The patterns of failure in patients with pathological stage I and II diffuse histiocytic lymphoma treated with radiation therapy alone

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??Original Contribution

THE PATTERNS OF FAILURE IN PATIENTS WITH PATHOLOGICAL STAGE I AND II DIFFUSE HISTIOCYTIC LYMPHOMA TREATED WITH RADIATION THERAPY ALONE M.D.,* RAMEZ FARAH, M.D.,*

DENNIS E. HALLAHAN, JACOB D. BITRAN,

M.D.,?*

JOHN E. ULTMANN,

EVERETT E. VOKES, M.D.,?*

M.D.,_F$ HARVEY

AND RALPH R. WEICHSELBAUM,

M. GOLOMB,

M.D.-j-$

M.D.*+

PritzkerSchool of Medicine, University of Chicago Radiation therapy was used to treat 36 patients with pathological Stage I and II diffuse histiocytic lymphoma at The University of Chicago Hospitals from 1970 to 1986. Twenty-two patients had pathological Stage I and 14 had pathological Stage II diffuse histiocytic lymphoma. The patients were treated with a median tumor dose of 50 Gy (range of 40-60 Gy). Therapy consisted of extended field radiation therapy in 27 patients (extended mantle or total nodal irradiation) and involved field irradiation in nine patients. The IO-year actuarial relapse-free survival for pathological Stage I and pathological Stage II patients was 91% and 35%, respectively (median follow-up of 7 years). None of the 22 pathological Stage I patients had bulky mediastinal or abdominal disease. Of the 22 pathological Stage I patients, one failed in an unirradiated contiguous lymph node and one relapsed with disseminated disease. Of the 14 pathological Stage II patients, two patients with bulky disease failed in field, one patient failed in a contiguous node, three patients failed within the abdomen, and three patients failed with disseminated disease. To better evaluate the efficacy of staging laparotomy, we analyzed the patterns of failure of 17 clinical Stage I and II diffuse histiocytic lymphoma patients. Four of these patients failed in field (three in sites of bulky disease), and five patients relapsed in the abdomen (three with disseminated disease). Salvage treatment with multiagent chemotherapy resulted in second complete responses in seven of ten patients; however, all but one have recurred and are dead of disease. Radiation therapy may be used as the sole treatment in patients with pathological Stage I diffuse histiocytic lymphoma without bulky disease. Patients with pathological Stage II diiuse histiocytic lymphoma and clinically staged patients have a higher incidence of dissemination and relapse within the abdomen. A benefit resulting from the administration of extended field irradiation was not revealed by this study. Pathologic stage, Diffuse histiocytic lymphoma,

Radiotherapy.

INTRODUCTION

17). This study summarizes our experience in treating patients using RT alone over a 16-year period.

The majority of patients with diffuse histiocytic lymphoma (DHL) present with advanced disease at the time of diagnosis, yet 60% have a durable complete response when treated with multiagent chemotherapy (4). In 10% to 20% of patients with a newly established diagnosis, the disease appears to be localized at the time of presentation (7). At The University of Chicago, patients with localized DHL were entered into a protocol in which staging laparotomy was followed by extended field radiation therapy (RT) ( 1,

METHODS The treated 1986, staging versity

AND

MATERIALS

clinical records of all patients with previously unStage I and II DHL were reviewed. From 1970 to 36 patients were treated with radiation alone after laparotomy. All patients were treated at The Uniof Chicago Hospitals. Patients with mixed cellular

Medical Center, Department of Radiation and Cellular Oncology, 5841 S. Maryland Avenue, Box 442, Chicago, IL 60637.

Presented at the American Society of Therapeutic Radiation Oncology, New Orleans, 1988. * Department of Radiation and Cellular Oncology, Michael Reese Medical Center and The University of Chicago Center

Acknowledgments-We thank Danny R. Spelbring, Ph.D., for data management and Denise Adams for secretarial services. Supported in part by The University of Chicago Cancer Re-

for Radiation Therapy, University of Chicago. t Department of Medicine, Joint Section Hematology/Oncology, The University of Chicago and Michael Reese Medical Center, University of Chicago. $ Cancer Research Center, University of Chicago. Reprint requests to: D. Hallahan, M.D., University of Chicago

search Center; Public Health Service Grant No. 2P30 CA- 145990 1- 15, National Cancer Institute, National Institutes of Health, DHHS; the Beverly Duchossois Cancer Research Fund; and the Julie Rosenthal Linker Cancer Research Foundation. Accepted for publication 13 April 1989. 767

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I. J. Radiation Oncology 0 Biology 0 Physics

or nodular histology, and those receiving chemotherapy and palliative RT, were eliminated from the study. All patients were staged by the Ann Arbor classification for Hodgkin’s disease (5). Staging included obtaining a complete blood count (CBC), chemistry profile (SMAI7), chest x-ray, liver and bone scans, bone marrow biopsy, intraveneous pyelogram, inferior venocavagram, and lymphangiogram. Gallium scans were performed on most patients. Computed tomography scans had been obtained during the past several years. Staging laparotomy was performed on 55 patients (pts) with clinical Stage (CS) I-III disease. Patients with CS I or CS II disease who were older than 65 or medically inoperable (11 pts) and patients staged at Michael Reese Hospital (6 pts) underwent clinical staging only. Patients presenting with infradiaphragmatic disease underwent exploratory laparotomy and left scalene node biopsy. Patients with supradiaphragmatic disease were treated with extended mantle (15 pts) and total nodal (4 pts) irradiation, and patients with infradiaphragmatic disease received inverted Y with or without whole abdominal irradiation (8 pts). Involved-field RT (7 PS I and 2 PS II pts) included the area of gross disease with a 2 to 5 cm border and adjacent lymph nodes. Waldeyer’s ring was treated in six of the above patients with DHL involving the head and upper neck (6 pts). Total tumor dose was 34-60 Gy (median 50 Gy). Contiguous nodes received 34-40 Gy and gross disease was typically boosted to 5055 Gy using 160-200 cGy fractions. A 2 MeV generator* was used to treat patients until 1976; since then, a 4 MeV linear accelerator has been used. Patients were treated with opposed fields treating 2 fields per day. Since 1982, patients with CS II and III disease have been treated with chemotherapy alone and these patients have not undergone staging laparotomy. To evaluate the efficacy of staging laparotomy and extended field irradiation, we have also analyzed the patterns of failure in 17 CS I and II DHL patients who were treated with involved-field RT alone. These patients were older than 65, medically unfit for laparotomy (11 pts), or staged at Michael Reese Hospital (6 pts). No attempt has been made to compare the RFS rates of these patients with those of the pathological Stage (PS) I and II patients. because these are two diverse patient populations. Only the patterns of failure have been analyzed.

October 1989, Volume 17. Number 4 Table 1. Staging laparotomy Pathological

stage

Clinical stage

I

I II III

14 5 3

1

1

7 6

PS total

22

14

II

results

III

IV

Total CS

2 7

2 4 3

18 18 19

10

9

55

an outside hospital, undergone incomplete laparotomy, or undergone chemotherapy treatment after staging laparotomy. Of the 55 remaining patients, 22 were diagnosed with PS I DHL and 14 were diagnosed with PS II DHL. Of the 18 CS I patients, four (22%) were upstaged to Stage II-IV and of the 18 CS II patients, six (33%) were upstaged. Of the 19 CS III and IV patients, nine (47%) were downstaged to PS I or II. Table 1 summarizes the results of staging laparotomy performed at The University of Chicago Hospital.

Patient characteristics Of the 36 PS I and II patients,

22 were men and 14 were women. The median age was 43 years with a range of 16 to 67 years. Patients were followed for 2 to 18 years (median, 7 years). Of the PS I patients, none had mediastinal or abdominal involvement, and 12 had disease localized to the head or neck: the inguinal or axillary nodes were involved in three patients each, and three patients had other peripheral sites of involvement. Of the PS II patients, two had mediastinal involvement, two had abdominal involvement, eight had head and neck presentations, and three had involvement in other sites. Only one PS II patient had B symptoms. Bulky disease (greater than 5 cm) was present in five PS II patients: two PS I patients had bulky neck masses.

Radiation therapy results The actuarial IO-year relapse free survival (RFS) rates for PS I and PS II patients were 9 1% and 35%, respectively. The median follow-up time was 7 years (Fig. 1). None of the 22 PS I patients had bulky mediastinal or abdominal disease. Eighty percent of the recurrences occurred within 2 years of irradiation.

Patterns oj‘failure RESULTS

Staging laparotomy During the 16-year period from 1970 to 1986, a total of 67 staging laparotomies were performed on patients with CS I to III DHL. Twelve patients were excluded from this study because they had received prior treatment at

* Van de Graaff generator, High Voltage Engineering, lington, MA 0 1803.

Bur-

None of the PS I patients relapsed in field 0~ transdiaphragmatically. Of the 22 PS I patients, one patient with a testicular primary failed in the unirradiated inguinal lymph nodes (contiguous lymph node). A second patient with a neck primary failed with disseminated disease. Of the 14 PS II patients, seven relapsed (Table 2). Two patients with bulky disease (greater than 5 cm) in the tonsil

Patterns of failure in PS I and 11DHL 0 D. E. HALLAHAN PATHOLOGIC

STAGED

PATIENTS

loo ‘F2 9.

14-:____17___M__---PS I

80Median 7.10 yrs.

70IO

3 .z ? z

605

PS II

20 IO

1

1

I

ON

0

2

4

6

8

IO

14

12

Survival Time in Years Fig. 1. Actuarial survival of pathological Stage I and II diffuse histiocytic lymphoma patients treated with radiation therapy alone.

and para-aortics relapsed in-field after receiving a total dose of 50 Gy. A marginal recurrence occurred at the base of tongue (BOT) after extended mantle irradiation of a patient with BOT primary. Failure in an unirradiated contiguous lymph node occurred in a patient with a neck primary after treatment with involved-field irradiation. Para-aortic recurrences occurred in two PS II patients: one with a testicular and para-aortic presentation and one with a bulky mediastinal primary. One of seven patients with Waldeyer’s ring presentation recurred in the stomach. Dissemination occurred in three PS II patients, two of whom failed in sites of bulky disease. PS II patients with

769

eta/.

a low risk of recurrence included patients with fewer than three sites of disease and no mediastinal or abdominal disease (75% 5-year RFS). One of six PS II patients over 50 years of age relapsed. To better evaluate the efficacy of staging laparotomy and extended field irradiation, we reviewed the patterns of failure in 17 patients with CS I and II DHL who were treated with involved-field irradiation. Two of the 17 patients failed within the abdomen and three failed with disseminated disease. Another four patients failed in-field after receiving 35-50 Gy; three of these four patients had bulky disease (greater than 10 cm). None of the 17 patients treated with involved field irradiation failed in contiguous lymph node sites. Of all of the pathologically and clinically staged patients, six have failed within the field of irradiation. Of the eight patients with bulky disease (greater than 5 cm), five patients failed in field after receiving a total tumor dose of 45-50 Gy. Excluding one marginal recurrence, only one patient with nonbulky disease failed in-field after receiving a dose of 45 Gy. Morbidity Acute toxicities resulting from extended field irradiation included nausea, vomiting, and diarrhea in 13 of the 46 patients. Two of these patients required hospitalization for rehydration during extended mantle treatment. Ofthe 28 patients treated with mantle or extended mantle irradiation, three patients developed esophagitis, three developed Lhermitte’s syndrome, and three developed Herpes Zoster. Myelosuppression, which necessitated a break in treatment, developed in six of the 27 patients receiving extended field irradiation. Late complications developing in patients treated with the extended mantle technique included pericarditis and pneumonitis in one patient. A 16-year old boy who received 44 Gy to an extended mantle field died from a myocardial infarction 8 years after treatment. Autopsy revealed coronary artery disease. A 28-year old man who was treated with 40 Gy to an extended mantle field developed osteosarcoma of the right posterior second rib 10 years after radiation therapy. Three patients are currently taking thyroid replacement for hypothyroidism 3 to 10 years after irradiation. One patient who received abdom-

Table 2. Failure pattern Stage I Involved field Extended field II Involved field Extended field

Note: A primary disease.

Number of patients

Primary

Contiguous lymph node

22 7 15 14 2 12

0 0 0 2 0 2

1 0 1 1 0 1

failure refers to a recurrence

in the site of original

disease.

Infradiaphragmatic

1 0

0 0 0 2 0 2 Brackets

indicate

Dissemination

:(2) 1 2 primary

failure in a site of bulky

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0 Biology 0 Physics

inal irradiation died of a myocardial infarction and one patient died of chronic obstructive pulmonary disease, which was diagnosed prior to mantle irradiation. The complications in 55 patients undergoing staging laparotomy included wound infection in two patients, infectious peritonitis in one, and bile peritonitis in one patient who had a cholecystectomy performed at the time of laparotomy. The latter patient died from this complication. The average hospital stay for patients undergoing staging laparotomy was 4.5 postoperative days.

Salvage ChemotherapJJ All but one of the ten patients who received multiagent chemotherapy as salvage treatment had recurrence of disease and are dead. Patients received COMLA ( 14) (3 pts), BACOP ( 13) ( 1 pt), COP (2) (2 pts), CHOP ( 10) (3 pts), COP-BLAM (8) ( 1 pt). Second complete responses were achieved in seven of the ten patients, however three recurred within 3 to 6 months and three others recurred within 1 to 4 years. One patient has no evidence of disease 3 years after salvage treatment with COMLA chemotherapy.

DISCUSSION Patients with Stage I DHL have an excellent RFS rate after stringent patient selection and aggressive staging followed by irradiation. Early stage DHL patients treated at M. D. Anderson Hospital underwent staging laparotomy followed by a radiation dose of 50 Gy to involved fields ( 15). Patients with disease located in the mediastinum or abdomen were treated with CHOP-Bleo. Patients with peripheral PS I and II disease achieved a 90%, 5-year survival with RT alone ( 15). A randomized trial carried out by Veronesi et al. does not support the efficacy of aggressive staging followed by RT alone (16). The 5-year RFS for patients with PS I DHL treated with RT was 64%. The improved survival rate obtained in patients who undergo pathological staging (PS) as compared to clinical staging (CS) may be due to patient selection. PS I patients treated with RT alone in this series and in the M. D. Anderson Hospital series (15) had no mediastinal or abdominal involvement; patients undergoing laparotomy tend to have a better performance status because patients who are not medically fit for laparotomy undergo clinical staging only. Patients selected for this protocol were also younger than the average DHL patient. Clinically staged patients also tend to be less aggressively staged with fewer lymphangiograms and gallium scans, and may therefore be understaged. Patients with CS I disease may have a 15-20% incidence of occult disease within the abdomen (16). Therefore, staging laparotomy must be performed by an experienced surgeon (11) if RT is to be used as the single modality of therapy. Less aggressive staging and selection of patients treated with RT alone results in RFS rates that are sig-

October

1989. Volume

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4

nificantly lower than those achieved with chemotherapy (6, 12). Patients with early clinical stage diffuse lymphomas, treated at the Dana-Farber Cancer Institute by a variety of multiagent regimens combined with RT. had significantly higher RFS rates as compared to patients treated with RT alone (9). However, this study included patients with high grade lymphoma, clinically staged and predominantly Stage II disease. Excellent RFS rates are achieved using multiagent systemic chemotherapy. M-BACOD was used to treat 121 patients with diffuse large cell lymphoma (4). Patients with Stage II disease have an 87%, 3-year RFS with this regimen. Prognostic factors that were predictive of poor survival included bulky disease (greater than 10 cm), poor performance status, and B symptoms. CS I and II DHL patients were treated at the University of Arizona with CHOP and RT administered to sites of bulky disease ( 10). The 3-year RFS rate was 80%. In each of these studies, patients with localized DHL have an excellent RFS when treated with chemotherapy and RT to bulky disease. Patients with bulky disease within the abdomen and mediastinum have been shown to have a higher incidence of recurrence (9, 15). The absence of patients with bulky disease in this study and in the M. D. Anderson RT alone series may be the primary reason for the low incidence of in-field recurrences. Patients in this study received a uniformly high radiation dose, which may improve the local control (3). The incidence of failure in contiguous lymph nodes in DHL was also found to be low (3, 15). We found no improvement in preventing recurrence in contiguous lymph nodes by using extended fields in this study. Studies evaluating the patterns of failure of clinically staged DHL patients have revealed a high incidence of distant failure (6, 12). Staging laparotomy may exclude patients at risk of failing in the abdomen and patients with dissemination by detecting occult disease within the abdomen. The present study demonstrated that patients with PS II disease involving more than two sites or patients with bulky disease also have a higher incidence of dissemination. It may be possible to select patients with PS II DHL who can be treated with RT alone by eliminating patients with bulky mediastinal and abdominal disease. The morbidity from systemic chemotherapy includes risk of neutropenic sepsis, bleomycin pulmonary toxicity, Adriamycin cardiac toxicity, neurotoxicity from vincristine, and treatment related leukemia associated with alkylating agents (4, 13). Preservation of fertility can be achieved in young adults by using RT as opposed to chemotherapy. The morbidity from staging laparotomy is extremely low (11). Typically, there is a 4 to 5-day hospital stay with rare complications. A single fatality was related to a cholecystectomy performed during lymph node sampling. Staging laparotomy followed by RT alone may be the preferred treatment in young patients with PS I DHL. Patients with a high probability of remaining relapsefree can be selected. Those patients with localized disease

Patterns of failure in PS I and II DHL 0 D. E. HALLAHAN

outside of the mediastinum and abdomen and who are found to be PS I after staging laparotomy can be treated with RT alone. Involved-field RT does not result in a high incidence of failure in contiguous lymph nodes. We must emphasize that patients who relapse after treatment with

et al.

RT alone are unlikely to respond to observed in this series. Thus, patients lapse, such as those with CS II disease abdominal presentations, should be motherapy.

771

salvage therapy as at high risk for reor mediastinal and treated with che-

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