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Long-Term Follow-Up of Patients with Intermediate or

High-Grade Non-Hodgkin Lymphoma Treated with a

Combination of Cyclophosphamide, Epirubicin,

Vincristine, and Prednisone

Fausto Rossini,M.D.1 Elisabetta Terruzzi,M.D.1 Daniele Perego,M.D.2 Isabella Miccolis,M.D.1 Franca Rivolta,M.D.1 Elena Manca,M.D.1 Enrico M. Pogliani,M.D.1

1Hematology Unit, Ospedale S. Gerardo, Monza,

Italy.

2Medical Unit, Ospedale di Desio, Desio, Italy.

Address for reprints: Fausto Rossini, Hematology Unit, Ospedale S. Gerardo, Via Donizetti 106, 20052 Monza (MI) Italy; Fax: (011) 39 23332440; E-mail: faustorossini@yahoo.it

Received July 8, 2003; revision received October 6, 2003; accepted October 8, 2003.

BACKGROUND.Doxorubicin cardiotoxicity is one of the most serious side effects of

the cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, regimen, especially among elderly patients. In the CEOP regimen, epirubicin was substituted for doxorubicin to reduce cardiotoxicity.

METHODS.Between March 1984 and September 1998, 186 previously untreated

patients with a histologically confirmed diagnosis of intermediate- or high-grade non-Hodgkin lymphoma according to the Working Formulation were treated with CEOP (cyclophosphamide, 750 mg/m2

, epirubicin, 75 mg/m2

, vincristine, 1.4 mg/ m2

; and prednisone, 60 mg per day orally on Days 1–5). Of 186 patients, 85 (45.7%) had Stage IV disease, and 60 (32.3%) had an International Prognostic Index score

⬎2. Comorbidity was present in 36 patients (19.3%).

RESULTS. Complete remission (CR) was achieved in 119 patients (64.3%), and

partial remission was achieved in 30 patients (16.2%). Among the patients who achieved a CR, 95 (79.8%) were still disease free at a median follow-up time of 86.9 months (range, 14 –200 months). The remaining 24 patients experienced disease recurrence, at a median follow-up time of 19 months (range, 3–101 months). The relative dose intensities were 0.69, 0.89, and 0.80 for vincristine, epirubicin, and cyclophosphamide, respectively. Two patients died of toxicity due to infection. Two patients, 59 and 73 years old, respectively, experienced arrhythmia. Another patient, age 64 years, who had a myocardial infarction 10 years earlier, had angina. One patient with hypertension experienced cardiac failure. No patients died of cardiac toxicity.

CONCLUSION.Long-term follow-up confirmed that CEOP is an effective and

well-tolerated chemotherapy regimen for intermediate- and high-grade lymphoma. The Results were promising, especially among elderly patients. Cancer 2004;100: 350 –5.© 2003 American Cancer Society.

KEYWORDS: lymphoma, chemotherapy, epirubicin, cardiotoxicity.

T

he cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapeutic regimen was introduced approxi-mately 25 years ago to treat patients with high-grade non Hodgkin lymphoma (NHL). Notwithstanding several attempts to identify more effective alternative regimens, two multicenter randomized studies have demonstrated that CHOP remains the best available treatment for patients with intermediate-to-high-grade NHL.1,2 However, the administration of doxorubicin (DOX) always has been limited by the risk of the onset of dose-related congestive cardiomyopathy, this risk dramatically increases after patients have received cumulative drug

© 2003 American Cancer Society DOI 10.1002/cncr.11907

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doses of 450 –550 mg/m2. The mechanism by which anthracyclines induce cellular cardiac damage has not been fully clarified. Formation of free radicals, with subsequent membrane damage, appears to be the main explanation. Other proposed mechanisms in-clude impairment of protein synthesis secondary to anthracycline binding of DNA to cardiac myocytes, accumulation of cardiotoxic metabolites in the myo-cardium, and impairment of mitochondrial function. Observed anthracycline-induced alterations in myo-cardial structure primarily include dilatation of the sarcoplasmic reticulum, myofibrillar loss, and intersti-tial fibrosis.3,4

Many strategies have been developed to overcome this obstacle, which in many instances represents the dose-limiting toxicity of DOX; these strategies include drug schedule modifications such as continuous infu-sion, the development of new and less cardiotoxic molecules, and, more recently, the association with cardioprotective agents.5

Of the less-toxic molecules, epirubicin (EPI) is the most well known. It is a semisynthetic L-arabino de-rivative of DOX in which the amino sugar, daunosamine, is replaced by acosamine. After inter-calation between DNA base pairs, EPI originates a topoisomerase II–DNA complex. This results in irre-versible DNA strand breakage, which gives the series of biochemical reactions that typically belong to the mechanism of action of anthracyclines.6

Therefore, cumulative high doses of EPI also can cause chronic irreversible cardiomyopathy, ultimately leading to congestive heart failure (CHF) that is qual-itatively identical to CHF observed after high cumula-tive doses of DOX.7 However, EPI toxicity occurs at cumulative doses⬎1000 mg/m2, considerably higher than the cumulative dose associated with DOX toxic-ity. The main reason for the reduced cardiotoxicity of EPI is that it does not accumulate in the myocardium to the same extent as DOX (approximately one-half as much).4In addition, other noteworthy adverse effects of anthracyclines, such as myelotoxicity, mucositis, nausea and vomiting, reversible alopecia, and local cutaneous reactions, are less frequent and less severe with EPI.5,6

Since its introduction in 1984, EPI has been used to treat NHL, replacing DOX in the CHOP regimen (CEOP regimen). The results indicated a better thera-peutic index, due to similar activity and a more favor-able safety profile for hematologic, nonhematologic, and cardiotoxicity.

The current study evaluated the rates of complete response, disease-free survival, overall survival, and toxicity in a group of patients treated with CEOP. Particular attention was paid to the evaluation of

out-come in elderly patients compared with younger pa-tients, because the treatment of older patients repre-sents one of the major challenges for the clinician.

MATERIALS AND METHODS

Between March 1984 and September 1998, 186 previ-ously untreated patients of both genders entered the current study. Requirements for entry in the protocol included a histologically confirmed diagnosis of NHL of intermediate or high grade, types E–H according to the Working Formulation (diffuse small cleaved cell; diffuse mixed, small, and large cell; diffuse large cell, cleaved or noncleaved; diffuse large cell immunoblas-tic), and Stage I–IV disease according to the Ann Arbor criteria. Patients previously treated for low-grade lym-phoma or patients who were infected with the human immunodeficiency virus were ineligible for participa-tion. Additional baseline eligibility criteria also in-cluded complete history and physical examination, performance status, weight, height, and tumor mea-surements. Laboratory and instrumental procedures and requirements comprised a complete blood count (leukocyte count ⱖ 3000/mm3 and platelet count

ⱖ 100,000/mm3 when not due to lymphoma), liver and kidney function tests (bilirubin levelⱕ1.3 mg/100 mL and serum creatinine level ⱕ 1.5 mg/100 mL), lactate dehydrogenase (LDH), electrolytes, protein electrophoresis (with immunoelectrophoresis when indicated), chest X-ray, chest and abdominal comput-erized axial tomography scan, bone marrow biopsy (usually performed from the iliac crest, with lumbar puncture and other biopsies performed only if needed), and electrocardiogram and echocardiogram to assess cardiac function (resting left ventricular ejec-tion fracejec-tion [LVEF]ⱖ50). On the basis of clinical and instrumental findings, the International Prognostic In-dex (IPI) score, which represents a predictive model of outcome for patients with aggressive NHL based on age, disease stage, performance status, number of ex-tranodal sites of disease, and LDH level, also was determined.

Treatment with the CEOP regimen consisted of cyclophosphamide, 750 mg/m2; epirubicin, 75 mg/m2; and vincristine, 1.4 mg/m2all intravenously adminis-tered on Day 1; and prednisone, 60 mg per day orally on Days 1–5. Cycles, up to a maximum of 6, were repeated every 3 weeks provided there was adequate bone marrow recovery. Patients with Stage I disease that was not bulky received only four courses. All patients with bulky disease received consolidation with radiotherapy on bulky localizations.

Clinical and laboratory investigations were re-peated after each 3-week cycle to define response. A complete blood count, with leukocyte and platelet

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counts, was performed weekly after the first course, before any following course, or when clinically indi-cated. Blood chemistry evaluations were repeated ev-ery 3 weeks to evaluate toxicity. Cardiac function was assessed to determine the resting LVEF before the first dose of EPI to monitor the occurrence of significant signs of cardiac impairment. The test was repeated after the end of therapy in patients age⬎55 years or in selected younger patients. In case of bone marrow involvement at baseline, a bone marrow biopsy also was performed at restaging.

The use of growth factors, even if not planned to maintain dose intensity, was allowed in selected pa-tients. A CR was defined as the disappearance of all detectable disease (i.e., no clinical signs and no evi-dence of disease on X-ray imaging) for a minimum of 4 weeks without the appearance of any new lesions and with the normalization of biochemical abnormal-ities related to lymphoma. A partial response (PR) was defined as a reduction of ⱖ50% in the sum of the products of the maximal perpendicular diameters of all measurable lesions for ⱖ4 weeks without the ap-pearance of any new lesions. Regression by⬍75%, no change, reappearance/progression of preexisting le-sions, or appearance of new lesions was considered to be no response.

Complete restaging was performed at the end of the six cycles of chemotherapy. Intermediate staging procedures were performed only for selected patients. After the completion of chemotherapy treatment, pa-tients with CR were observed for follow-up every 3 months during the first 2 years, every 6 months during the following 3 years, and yearly thereafter.

Age, gender, performance status, stage of disease, histologic type, number of extranodal sites, bone mar-row involvement, LDH, erythrocyte sedimentation rate, and serum albumin levels were the prognostic variables included in the univariate and multivariate statistical analyses. Survival curves were calculated according to the Kaplan–Meier method. The relative dose intensity (RDI), assessed separately for cyclo-phosphamide, EPI, and vincristine according to the method of Goldie and Coldman, was calculated only for patients who received at least four courses of che-motherapy. Comorbidity also was recorded.

RESULTS

The cohort of 186 patients who were treated with the CEOP regimen comprised 97 (52.2%) males and 89 (47.8%) females. Patients, had a median age of 55.8 years (range, 17– 81 years). Table 1 summarizes the main patient characteristics and the outcome of treat-ment observed in the entire sample of 186 patients and in 2 subsets of patients stratified by age (⬍ 55

years or ⬎ 55 years). Of the 119 patients age ⬎ 55 years, 37 were⬎70 years old. There was a prevalence of histologic type F and G (103 of 186 patients [55.3%]), which, according to the most recent classifications, correspond to diffuse large cell lymphoma. In addi-tion, approximately one-half of all 145 patients had Stage IV disease (85 of 186 [45.7%]), and one-third (60 of 186 [32.3%]) had an IPI score⬎2.

Comorbidity was present in 36 patients (19.3%). Comorbid conditions included arterial hypertension, cirrhosis, chronic obstructive pulmonary disease, and diabetes mellitus. Overall survival rates are shown in Figure 1. CR was observed in 119 patients (64.3%), and PR was observed in 30 patients (16.2%). Among the patients who achieved CR, 95 (79.8%) remained dis-ease free at a median follow-up time of 86.9 months (range, 14 –200 months). The remaining 24 patients experienced disease recurrence, at a median follow-up time of 19 months (range, 3–101 months). Of the pa-TABLE 1 Patient Characteristics Characteristic Total sample (n186) (%) Age<55 yrs (n67) (%) Age>55 yrs (n119) (%) P Gender Male 97 (52.2) 37 (55.2) 60 (50.5) Female 89 (47.8) 30 (44.8) 59 (49.5) WF type E 38 (20.4) 16 (23.9) 22 (18.5) F 45 (24.2) 14 (20.9) 21 (17.6) 0.0001 G 70 (37.6) 25 (37.3) 45 (37.8) H 33 (17.7) 12 (17.9) 21 (17.6) Disease stage 1 32 (17.2) 15 (22.4) 17 (14.3) 2 38 (20.4) 19 (28.4) 19 (15.6) 0.0001 3 31 (16.7) 11 (16.4) 20 (16.8) 4 85 (45.7) 22 (32.8) 51 (42.9) IPI score 0–1 86 (46.2) 34 (50.7) 52 (43.7) 2 40 (21.5) 16 (23.9) 24 (20.2) 3 32 (17.2) 9 (13.4) 23 (19.3) 4 28 (15.1) 8 (11.9) 20 (16.8) Comorbidity 36 (100.0) 5 (7.5) 31 (26.1) RDI Vincristine 0.69 0.65 Epirubicin 0.89 0.82 Cyclophosphamide 0.80 0.82 Treatment outcome CR 119 (64.0) 51 (76.1) 68 (57.1) 0.006 PR 30 (16.1) 4 (6.0) 26 (21.8) Mean follow-up (95% CI) (mos) 72.3 (64.5–80) 84.6 (72.5–96.7) 67.3 (56.3–78.3)

WF: Working Formulation; IPI: International Prognostic Index; RDI: relative dose intensity; CR: com-plete remission; PR: partial remission; CI: confidence interval.

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tients who experienced CR, three were lost to follow-up and four died due to causes that definitely were not related to lymphoma. On the contrary, all deaths among unresponsive patients were related to the dis-ease. The RDI values for vincristine, EPI, and cyclo-phosphamide, respectively, were 0.69, 0.89, and 0.80 in younger patients and 0.65, 0.82, and 0.82 in elderly patients. When patients were divided according to IPI score (Table 1), the following CR rates were noted: IPI 1, 72 of 86 (83.7%); IPI 2, 21 of 40 (52.5%); IPI 3, 15/32 (46.9%); and IPI 4, 11 of 28 (39.3%).

Univariate analysis indicated that Ann Arbor stage, IPI score, and age were significant prognostic factors for survival. Figure 2 shows overall survival results according to disease stage (I–II vs. III–IV). Fig-ure 3 shows overall survival results according to IPI score. Recurrence-free survival rates at 5 years for patients achieving CR in the four IPI groups were as follows: IPI 1, 88%; IPI 2, 73%; IPI 3, 53%; and IPI 4,

43%. Using multivariate analysis, IPI score was found to be the most significant prognostic parameter.

Two patients died of toxicity due to infection. Ten patients were hospitalized because of infection. Six of these patients also experienced lymphoma progres-sion.

Two patients, 59 and 73 years old, respectively, experienced arrhythmias. One patient, age 64 years, had a myocardial infarction 10 years earlier, devel-oped angina. One patient with hypertension experi-enced cardiac failure. No patients died of cardiac tox-icity. No significant difference between pretherapy and posttherapy LVEF was observed in elderly pa-tients.

As expected, the analysis of subsets of patients indicates a worsening of prognostic factors (histology, stage), risk factors (IPI score), and comorbidity status. All were directly related to the increase in age and resulted in a lower RDI and a poorer response rate.

DISCUSSION

Several new and very intensive multidrug chemother-apy regimens (e.g., ProMACE-CytaBOM, m-BACOD, MACOP-B) have been tested for the treatment of ag-gressive NHL. In uncontrolled studies, these regimens appeared to represent a step forward, especially as far as efficacy was concerned. However, based on the results of randomized trials, CHOP has reemerged as the standard therapy not only in terms of activity but also in terms of its cost/benefit ratio.1,2,8

The development of EPI and the subsequent in-troduction of the CEOP regimen have further im-proved the therapeutic index of this treatment. EPI at doses approximately equimolar with DOX achieved the same response rates, but with significantly less toxicity.4 – 6

FIGURE 1.Overall survival for all patients.

FIGURE 2.Overall survival according to disease stage.

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Consequently, the use of EPI may be particularly suitable for more aggressive treatments, based on its dose intensity and dose density, without the need for autologous stem cell transplantation or the support of growth factors.7However, it has not yet been proved that the routine use of these more intensive regimens improves the outcome of patients with NHL, and it is likely that they would be beneficial only in certain limited patient populations.9 –13

The patients enrolled in the current study (Fig. 1) and the risk factors identified by the IPI score reflect the characteristics observed in the majority of the populations with intermediate-to-high-grade NHL. It also appears that the results obtained after treatment with CEOP (CR, 64.0%; projected disease-free survival for complete responders, 77% at 150 months) are sim-ilar to those achieved with CHOP or other newer mul-tidrug combinations. Our data confirm the safety of the CEOP regimen in terms of myelotoxicity and car-diotoxicity, especially in patients with low or interme-diate-low IPI risk. Although our study was not com-parative, our results are better than those achieved with other anthracycline-containing regimens re-ported in the literature. The analysis of patients by age also showed that approximately one-third of all pa-tients were⬎55 years old. In particular, there were 37 patients age⬎70 years. A comparison of elderly and younger patients (age⬍55 years) showed that treat-ment outcome progressively worsens with increasing age (CR: 76.1% for patients age⬍55 years vs. 65.1% for patients age⬎55 years), probably due to the presence of a higher comorbidity rate among older patients (7.5% for patients age⬍55 years vs. 26.1 for patients age⬎ 55 years). Therefore, age has a direct negative impact on survival not only for reasons unrelated to lymphoma, but also because it prevents patients from receiving full doses of the planned chemotherapeutic program (RDI of EPI, 0.89% for patients age⬍55 years vs. 0.82% for patients age⬎55 years). Therefore, it can be argued that age is the most important prognostic factor.14,15

Because the incidence of lymphoma increases with age, the clinician very often is faced with treating elderly patients who should not be denied potentially curative therapy because of their age. In other words, whenever possible, treatment of elderly patients with aggressive NHL should be regarded as a curative at-tempt and not as palliation.16However, although stan-dard treatment easily can be administered to elderly patients with good performance status and well-con-trolled comorbid disease, problems arise when the clinician has to deal with patients with severe como-bidity and a poor performance status. For these pa-tients, the optimal regimen and intensity of therapy

have not been defined. Consequently, the final selec-tion of a regimen is based on the clinician’s personal estimate of how much toxicity due to a given regimen can be tolerated by each patient.17,18

A study performed by Fisher et al.11showed that CHOP can be considered the gold standard regimen for elderly patients with NHL, despite the fact that an increase in the death rate due to toxicity and a de-crease in the CR rate due to drug dose reductions were observed. Therefore, the availability of a chemother-apy regimen that is as effective as CHOP but signifi-cantly less toxic represents a very good opportunity, especially for elderly patients.16 The more favorable therapeutic index of CEOP could result in an increased number of patients who can receive full doses of che-motherapy with fewer limitations and fewer reports of hematologic, nonhematologic, and cardiotoxicity and, consequently, in an increased response rate and an improved overall outcome.

In conclusion, nonrandomized studies performed with different selection criteria in different patient populations suggest that CEOP is superior to CHOP in the treatment of aggressive NHL, especially among elderly patients.19 –21However, only randomized, con-trolled, double-blind clinical trials will provide defin-itive answers.

REFERENCES

1. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemother-apy regimens for advanced non-Hodgkin’s lymphoma.

N Engl J Med.1993;328:1002–1006.

2. Gordon LI, Harrington D, Andersen J, et al. Comparison of a second-generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkin’s lymphoma.N Engl J Med.1992;327: 1342–1349.

3. Capranico G, Zunino F, Kohn KW, Pommier Y. Sequence-selective topoisomerase II inhibition of anthracycline deriv-atives in SV40 DNA: relationship with DNA binding affinity and cytotoxicity.Biochemistry.1990;29:562–569.

4. Moreb JS, Oblon DJ. Outcome of clinical congestive heart failure induced by anthracycline chemotherapy. Cancer.

1992;70:2637–2641.

5. Bonadonna G, editor. Advances in anthracycline chemo-therapy: epirubicin. Milan: Masson, 1984.

6. Bonadonna G, Gianni L, Santoro A, et al. Drugs ten years later: epirubicin.Ann Oncol.1993;4:359 –369.

7. Basaran M, Bavbek ES, Sakar B, et al. Treatment of aggres-sive non-Hodgkin’s lymphoma with dose-intensified epiru-bicin in combination of cyclophosphamide, vincristine, and prednisone (CEOP-100): a Phase II study.Am J Clin Oncol.

2001;24:570 –575.

8. Lorusso V, Palmieri G, Bianco AR, et al. CEOP-B/VIMB vs. promace-CytaBOM in the treatment of intermediate or high grade non-Hodgkin’s lymphoma: a randomised multicenter study of Southern Italy Cooperative Group. Int J Oncol.

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9. Economopoulos T, Dimopoulos MA, Mellou S, et al. Treat-ment of intermediate- and high-grade non-Hodgkin’s lym-phoma using CEOP versus CNOP.Eur J Haematol.2002;68: 135–143.

10. Fridrik MA, Hausmaninger H, Linkesch W, et al. CEOP-IMVP-Dexa in the treatment of aggressive lymphomas: an Austrian multicenter trial.J Clin Oncol.1996;14:227–232. 11. Fridrik MA, Greil R, Hausmaninger H, et al. Randomized

open label Phase III trial of CEOP/IMVP-Dexa alternating chemotherapy and filgrastim versus CEOP/IMVP-Dexa al-ternating chemotherapy for aggressive non-Hodgkin’s lym-phoma (NHL). A multicenter trial by the Austrian Working Group for Medical Tumor Therapy.Ann Hematol.1997;75: 135–140.

12. Chim CS, Kwong YL, Lie AK, Lee CK, Liang R. CEOP treat-ment results and validity of the International Prognostic Index in Chinese patients with aggressive non-Hodgkin’s lymphoma.Hematol Oncol.1998;16:117–123.

13. Abate G, Tafuto S, Romano A, Gailli E, Corazzelli G. CEOP/ PEB alternating chemotherapy in advanced intermediate and high-grade non-Hodgkin’s lymphomas.Haematologica.

1992;77:322–325.

14. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non Hodgkin’s lymphoma.N Engl J Med.1993;329:987–994. 15. Zagonel V, Monfardini S, Tirelli U, Carbone A, Pinto A.

Management of hematologic malignancies in the elderly:

15-year experience at Aviano Cancer Center, Italy.Crit Rev Oncol Hematol.2001;39:289 –305.

16. Meyer RM, Browman GP, Samosh ML, et al. Randomized Phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin’s lymphoma.J Clin Oncol.1995;13:2386 –2393.

17. Aviles A, Nambo MJ, Talavera A, et al. Epirubicin (CEOP-Bleo) versus idaurubicin (CIOP-(CEOP-Bleo) in the treatment of elderly patients with aggressive non-Hodgkin’s lymphoma: dose escalation studies.Anticancer Drugs.1997;8:937–942. 18. Dixon DO, Neilan B, Jones SE, et al. Effect of age on

thera-peutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol.

1986;4:295–305.

19. Lambertenghi Deliliers G, Butti C, Baldini L, et al. A coop-erative study of epirubicin with cyclophosphamide, vincris-tine and prednisone (CEOP) in non-Hodgkin’s lymphoma.

Haematologica.1995;80:318 –324.

20. Mugitani A, Tatsumi Y, Tanaka K, Yasui Y, Inoue T. Cyclo-phosphamide, epirubicin, vincristine, prednisone, bleomy-cin, etoposide (CEOP-BE) therapy for intermediate- and high-grade non-Hodgkin’s lymphomas. Anticancer Res.

1999;19:3393–3397.

21. Zinzani PL, Mazza P, Gherlinzoni F, et al. CEOP regimen in the treatment of advanced low-grade non-Hodgkin’s lym-phomas: preliminary report.Tumori.1990;76:533–536.

References

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