Outcomes Using Doxorubicin-Based Chemotherapy with orwithout Radiotherapy for Early-Stage Peripheral T-cell

Lymphomas

HOON K. LEEa, RICHARD B. WILDERa,*, DAN JONESb, CHUL S. HAa, BARBARA PROc, MARIA A. RODRIGUEZc, JORGEE. ROMAGUERAc, FERNANDO CABANILLASc, JOSE RODRIGUEZd and JAMES D. COXa

aDepartment of Radiation Oncology, Box 97, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., University of Texas, Houston, TX 77030-4009 USA;bDepartment of Hematopathology, M.D. Anderson Cancer Center, University of Texas, Houston, TX USA; cDepartment of Lymphoma, M.D. Anderson

Cancer Center, University of Texas, Houston, TX USA; dHospital Universitario Son Dureta, Palma De Mallorca, Spain

(In final form 20 February 2002)

There is little information in the literature on outcomes using doxorubicin-based chemotherapy with orwithout radiotherapy for early-stage peripheral T-cell lymphomas. The purpose of this study was toanalyze The University of Texas M.D. Anderson Cancer Center results in such patients. From 1985 to1998, 39 patients with Stage I or II World Health Organization classification anaplastic large celllymphoma (ALCL; n ¼ 20), peripheral T-cell lymphoma, unspecified (PTCLu; n ¼ 11), or nasal-typeNK/T-cell lymphoma (NKTCL; n ¼ 8) were treated using doxorubicin-based chemotherapy (median, 6cycles) with ðn ¼ 24Þ or without ðn ¼ 15Þ radiotherapy (median dose, 40 Gy). Median age was 41years. Median follow-up of surviving patients was 85 months. Even though patients who presented withbulky disease or who achieved less than a complete response to chemotherapy were the ones typicallytreated with combined modality therapy rather than chemotherapy alone, there was no significantdifference in local control (5-year rates: 60 vs. 70%, p ¼ 0:49), progression-free survival (5-year rates:65 vs. 60%, p ¼ 0:62), or overall survival (5-year rates: 74 vs. 67%, p ¼ 0:47) between the groupstreated with combined modality therapy and chemotherapy alone. Fifteen (38%) patients relapsed.Twelve relapses were limited to the initial site of disease; two involved the initial site and new sites, andone involved only new sites. Based on the significant risk of relapse at the initial site of disease,different approaches, including chemotherapy with concomitant radiotherapy to doses $45 Gy, warrantinvestigation.

Keywords: T-cell lymphoma; Chemotherapy; Radiotherapy; Prognosis

INTRODUCTION

Most [1–5] but not all [6–8] groups have observed that

T-cell lymphomas have a worse prognosis than B-cell

lymphomas. Anaplastic large cell lymphoma (ALCL),

peripheral T-cell lymphoma, unspecified (PTCLu), and

nasal-type NK/T-cell lymphoma (NKTCL) are some of

the most common subtypes of mature peripheral

T-cell neoplasms [9]. In general, PTCLu and NKTCL

have a worse prognosis than ALCL [5,10]. Other

subtypes of mature peripheral T-cell neoplasms occur

rarely [11].

The diagnoses of ALCL, PTCLu, and NKTCL have

been made with increasing frequency based on improved

diagnostic methods [12]. No consensus has been reached

regarding optimal treatment. For example, the role of

involved-field radiotherapy remains unclear in patients

with early-stage disease. Considering that ALCL, PTCLu,

and NKTCL constitute only 12% of aggressive lympho-

mas [11], one cannot use Southwest Oncology Group

study 8736 [13], Eastern Cooperative Oncology Group

study E1484 [14], or Groupe d’Etude des Lymphomes de

l’Adulte study LHN93-1 [15] to determine the role of

radiotherapy in such patients. Since it is unlikely that a

prospective, randomized trial will be conducted specifi-

cally in patients with early-stage peripheral T-cell

lymphomas, we performed a retrospective analysis of

our results.

ISSN 1042-8194 print/ISSN 1029-2403 online q 2002 Taylor & Francis Ltd

DOI: 10.1080/1042819021000006277

*Corresponding author. Tel.: þ1-713-792-3400. Fax: þ1-713-745-6994. E-mail: rwilder@mdanderson.org

Leukemia and Lymphoma, 2002 Vol. 43 (9), pp. 1769–1775

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MATERIALS AND METHODS

Prognostic Systems

The M.D. Anderson tumor score (MDATS) [16] and the

international prognostic index (IPI) [17] are presented in

Table I. MDATS differs from IPI in that bulky disease [18]

and serum beta-2 microglobulin [19,20] are taken into

consideration. Stage-adjusted scores were calculated in this

study since none of the patients had Stage III–IV disease.

The median stage-adjusted MDATS was 1 (range, 0–4) and

the median stage-adjusted IPI was also 1 (range, 0–2) for

the 39 Stage I–II peripheral T-cell lymphoma patients.

Patient Characteristics

Thirty-nine patients with Ann Arbor Stage I or II [21]

PTCLu ðn ¼ 11Þ; NKTCL ðn ¼ 8Þ; or ALCL (n ¼ 20 : 15

systemic and five primary cutaneous) were treated at The

University of Texas M.D. Anderson Cancer Center from

1985 to 1998. Because of their rarity, we did not include

other subtypes of peripheral T-cell lymphomas. Twenty-

two patients had Stage I disease, and 17 patients had Stage

II disease. Median age was 41 years. Table II lists patient

characteristics in terms of the treatment delivered, which

is described below.

Pathologic Evaluation

All cases were reviewed by pathologists at M.D.

Anderson. Hematoxylin and eosin staining was performed

in all cases. Immunophenotyping was done by cryostat or

paraffin-section immunohistochemistry or by a flow

cytometric panel of B- and T-cell markers. Cases were

diagnosed according to the World Health Organization

(WHO) classification [9] based on morphological features

and immunoreactivity for at least one NK- or T-cell

lineage-associated marker. Lymphoblastic tumors were

excluded. All cases diagnosed as ALCL demonstrated

positivity for CD30. Cases demonstrating positivity for B-

cell markers were excluded. Immunostains for the

anaplastic lymphoma kinase (ALK) protein (ALK1

mouse monoclonal antibody, Dako, Carpinteria, CA)

were performed on the 14 available ALCL specimens (six

of the ALCL specimens were no longer available). All

cases of NKTCL were positive for Epstein–Barr virus

(EBV) sequences detected by in situ hybridization with an

oligonucleotide probe for EBV-related RNAs.

Staging

All patients underwent routine laboratory studies and

computed tomography (CT) scans of the head and neck as

appropriate, chest and abdomen for staging. Twenty-two

TABLE I Prognostic systems

Variable Adverse Feature

(A) The University of Texas M.D. Anderson Cancer Center’s tumor score (MDATS) for aggressive lymphomas*Lactate dehydrogenase $ 1:1 £ upper limit of normal, i.e. $ 685 IU=l at M.D. AndersonAnn Arbor Stage III or IVSymptoms “B” ¼ (1) unexplained, recurrent or sustained fevers ðT . 388CÞ; (2) drenching night sweats; or

(3) weight loss . 10% over the 6 months prior to diagnosisTumor bulk† MassðesÞ $ 7 cm or a mediastinal mass visible on a standing, PA chest X-rayBeta-2 microglobulin‡ $ 1:5 £ upper limit of normal, i.e. $ 3:0 mg=l at M.D. Anderson

(B) International prognostic index{

Lactate dehydrogenase . normalAnn Arbor Stage III or IVZubrod performance status $ 2Extranodal involvement . 1siteAge . 60 years

* Each adverse feature is assigned one point. One point is assigned for each bulky mass. The sum of the points is the tumor score.† Cases with extranodal head and neck presentations, not measurable bidimensionally, are assessed using the 1992 American Joint Committee on Cancer staging systemwherein T3–T4 tumors are considered bulky. Other extranodal presentations such as in the stomach, kidneys or liver: if not measurable, are considered bulky if $ 2=3 of theorgan is involved.‡ For primary mediastinal lymphomas, $ 0:8 £ upper limit of normal for lymphomas arising at any site, i.e. $ 1:6 mg=l at M.D. Anderson.{ Each adverse feature is assigned one point. The sum of the points is the international prognostic index (IPI).

TABLE II Patient characteristics

Chemotherapyonly ðn ¼ 15Þ

Chemotherapy andRadiotherapy ðn ¼ 24Þ p value

HistologyALCL 10 10PTCLu 4 7NKTCL 1 7 0.18

StageI 7 15II 8 9 0.33

GenderFemale 4 9Male 11 15 0.49

Age, yearsMedian 39 48.5 0.52

MDATS0–2 11 183–4 4 6 0.91

IPI0–1 13 212 2 3 0.94

ALCL, anaplastic large cell lymphoma; PTCLu, peripheral T-cell lymphoma-unspecified; NKTCL, nasal-type NK/T-cell lymphoma; IPI, internationalprognostic index; MDATS, M.D. Anderson tumor score.

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patients underwent lymphangiograms. Two patients

underwent staging laparotomies. Bone marrow biopsies

were performed in all but two patients. Gallium or

positron emission tomography scans were not routinely

obtained.

Treatment Modality

The chemotherapy was doxorubicin-based, and a median

of six cycles was administered (range, 1–9). The most

common chemotherapeutic regimen used was cyclophos-

phamide, doxorubicin, vincristine, and prednisone

(CHOP; n ¼ 26). The doses for each 3-week cycle of

CHOP were 750 mg/m2 cyclophosphamide intravenously

(i.v.) on day 1, 25 mg/m2/day doxorubicin i.v. by

continuous infusion on days 1 and 2, 1.4 mg/m2

(maximum, 2 mg) vincristine i.v. on day 1, and 100 mg

prednisone orally on days 1–5. The second most common

chemotherapeutic regimen used was doxorubicin, methyl-

prednisolone, cytarabine, and platinum (ASHAP; n ¼ 7).

Fifteen patients received chemotherapy as their sole

treatment (Table II). Response to chemotherapy was

assessed according to international working group

guidelines [22]. Twenty-four patients received chemother-

apy followed 3–4 weeks later by involved-field radio-

therapy. Total radiotherapy dose ranged from 5 to 60 Gy,

with a median of 40 Gy given in 20 daily 2-Gy fractions.

There was no significant difference in age, gender,

histology, stage, or prognostic scores between the groups

treated with chemotherapy alone or chemotherapy

followed by radiotherapy (Table II).

Statistical Analysis

Kaplan–Meier curves [23] were generated for local

control, progression-free survival, and overall survival.

Curves were compared using the log-rank test [24]. The

two-sided Fisher’s exact test and the Pearson chi-square

test were used to compare treatment groups. Patients with

stage-adjusted MDATS of 0–2 or IPI of 0–1 were

considered the low-risk group [16,17], whereas patients

with higher scores were considered the intermediate-risk

group.

RESULTS

The median follow-up of surviving patients was 85

months.

Histology and Stage

The 5-year local control, progression-free survival, and

overall survival rates for all 20 ALCL patients were 74, 74,

and 79%, respectively. Comparison of outcome by

whether immunohistochemical staining for ALK was

positive ðn ¼ 3Þ or negative ðn ¼ 11Þ showed no

significant difference in local control (5-year rates:

67 vs. 64%, p ¼ 0:99), progression-free survival (5-year

rates: 67 vs. 64%, p ¼ 0:99), or overall survival (5-year

rates: 100 vs. 82%, p ¼ 0:29), though the statistical power

was limited. There was no significant difference in local

control (5-year rates: 68 vs. 80%, p ¼ 0:59), progression-

free survival (5-year rates: 68 vs. 80%, p ¼ 0:59), or

overall survival (5-year rates: 78 vs. 80%, p ¼ 0:69) for

ALCL patients treated with chemotherapy and radio-

therapy vs. chemotherapy alone.

Eight of 11 (73%) PTCLu patients had a stage-adjusted

MDATS ¼ 0–2 and 9/11 (82%) had a stage-adjusted

IPI ¼ 0–1: The 5-year local control, progression-free

survival, and overall survival rates for all 11 PTCLu

patients were 64, 64, and 73%, respectively. Local control

(5-year rates: 86 vs. 25%, p ¼ 0:02) and progression-free

survival (5-year rates: 86 vs. 25%, p ¼ 0:02) were

significantly better in PTCLu patients who received

chemotherapy and radiotherapy as opposed to chemother-

apy alone. However, there was no significant difference in

overall survival between the two treatment groups (5-year

rates: 86 vs. 50%, p ¼ 0:41).

There was a trend towards inferior local control in

patients with NKTCL, with a 5-year local control rate of

50% compared to 70% for patients with ALCL or PTCLu

ðp ¼ 0:08Þ: Similarly, patients with NKTCL had inferior

progression-free survival compared to patients with ALCL

or PTCLu (Fig. 4; 5-year rates: 38 vs. 70%, respectively;

p ¼ 0:03). The 5-year overall survival rate for patients

with NKTCL was 50% compared to 77% for patients with

ALCL or PTCLu ðp ¼ 0:24Þ: In the six NKTCL patients

with a stage-adjusted MDATS ¼ 0–2; the 5-year local

control, progression-free survival, and overall survival

rates were 67, 50, and 67%, respectively. There was a

trend toward improved local control (5-year rates: 57 vs.

0%, p ¼ 0:08), progression-free survival (5-year rates: 43

vs. 0%, p ¼ 0:08), and overall survival (5-year rates: 57

vs. 0%, p ¼ 0:13) in NKTCL patients who received

chemotherapy and radiotherapy rather than chemotherapy

alone.

Treatment Modality

Patients with bulky disease as defined by the MDATS

(Table I) were typically treated with chemotherapy and

involved-field radiotherapy rather than chemotherapy

alone (75 vs. 33%, p ¼ 0:02). However, the percentage

of low-risk patients based on stage-adjusted MDATS or

IPI was not significantly different between the two

treatment groups (Table II). Even though patients with

mature peripheral T-cell neoplasms who achieved less

than a complete response to chemotherapy tended to be

treated with chemotherapy and radiotherapy rather than

chemotherapy alone (25 vs. 0%, p ¼ 0:06), there were no

significant differences in local control, progression-free

survival, or overall survival between the two treatment

groups (Table III).

EARLY STAGE PERIPHERAL T-CELL LYMPHOMAS 1771

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Prognostic Systems

Local control for the low- and the intermediate-risk

patients based on stage-adjusted MDATS and IPI is shown

in Fig. 1. A significant difference in local control between

the two risk groups was observed when the MDATS

system was used ðp ¼ 0:007Þ: In contrast, no significant

difference in local control was observed using the IPI

system ðp ¼ 0:29Þ: Progression-free survival based on the

two prognostic systems is shown in Fig. 2. When MDATS

was used to assign score, progression-free survival was

significantly different ðp ¼ 0:01Þ between the low- and the

intermediate-risk groups. No significant difference in

outcome was observed if IPI was used to assign score

ðp ¼ 0:34Þ: In Fig. 3, overall survival is displayed based

on MDATS and IPI. Overall survival was significantly

different for the low- and intermediate-risk groups when

stage-adjusted MDATS was used as the prognostic system

ðp ¼ 0:001Þ: In contrast, stage-adjusted IPI did not predict

for significantly different outcomes ðp ¼ 0:40Þ; though the

conclusion is limited by the low statistical power.

Patterns of Failure

Fifteen (38%) patients relapsed. Local relapse was the

predominant pattern of failure, regardless of the WHO

diagnosis. In 12 of 15 (80%) patients, first recurrence was

limited to the initial site of disease. Seven of these patients

received chemotherapy followed by involved-field radio-

therapy and five received chemotherapy alone. In one

patient, whose primary tumor originated in the axilla,

recurrence was limited to a cervical lymph node. In two

patients, initial recurrences appeared in both local and

distant sites. Among the 24 patients who received

chemotherapy and involved-field radiotherapy, the

response to induction chemotherapy (complete vs. less

than complete) did not significantly affect local control (5-

year rates: 71 vs. 67%, respectively, p ¼ 0:84).

DISCUSSION

Most [10,25–27] though not all [19] groups have been

able to predict the outcome of patients with peripheral T-

cell lymphomas using the IPI [17]. The results from our

study ðn ¼ 39Þ suggest that, in the subgroup of patients

with early-stage ALCL, PTCLu, or NKTCL, MDATS may

be a better prognostic system than IPI. However, this

hypothesis needs to be tested prospectively.

The MDATS (Table I) was proposed as a prognostic

system for aggressive lymphomas in 1992 [16]. Most of

the factors that comprise the MDATS are tumor-dependent

rather than patient-related, e.g. factors such as age and

performance status were not included. In contrast, bulky

disease [18] and serum beta-2 microglobulin [19,20] were

included in an effort to reflect the biological character-

istics of the tumor. Our group [4] previously reported the

outcomes of 560 patients with aggressive lymphoma in

terms of MDATS and IPI. MDATS and IPI were

TABLE III Local control, progression-free survival, and overall survival based on treatment

5-year local 5-year progression-free 5-year overall

Treatment Control (%) p value Survival (%) p value Survival (%) p value

Chemotherapy only ðn ¼ 15Þ 70 60 67Chemotherapy and Radiotherapy ðn ¼ 24Þ 60 65 74

0.49 0.62 0.47

FIGURE 1 Local control in terms of the stage-adjusted M.D. Anderson tumor score (MDATS) and international prognostic index (IPI).

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independent predictors of failure-free survival and overall

survival.

Adverse prognostic features such as an elevated serum

beta-2 microglobulin level or the presence of B symptoms

are commonly present in patients with PTCLu

[2,4,5,8,19,28,29]. Lopez-Guillermo et al. [10] reported

on 174 patients with PTCLu and observed that the

presence of B symptoms or an elevated serum beta-2

microglobulin level was associated with poor overall

survival. Lippman et al. [1] observed that the presence of

B symptoms was associated with poor disease-free

survival. Hatta et al. [29] studied 53 patients with

sinonasal tract lymphoma. Patients with B symptoms had

a poor prognosis. The usefulness of the MDATS in

patients with peripheral T-cell lymphomas may in part be

explained by the relatively high incidence of B symptoms

and an elevated beta-2 microglobulin level in such

patients.

Patients with PTCLu typically present with dissemi-

nated disease, including bone marrow involvement [5].

This study was limited to patients with early-stage disease

and included only 11 patients with PTCLu, most of whom

had #2 adverse prognostic features, which helps to

explain the relatively favorable 5-year progression-free

and overall survival rates of 64 and 73%, respectively.

Seven of the 11 PTCLu patients were treated with

consolidative radiotherapy, which resulted in a significant

improvement in local control and progression-free

survival. Based on the 5-year progression-free and overall

survival rates of only 26 and 24%, respectively, that have

been observed in peripheral T-cell lymphoma patients

with a MDATS . 2 [4], we are currently studying high-

dose chemotherapy and transplantation as the initial

treatment for these patients [30].

The patients with NKTCL in our study tended to

experience worse local control and overall survival and

experienced significantly worse progression-free survival

(Fig. 4) than the patients with ALCL or PTCLu. Poor

outcomes in patients with NKTCL has been described by a

number of groups [29,31–35]. In contrast, ALCL has a

relatively favorable prognosis, especially in ALK þ

patients [5,10,25,27,36]. Gascoyne et al. [27] reported

FIGURE 2 Progression-free survival in terms of the stage-adjusted M.D. Anderson tumor score (MDATS) and international prognostic index (IPI).

FIGURE 3 Overall survival in terms of the stage-adjusted M.D. Anderson tumor score (MDATS) and international prognostic index (IPI).

EARLY STAGE PERIPHERAL T-CELL LYMPHOMAS 1773

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5-year overall survival rates of 79% vs. only 46% in

patients with ALK þ vs. ALK 2 ALCL, respectively. In

support of these findings, Falini et al. [25] reported 5-year

overall survival rates of 71 and 15% in patients with

ALK þ and ALK 2 ALCL, respectively. While our

study had too few patients to make a meaningful

comparison between ALK þ and ALK 2 ALCL, we

observed a 5-year overall survival of 79% (95%

confidence interval: 57–92%) for all 20 patients with

ALCL (Table III), which is consistent with other

published reports [5,10].

Kim et al. [33] reported results in patients with NKTCL

of the head and neck who received involved-field

radiotherapy alone (median dose, 50.4 Gy). In their

study, 50% of patients developed a local recurrence and

25% relapsed in a distant site. Shikama et al. [37] reported

a 5-year disease-free survival rate of 83% using

radiotherapy (median dose, 49 Gy) with or without

chemotherapy in 25 stage IE patients with nasal

lymphoma. The most common recurrence site was local,

and 5/6 patients with a local recurrence received ,50 Gy.

Hence, doses ,50 Gy must be considered inadequate in

patients who receive radiotherapy alone. Kim et al. [31]

observed no relapses in 4 NKTCL patients who

completely responded to 4 cycles of CHOP chemotherapy

and then received radiotherapy to 45 Gy. Fifteen (38%)

patients in our study relapsed, with the majority (80%) of

the first relapses occurring only at the initial site of

disease. The median dose in our study was 40 Gy.

The patterns of failure described above suggest that

prevention of relapse in the initial site of disease is a

worthwhile goal in patients with peripheral T-cell

lymphomas. Adjuvant radiotherapy doses $45 Gy appear

to be warranted in patients with peripheral T-cell

lymphomas, even if a complete response to induction

chemotherapy is achieved. Since NKTCL is almost

universally associated with Epstein–Barr virus [38],

immunotherapy strategies targeting Epstein–Barr virus

antigens expressed by malignant cells are worth exploring

[34]. More effective systemic therapy, combined with

radiotherapy to $45 Gy, may improve local control. The

use of chemotherapy and concurrent radiotherapy, which

is effective in epithelial tumors, also warrants study. In

addition, high-dose chemotherapy followed by bone

marrow transplantation has been used in patients with

recurrent PTCLu and NKTCL with encouraging results

[30,35].

In conclusion, patients with NKTCL experienced

suboptimal results even when they presented with few

adverse features. The main pattern of failure was at the

initial site of disease after the delivery of doxorubicin-

based chemotherapy with or without involved-field

radiotherapy to a median dose of 40 Gy. Consequently,

we believe that systemic therapy and radiotherapy to doses

of least 45 Gy warrants investigation. We hope that new

approaches, such as cyclophosphamide, vincristine, and

prednisone chemotherapy with concomitant involved-field

radiotherapy to 45 Gy given in 25 daily 1.8-Gy fractions,

will improve the outlook for patients with peripheral T-

cell lymphomas.

Acknowledgements

This work was supported by grants CA 6294 and CA

16672 from the National Cancer Institute, National

Institutes of Health, U.S. Department of Health and

Human Services. Presented at the 2001 Pan Pacific

Lymphoma Conference, June 19–22, 2001, Wailea, HI.

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