0 4

0 .0 6

0 .0 8

0 .1 0

T im e ( m o n th s )

Cum

ulat

ive

inci

denc

e

Figure 4: cumulative probability of incidence of late non-neoplastic toxicity after ACVBP

regimen in 2837 patients.




25

Characteristics

Total cohort

N= 2837

LNH84

N=779

LNH87

N=954

LNH93

N=1104

Median age 54 (8-79) 48 (8-79) 58 (15-70) 52 (15-69)

Male 59% 62% 56% 60%

ECOG >1 21% 26% 19% 18%

Stage III-IV 60% 62% 59% 59%

LDH > normal 49% 48% 48% 50%

Marrow involvement 21% 29% 19% 18%

Extra-nodal >1 36% 39% 37% 34%

IPI 0-2 66% 66% 65% 67%

3-5 34% 34% 35% 33%

Diffuse large cell 43% 53% 64% 55%

Phenotype cell B NA 80% 84% 83%

Initial radiotherapy 4% 6% 5% 3%

Additional treatments for refractory or relapsing disease

No treatment 34.2% 36.9% 21.3% 31%

CT 44 % 37.9 % 37.3 % 40%

RDTH 3% 2% 2.5% 2.5%

RDTH and CT 8.3% 11.6% 11.3% 10.2%

CT and ASCT 8.7% 6.5% 15.7% 10.3%

CT, ASCT and RDTH 1.8% 5.1% 11.9% 6%

Table 1: characteristics of the patients.




26

Second cancer Observed SIR 95% CI P value Excess numbers

All types 22 0.94 0.59-1.42 0.64 -

Solid tumors 14 0.63 0.35-1.06 0.97 -

Breast 4 0.47 0.13-1.20 0.97 -

AML/MDS 7 19.89 7.98-40.97 <0.001 15.9

Table 2: SIR and excess number of second cancer in the female population (947 patients)

Second cancer Observed SIR 95% CI P value Excess numbers

All types 44 0.92 0.67-1.24 0.73 -

Solid tumors 35 0.77 0.54-1.07 0.95 -

- lung 19 2.45 1.48-3.83 <0.001 19.9

-head and neck 2 0.38 0.005-1.37 0.97 -

-digestive 5 0.52 0.17-1.12 0.96 -

AML/MDS 4 5.65 1.54-14.46 0.006 5.8

.

Table 3: SIR and excess number of second cancer in the male population (1320 patients)




27

CAUSES N= Death

Infectious 61 29

Cardio-vascular 54 14

Neurological 20 2

Psychological 19 3

Pulmonary 12 6

Miscellaneous 36 7

TOTAL 222 61

Table 4 : late non-neoplastic toxicities and related death.




Documents

Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients