stage i-ii follicular lymphoma: treatment results for 76 patients

Stage 1-11 Follicular Lymphoma

Treatment Results for 76 Patients

PETER MCLAUGHLIN, MD,’ LILLIAN M. FULLER, MD,t WILLIAM S. VELASQUEZ, MD,* JANE A. SULLIVAN-HALLEY, BS,* JAMES J. BUTLER, MD,* AND FERNANDO CABANILLAS, MD*

Clinical features and treatment results are analyzed for 76 patients with Stage 1-11 follicular lymphoma seen between 1974 and 1981. During this period, 66% of the patients received involved-field radiotherapy (XRT) alone, and 34% received chemotherapy with or without XRT. At 5 years, the overall survival was 67%, the cause-specific survival was 73%, and the relapse-free survival (RFS) was 48%, with no relapses to date among nine patients followed beyond 60 months. Adverse prognostic features for survival included extranodal disease and elevated serum lactate dehydrogenase. For RFS, adverse features included extranodal disease and bulky abdominal disease. The RFS was significantly better for patients receiving chemotherapy with or without XRT than for XRT alone (64% versus 37% at 5 years, P = 0.02), despite a higher frequency of adverse prognostic features in the chemotherapy-treated group. About 50% of Stage 1-11 follicular lymphoma patients may be curable, and the inclusion of chemotherapy in the initial treatment may increase the potentially curable fraction.

Cancer 581596-1602,1986.

OST PATIENTS with follicular lymphomas present M with Stage I11 or Stage IV disease, with as few as 6% to 25% remaining Stage 1-11 after extensive staging procedures. ’,* The rarity of Stage 1-11 follicular lymphoma accounts for the paucity of information available on these entities. Stage 1-11 patients tend to survive longer than those with more advanced disease, with 50% to 100% alive at 5 years after involved-field radiotherapy (XRT).3,4 Re- cent reports suggest that 50% of XRT-treated patients may be “cured” of their

The role of chemotherapy in the primary treatment of patients with Stage 1-11 follicular lymphoma is not well defined. In a small group of pathologically Staged 1-11 patients, Monfardini et al. showed no significant im- provement in results between patients treated with XRT only and those who also received adjuvant cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. However, there was a trend for a better 5-year survival for patients who received CVP.8 There is even less information available on the impact of chemotherapy in clin- ically staged patients. This group is important because many follicular lymphoma patients are elderly and are

From the Departments of *Hematology, ?Radiotherapy, and $Pa- thology, The University of Texas M. D. Anderson Hospital and Tumor Institute, Houston, Texas.

Supported in part by Grants CA 06294 and CA 16672 from US Public Health Service.

Address for reprints: Peter McLaughlin, MD, UTMD Anderson Hos- pital, 6723 Bertner Avenue, Houston, TX 77030.

Accepted for publication February 10, 1986.

unable to undergo laparotomy, and because many clini- cally staged patients have occult abdominal making cure unlikely with localized radiotherapy alone.

The current review summarizes our experience with Stage 1-11 follicular lymphoma over an 8-year period. Clinical features are correlated with therapeutic strategies and with treatment results.

Materials and Methods

The population included 76 patients with previously untreated Stage 1-11 follicular lymphoma who were treated between 1974 and 198 1. All biopsy material was classified according to the Rappaport scheme” at the time of re- ferral; slides were reviewed at the time of this analysis and reclassified according to the Working Formulation. ’ Staging was done according to the Ann Arbor classification.’*

Patient characteristics are outlined in Table 1. The median age was 56 years (range, 24-83 years). Staging procedures included lymphangiography in 88%, bone marrow biopsy in 99%, and computerized tomography (CT) scan and/or ultrasound of the abdomen in 32%. Fifteen patients (20%) had staging laparotomy, and 16 others (21%) had diagnostic laparotomy without full surgical staging. Sev- enteen percent had extranodal sites of involvement at presentation, including four with follicular small cleaved (FSC) histologic type, two with follicular mixed small cleaved and large cell (FM), and seven with follicular large

1596

No. 8 STAGE 1-11 FOLLICULAR LYMPHOMA * McLaughlin et al. 1597

cell (KC). Extranodal sites included the small bowel in five, colon in two, thyroid in two, and one each with involvement of the tonsil, tongue, ovary, and brachial artery. Thirteen percent had constitutional (B) symptoms. Bulky abdominal disease was defined as a palpable abdominal mass, or radiographic evidence of a mass measuring greater than 5 cm in diameter, compressing a visceral or- gan, or producing obstructive uropathy. Bulky abdominal disease was present in 20 of 42 patients with lower torso disease; mediastinal involvement was noted in 3 of 34 patients with upper torso disease. The distinction between “contiguous” and “discontiguous” Stage I1 disease was done as described by Bush and Gospodarowic~.~

Follow-up evaluation included reassessment of all sites of known disease by physical exam, appropriate radio- graphs, and endoscopy when indicated. Reevaluation was done every 3 to 6 months during the first 3 years from diagnosis, and every 6 to 12 months thereafler.

Treatment Programs

Fifty patients received involved-field XRT alone as initial therapy. Upper torso sites generally received a tumor dose of 4000 rad in 20 fractions (4 weeks). The treatment fields in lower torso disease generally covered the entire abdomen and pelvis, which were treated sequentially. Lower torso tumor doses were generally limited to 3000 rad in 20 fractions. During abdominal treatment, the kid- neys were shielded to limit the dose to 1800 rad and, in patients who received chemotherapy, the right lobe of the liver was shielded to limit the dose to 1500 rad.

Nineteen patients received chemotherapy in conjunc- tion with the radiotherapy, most in accord with ongoing protocols. However, there was a trend to use chemotherapy in patients who were considered to have adverse prognostic features including large cell histologic type, constitutional symptoms, and elevated Serum lactate dehydrogenase (LDH). Of these 19 patients, 9 received cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo), 7 received cyclophosphamide, vincristine, prednisone and bleomycin (COP-Bleo), and 3 received chlorambucil with or without prednisone. Seven other patients received chemotherapy only, generally because of the patients’ inability to return for radiotherapy. Two of these patients received CHOP-Bleo, one received COP, and four received chlorambucil. Treatment allocation by histology and other disease features is shown in Table 2.

Data Analysis

A cause-specific survival is used, by which patients in complete remission off therapy who died of causes unrelated to the lymphoma or the treatment were carried as alive and free of disease at the time of last follow-up.

TABLE 1. Patient Features

B patients by cell type

Small All cleaved Mixed Large cell patients

Feature (N = 43) (N= 14) (N = 18) (N = 76)

Sex Female 53 64 56 57 Male 47 36 44 43

I 30 22 17 26 IE 2 14 6 5 I1 Contiguous 14 14 22 16 IIE Contiguous 5 - 1 1 5 I1 Discontiguous 47 50 22 41 IIE Discontiguous 2 - 22 7

Extranodal site 9 14 39 17

Constitutional symptoms 7 14 28 13

Lower torso site 67 50 33 55 Bulky 26 29 28 26

Upper torso site 33 50 67 45 - 17 4 Mediastinal -

Hemoglobin <I2 g/dl 9 7 22 12

LDH > 225 mU/ml 5 21 35 15

Stage

LDH: lactate dehydrogenase.

TABLE 2. Correlation of Disease Features and Initial Treatment

Chemotherapy Total

patients XRT Alone With XRT Feature (N = 76) ( N = 50) ( N = 7 ) (N = 19)

Cell type Small cleaved 43 32 5 6

3 Mixed 14 I 1 - Large cell 18 6 2 10 Unclassified 1 1 - -

Stage I IE I1 IIE

6 20 14 - 4 4

43 28 6 9 9 4 I 4

- -

Constitutional

Lower torso site

symptoms 10 5 3 2

All 42 30 4 8 Bulky 20 13 1 6

Upper torso site 34 20 3 1 1

Hemoglobin

LDH >225

<I2 gJdl 9/75* 5 1 31 18;

mU/ml 11/74’’ 6 1 41 17.

* Denominator indicates no. with available data. XRT radiation therapy; LDH lactate dehydrogenase.

I598 CANCER October 15 1986 Vol. 58

“t Total Fail

201 , i;, ;:,;?:’, , , Non-Failure

0 0 24 48 72 96

Months

FIG. 1. Survival for all 76 patients and relapse-free survival for 75 evaluable patients. Overall survival includes all deaths; cause-specific survival censors five deaths due to causes unrelated to lymphoma or therapy.

Cause-specific survival removes expected deaths from the survival data and thus focuses on the impact of the lymphoma; it is identical to “adjusted” or “corrected” survival which are other terms used in the literature.

Relapse-free survival (RFS) and survival were measured from the time of our first evaluation to first relapse, and to the time of last follow-up or death, respectively. Survival from first relapse was measured from the time of first relapse to the time of last follow-up or death. One patient with follicular lymphoma, cell type unclassified, was excluded from the analysis by histologic subtype but included in all other analyses. One patient with EM lymphoma is excluded from the RFS analysis because therapy for a second malignancy (adenocarcinoma of prostate) made this assessment impossible. All others are included in the RFS analysis including nonresponders who were considered failures from the outset.

Curves were calculated according to the method of Kaplan and Meier.I3 Gehan’s modification of the generalized Wilcoxon test was employed to evaluate differences in survivd.l4

Results

Complete remission was achieved in 73 of the 76 patients. The overall 5-year survival was 67%, the cause- specific 5-year survival was 73%, and the 5-year RFS for

the evaluable 75 patients was 48%, with a median follow- up of 51 months (range, 11-105 months). No relapses have occurred to date among nine patients followed beyond 5 years (Fig. 1).

Survival

Survival was influenced adversely by the presence of extranodal disease (P < 0.0 1) and to a lesser extent by an elevated LDH (P = 0.08) (Table 3). Factors that did not significantly influence survival included age, histologic type, stage, and constitutional symptoms. Patients with bulky abdominal disease had a slightly worse 5-year survival than those without this feature (P = 0.14). More patients younger than 50 years survived 5 years than did older patients, but this was not statistically significant.

Patients with FLC histologic type had a 5-year survival of 56%, which was not significantly worse than the cor- responding figures of 78% for FSC (P = 0.18) or 80% for FM (P = 0.37). However, a disproportionately high fi-ac- tion of FLC patients received more intensive therapy (Ta- ble 2).

TABLE 3. Treatment Results by Disease Features

5-yr Relapse-free

S-Yr survival Feature SUrvlVal(%) (%)

All patients 13 48

Cell type Small cleaved 49

Large cell 56 43 Mixed 2 I) P = 0.19 44

90 66

Stage I 79 I1 Contiguous 56 I1 Discontiguous 75

58 43

3 I P=0.12 39 J

Stage I I1 IE IIE

7840 I ] P < 0.01 15 32 I

Constitutional symptoms 90 80 Asymptomatic 70 42

Lower torso Bulky

Upper torso

LDH

Not bulky ] P=0.14 5 1 P = 0.02

52 36 P = 0.08 5225 mU/mI

>225 mU/ml

LDH: lactate dehydrogenase.

No. 8

80

60

STAGE 1-11 FOLLICULAR LYMPHOMA - McLaughlin et al. 1599

-

-

FIGS. 2A AND 2B. Results according to initial therapy, comparing radiotherapy (XRT) alone to chemotherapy + XRT. (A, left) Cause- specific survival (P = 0.9). (B, right) Relapfree survival (P = 0.02).

20

- Total Relapse

14 3 A Chemo i XRT - 42 23 o XRT

I Rehpse-Free

401

SURVIVAL ?%*

k. Totel Deed

20 1 , E, J , , C h g m , = X R l , , , , *Tv.

0 0 24 48 72 96

Months

When the analysis of prognostic factors was limited to those with low-grade histologic types (FSC and FM), an adverse impact on survival was seen for those with elevated LDH, with 40% alive at 5 years compared to 86% with normal LDH (P < 0.0 1). No other significant factors were identified, although adverse trends were noted for patients with extranodal disease (P = 0. lo), and those with bulky abdominal disease (P = 0.17).

Relapse-Free Survival

Relapse-free survival was influenced adversely by the presence of extranodal disease (P = 0.02) and by bulky abdominal disease (P = 0.02) (Table 3). No other factors were identified that significantly affected relapse-free survival. Patients with Stage I and contiguous Stage I1 disease had marginally better RFS than those with discontiguous Stage I1 (55% versus 39% at 5 years, P = 0.12).

When the analysis of RFS was restricted to patients with low-grade histologic types, those with bulky abdominal disease had a trend for a worse RFS than those without bulky disease (43% versus 48%, P = 0.13). No other factors were identified that significantly affected RFS among patients with low-grade histologic types.

Analysis Based on Therapy

Since several treatment strategies were used over the period of this review, the selection of therapy was ex- amined from the standpoint of specific disease features (Table 2). There was a disproportionately high frequency of chemotherapy chosen for patients with the following characteristics: FLC histologic type; constitutional (B) symptoms; low hemoglobin; and elevated LDH.

Figures 2A and 2B show the survival and RFS curves for patients treated with XRT alone compared with those

100 RELAPSE-FREE SURVIVAL

80

60

40

Total Relwse 26 8 A Chemo t XRT 49 28 0 XRT

20

I Rehpse-Free

96 0

0 24 48 72 Months

treated with chemotherapy with or without XRT. At the time of analysis, there was no significant difference between their 5-year survivals of 74% and 73%, respectively. However, the RFS for patients receiving chemotherapy was significantly better (64% versus 37% at 5 years, P = 0.02). When the RFS analysis was restricted to patients with low-grade histologic types (FSC and FM), the same benefit was demonstrated (7 1% versus 40% at 5 years, P < 0.01) (Fig. 3). No relapses have occurred in either group among nine patients followed beyond 60 months.

60 -

c

5 n g

I I I I I I I I I 0 24 48 72 96

Months

FIG. 3. Relapse-free survival of patients with low-grade histologies (FSC and FM), comparing XRT alone with chemotherapy f XRT (P = 0.008).

1600 CANCER October 15 1986 Vol. 58

I t I , I 1 I

24 48 72 96

Months

FIG. 4. Survival from first relapse, comparing limited nodal relapse with extensive nodal or disseminated relapse (P = 0.002).

Complications

Treatment was generally well tolerated. Myelosuppres- sion was modest and reversible. There were five episodes of infections and in one nonresponder the infection was fatal. Radiation hepatitis occurred in three, but responded promptly to steroid therapy. One patient died of gastroin- testinal bleeding attributed to radiation gastritis; this occurred 1 month after a laparotomy for a persistent mass lesion, so adhesions and/or coincident stress ulceration may have been contributory factors. There were two episodes of hemorrhagic cystitis; both patients had received pelvic radiation and one also received cyclophosphamide. Two patients developed Herpes zoster. One patient had an ileus attributed to vincristine.

Patterns of Progression and Secondary Therapy

Two patients had primary resistant disease, one with FSC and one with FM. Both developed progressive disease during initial radiotherapy, one within the radiation fields and the other in transdiaphragmatic nodes. Both died, one at 18 months after minimal response to subsequent chemotherapy, and the other at 9 months of gastritis attributed to radiation therapy. One patient with JXC died of infection during induction chemotherapy and was carried as a failure, despite apparent treatment response; her course had previously included several severe complications after diagnostic laparotomy.

Relapse from complete remission occurred in 33 patients. Limited nodal relapse occurred in 18 patients; in 15 of these the relapse sites were transdiaphragmatic. The remainder had extensive nodal and/or disseminated disease at relapse; nine patients had extranodal involvement that included liver, lung, pleura, stomach, skin, conjunc- tiva, bone, and bone marrow. Secondary therapy varied according to the clinical circumstances at relapse, and included further XRT or various chemotherapy programs, including chlorambucil and cyclophosphamide-based and doxorubicin-based combinations. Survival from the time of first relapse correlated with the pattern of initial relapse (Fig. 4). Those with limited nodal relapse had a significantly longer survival after relapse than those with generalized nodal or disseminated disease at relapse (72% versus 34% at 5 years, P < 0.01). A short first remission did not preclude a long second remission. Although a second relapse usually signaled a downhill course, five patients have survived more than 2 years beyond their second relapse (range, 27-65+ months).

Discussion

Only a minority of patients with follicular lymphoma have Stage 1-11 disease at the time of diagnosis, and little emphasis has been placed on the early diagnosis and therapy of these patients. The current report and ~ t h e r s ~ - ~ indicate that some Stage 1-11 patients are potentially curable. Other reports suggest a particularly good outlook for Stage I pat ien t~ .~ , '~"~ Since Stage 111-IV patients are generally considered incurable with current treatment ap- proa~hes, '~, '~ the recognition and timely therapy of Stage 1-11 patients is advisable.

The detection of follicular lymphoma when it is limited to Stage 1-11 is problematic, because of both delay in es- tablishing the diagnosis and the frequency of subclinical dissemination. Patients are often asymptomatic; many give a history of awareness of adenopathy for long periods of time before seeking medical attention. Those with localized disease by clinical evaluation are often upstaged by lymphangiography and bone marrow biopsy.',2 After thorough clinical staging, occult abdominal disease will still be detected in up to 6 1% of patients at laparotomy.' The analysis of peripheral blood lymphocytes for light chain predominance may be an additional useful indicator of subclinical dissemination. 19,*0

The frequency of occult disseminated disease suggests a possible role for systemic therapy. Paryani et aL6 showed no survival difference among patients who received involved-field, extended-field, or total lymphoid irradiation, but did show better freedom from relapse for those who received total lymphoid irradiation. Monfardini et aL8 explored the role of adjuvant CVP chemotherapy in a

No. 8 STAGE 1-11 FOLLICULAR LYMPHOMA * McLaughlin et al. 1601

small series of laparotomy-staged patients and concluded that chemotherapy offered no significant benefit. How- ever, their data did show a trend for better survival at 5 years for patients treated with XRT and CVP than for XRT alone (93% versus 62%, P = 0.1). In other reports, it is difficult to draw conclusions on the impact of extended-field XRpp2l or of ~hemotherap$~,~~ because of the limited numbers of patients in these series. The current report does suggest a benefit from chemotherapy, with a significantly better RFS for patients receiving chemotherapy, even among those with low-grade histologic types (Fig. 3).

The significance of our observed 64% 5-year RFS with the addition of chemotherapy is based on the comparison with our 37% RFS for those who got XRT alone. The 5- year RFS reported by Gospodarowicz et al. was 54% with XRT alone.7 The subset of Stanford patients who got involved-field or extended-field XRT had a 5-year RFS of about 50%.6 The reasons for the somewhat better RFS results with XRT alone of these other series are not fully apparent. The staging procedures for our patients were similar to those at Stanford, and more thorough than the Princess Margaret series, where bone marrow examination was done in only 24%. The XRT doses and ports are comparable in all three series. The Princess Margaret group had somewhat fewer patients with bulky abdominal disease than our series, and the Stanford group had fewer patients with large cell histologic type, extranodal sites, and constitutional symptoms. Within our population, those who received chemotherapy had a higher frequency of adverse prognostic features including elevated LDH, large cell histologic type, and constitutional symptom^.'^,^^ In the current report, the last two factors were not unfa- vorable, suggesting that the chemotherapy may have counteracted their expected adverse impact.

Since involved-field XRT alone may cure up to 50% of Stage 1-11 patients with FSC and FM lymphoma, it would be desirable to identify those likely to be cured by XRT alone. But whereas several adverse prognostic factors have been identified, the RFS figures in Table 3 show that no subset of patients is without substantial risk of relapse. Until precise identification of very favorable patients is possible, we advocate the addition of chemotherapy for all patients, based on its apparent potential to prolong RFS.

Further follow-up is required to determine if chemotherapy prevents or merely delays relapse in these patients. We suspect the former, since our median follow-up is 5 1 months, and relapse beyond 5 years has been seen infre- quently in radiotherapy series with long follow-up.697 Thus, further study of the addition of chemotherapy is war- ranted: prolonged RFS is a desirable result in itself, and may indeed translate into an increase in the percentage of patients cured.

The optimum chemotherapy regimen for these patients cannot be determined from this analysis. Even in advanced stage disease, there is controversy about the choice of ~hemotherapy.~~-~~ The chemotherapy-treated patients in the current report all received an alkylating agent, and the majority also received vincristine, prednisone, and bleomycin; only a minority received doxorubicin. Based on this experience, our current approach is to treat Stage 1-11 FSC and FM lymphoma patients with COP-Bleo chemotherapy and involved-field XRT. For FLC lymphoma, more intensive doxorubicin-containing therapy is re~ommended.~~

The recommendation for early intervention for Stage 1-11 follicular lymphoma patients contrasts with the prev- alent attitude that early intervention in Stage 111-IV low- grade lymphoma is not always indi~ated.~’.~’ It is note- worthy that proponents of deferral of therapy for advanced-stage patients do recommend treatment for Stage 1-11 patients.6 Emerging long-term treatment results for patients with Stage 1-11 disease, and for some series of patients with Stage I11 d i ~ e a s e , ~ ~ , ~ ~ challenge the concept that all follicular lymphomas are incurable.

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stage i-ii follicular lymphoma: treatment results for 76 patients

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