Medical and Pediatric Oncology 1:235-263 (1975)

NON-HODGKIN’S LYMPHOMA IN CHILDREN Norma Wollner, M.D., Joseph H. Burchenal, M.D., Philip H. Lieberman, M.D., Philip R. Exelby, M.D., Giulio J. D‘Angio, M.D., and M. Lois Murphy, M.D. Departments of Pediatrics, Medicine, Pathology, Surgery, and Radiation Therapy, Memorial Sloan-Kettering Cancer Center, New York City

In a study of non-Hodgkin’s lymphoma in children, 104 children were treated and followed at Memorial Sloan-Kettering Cancer Center from 1964 through June 1974. Forty-three patients, previously treated and untreated, received a nonspecific group of various chemotherapeutic agents and attained an 1 1% disease-free survival rate. A second group of 18 previously untreated patients, who received a chemotherapeutic regimen consisting of cyclophosphamide alone, achieved a 33% disease-free survival rate. The last group, 43 previously untreated patients (77% of whom had far advanced disease and 86% of whom had diffuse histological types) who received a new and intensive multiple-drug regimen ( t h e LSAz -Lz protocol) consisting of induction, consolidation, and maintenance phases, has maintained an 8 1% disease-free survival rate after a median observation time of 2 1+ months. Although nervous system involvement and recurrence o r metastases at any time are poor prognostic factors, initial marrow involvement and t h e amount of bulky disease are no longer considered negative prognosticators when intensive treatment is initiated immediately after diagnosis, is continued for 2-3 years, and includes radiation therapy t o sites of bulky disease and CNS prophylaxis. The LSAz-Lz treatment is effective in accornplishing t h e dual aims of not only increasing the numbers of disease-free patients but also prolonging their survival. KEY WORDS: non-Hodgkin’s lymphoma, multidisciplinary therapy (LSAz -Lz), survival, histology, staging

INTRODUCTION The treatment of childhood non-Hodgkin’s lymphoma has been discouraging, regardless of staging, histologic type, and the size and location of the primary tumor (1-19). Abbreviations: AraC, arabinosylcytosine; BCNU, 1,3-Bis (2-chloroethyl)-l-nitrosu1ea;CNS, central nervous system; DH, diffuse histiocytic; DLPD, diffuse lymphocytic poorly differentiated; DLWD, diffuse lymphocytic well differentiated; DM, diffuse mixed; DU, diffuse undifferentiated; IV, intravenous; IT, intrathecal; LSA, lymphosarcoma; NLPD, nodular lymphocytic poorly differentiated; NLWD, nodular lymphocytic well differentiated; NM, nodular mixed; NU, nodular undifferentiated; NP, nonprotocol (patients); RCS, reticulum cell sarcoma. Presented March 1974 at the Annual Meeting of the American Association for Cancer Research, Houston, Texas. Address reprint requests to Dr. N. Wollner, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021.

01975 Alan

R. Liss, Inc., 150 Fifth Avenue, New York, N.Y. 10011

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Short survival in these disorders is related to frequent recurrences and early dissemination to the bone marrow and nervous system (20-30). In children and adults the long-term results of treatment with single and multiple agents have varied from very poor to good, but the best results have been obtained with adults (7,3 1-48). Lately increased interest has been focused on Rappaport's histological classifications (3,31,49-54) and their correlation with survival. There have been, however, few reports analyzing recent changes in therapy, staging, histological classification, and survival in childhood non-Hodgkin's lymphoma. The objectives of the present study are four-fold: (1) To compare treatment results in relation to presentation, histology. staging, and primary tumor sites and to determine their relation to survival. (2) To determine causes of past and present therapeutic failure, times for recurrences and dissemination, and their relation to survival. (3) To present the rationale and results of the =A2 -L protocol. (4) To recognize future possibilities for improvements in therapy. MATERIALS AND METHODS Treatment Modalities

Three therapeutic modalities were used in the patient population to be discussed; they were: (1) The nonprotocol (NP)treatment. These 43 children, previously treated and untreated, were given various chemotherapeutic agents' and radiation therapy to multiple or single sites (including the skull or spine or both) in doses ranging from 200 to 2,800 rads (55,56). (2) The LSA' protocol. In this second group 18 previously untreated children received 1,200 mg/mZ (40 mglkg) cyclophosphamide IV at intervals of 3-4 weeks for 6 months (with or without radiation therapy to primary or multiple sites). Fifteen of these patients received radiation therapy initially in doses ranging from 200 to 4,200 rads. (3) The LSA2-bprotocol. There were 43 previously untreated children in the last group. This multiple-drug therapeutic regimen has the same three phases - induction, consolidation, and maintenance - as treatment for leukemia at Memorial Hospital (57-59). Radiation therapy was administered simultaneously with drugs during induction to 22 patients; doses ranged from 200 to 6,200 rads. LSAz -L2 Protocol

Induction phase. On the first day 1,200 mg/mZ (40 mg/kg) cyclophosphamide are given in a single push injection to reduce the bulk of the tumor (Fig. 1). Radiation therapy to the primary site of disease is started either on the same day or within the next 3 days. On day 3 or 4 a 28-day course is started; this consists of daily oral prednisone, 60 mg/mZ (2 mg/kg), divided into 3 daily doses; weekly IV injections of vincristine, 1.5-2.25 mg/mZ (0.05-0.075 mglkg); IT methotrexate, 6.25 mg/m2, between the first and second vincristine

' These included HN' , oral and IV cyclophosphamide in small doses, 6-mercaptopurine, methotrexate, daunomycin alone, daunomycin in combination with other drugs, IT methotrexate, vinblastine, actinomycin-D, and prednisone alone or in combination with vincristine.

Non-Hodgkin's Lymphoma in Children

237

INDUCTION

)

(

-_ _ - - - --- METHOTREXATE. INTRATHECAL 6.25 mg/ML

I

I1

RADIATION THERAPY CYCLOPHOSPHAMIDE,

I&

mg/M2

I

- - - - ---

I1

ARAB IN0 SY LCYTO 5 I NE, i .v .

BCNU, i.!.

60 mg/M

t

~vuNoMY"". mglM

1

Weeks

>

CON SOL I DAT ION

1

1

I

2

I

2

1

1

3

I

4

1

5

I

6

I

7

I

8

I

9

I

10

I

11

A

I

12

13

Fig. 1 . Schematic of the LSA2-L2 protocol. Induction and consolidation.

injections; and 2 consecutive doses of IV daunomycin, 60 mg/m2 (2 mg/kg) each, between the second and third vincristine injections. After completion of this 28-day course and while the prednisone dose is being tapered, two more IT injections of methotrexate are given, 2-3 days apart. Consolidation phase. This phase starts within 1 week from the last dose of IT methotrexate and consists of a combination of 15 IV doses of Ara-C, 150 mg/m2 (5 mg/ kg), daily (Monday through Friday) and thioguanine given orally, 75 mg/m2 (2.5 mg/kg), 8-12 hours after the injection of Ara-C. If the white blood count remains adequate on the fifth day of Ara-C, the patient continues to receive the same dosage of thioguanine over the weekend. However, both drugs are discontinued temporarily when there is bone marrow depression; this usually occurs after the initial seventh to tenth doses of the combination and ordinarily recovers within 7- 10 days. Hence, the patient may receive more than 15 doses of thioguanine orally but may receive only 15 doses of IV Ara-C. This first phase of the consolidation takes an average of 30-35 days. The second phase of consolidation is started immediately after completion of the 15 doses of Ara-C; it entails daily IV administration of Lasparaginase, 60,000 U/m2 (2,000 U/kg), for a total of 12 injections. Within 2-3 days after the last injection of L-asparaginase, two more IT injections of methotrexate are given. These are followed within a few days by an IV injection of 1,3-Bis-(2-chloroethyl)-l-nitrosurea(BCNU), 60 mg/m* (2 mglkg), which completes the consolidation. The average duration of induction and consolidation is 125-135 days.

Wollner et al.

2 38

There are 4 periods of hematological depression during induction and consolidation. Hematological depression is defined here as a total white blood count of less than l,SOO/ m 3and a platelet count of less than 150,000/mm3 ;this type of depression occurred in approximately 60% of the patients. The first depression occurs 6-9 days after the injection of cyclophosphamide with a moderate to severe leukopenia, depending on the level of initial marrow involvement. This depression is self-limiting and usually lasts for 3-4 days. The second depression, characterized by a marked pancytopenia, occurs 6-9 days after the second dose of daunomycin; this may last for a week or longer. Sepsis may occur in this phase; precautionary measures with appropriate cultures and antibiotic therapy should be taken immediately if the patient exhibits temperature spikes or changes in vital signs. Although fever was present in about 30% of these patients, sepsis documented by culture occurred in only 15%. The third depression occurs during the consolidation phase, usually after the seventh to tenth doses of AraC, and requires platelet and blood transfusions or hospital admission if there are signs of infection. The last depression is manifested by pancytopenia, usually 2-3 weeks after the administration of BCNU, and it might delay maintenance for 7-10 days. Maintenance was postponed in approximately 70% of these children. Maintenance phase. Maintenance starts within 1 week of the end of consolidation and comprises 5 cycles of 5 days each, with intervals of 7-10 days between each cycle (Fig. 2).

Part

IS

REMISSION MAINTENANCE TNRAPY DRUG

Daun

DAYS CYClES

1

I

I n

DOSE rqlkg

Thioguanine flG) ............................. 10 P.O. Cyclophaphamide ICYTI. ..................... M i.V. Hydrmyurea I H U I ............................ 80 P.O. Daunom)cin (Daunl........................... 1.5 i.v. Mdhdrexate IMTXI.. ................10 mglM21 dose P.O. 1.3-BisQ-Chbroethyll - 1-nitroswrea IBCNUI..~ i.v. i.v. Arabinosylcytaine IAra-Cl................... ..5 Vincristine NCRI., ........................... 0.075i.v. Methotrexatg lntrathecal IMTXI ..........6.?5mg/MZ IT

I

m I

L

d

P

Fig. 2. Schematic of the LSA2-L2 protocol. Maintenance

239

Non-Hodgkin’s Lymphoma in Children

The first cycle starts with oral thioguanine, 300 mg/m2 (10 mg/kg), for 4 days, followed by IV cyclophosphamide, 600 mg/mZ (20 mg/kg), on day 5. The second cycle consists of oral hydroxyurea, 2,400 mg/m2 (80 mg/kg), for 4 days followed on day 5 by IV daunomycin, 45 mg/m2 (1.5 mg/kg). In the third cycle, oral methotrexate, 10 mg/m2, is given for 4 days, followed by IV BCNU, 60 mg/m2 (2 mglkg), on day 5. The fourth cycle consists of daily injections of Ara-C, 150 mg/m2 (5 mg/kg), for 4 days followed by an IV injection of vincristine, 1.5 mg/mZ (0.075 mg/kg), on day 5. The fifth cycle consists of 2 IT injections of methotrexate, 6.25 mg/m2, 2-3 days apart. The cycles are restarted beginning with thioguanine after a 7- to 10-day rest period. Each of these 5cycle courses of maintenance therapy takes from 55 to 65 days. Patients with stage I, 11, or I11 disease are treated for 2 years, and patients with stage IV disease are treated for 3 years, provided that no recurrence or dissemination of disease takes place (Table I). TABLE 1. Staging of Nodal and Extranodal Disease in Non-Hodgkin’s lymphoma in Children Nodal

Stage ~~

One site Two or more sites either above or below diaphragm

Two or more sites above and below diaphragm extensive intrathoracic extensive intra-abdominal Central nervous system and/or bone marrow involvement

~

Ex tranodal

~~~

I I1

Ill

IV

One site One site + regional node Two sites + regional nodes either above or below diaphragm Two or more sites above and below diaphragm extensive intrathoracic extensive intra-abdominal Central nervous system and/or bone marrow involvement

Work-Up

Initial work-up of the disease was done clinically and by laboratory tests, including a complete blood count, urinalysis, spinal tap with cell count and determination of glucose and protein content, appropriate blood chemistries to assess renal and hepatic function, and specific cytologic examinations of spinal fluid and urine. Until 1971 one bone marrow aspriation or biopsy was considered adequate; since 1971, however, marrow aspirations from at least 3 different sites have been performed, even in the presence of normal peripheral white blood counts and differentials. Marrow biopsy was performed when aspiration was suspicious but not diagnostic (60-63). All original pathology slides were reviewed by one of us (P.H.L.). Paraffin blocks for further sections and study were requested in all cases but were unavailable for review in 5 NE’ patients. When the initial biopsy was inadequate for diagnosis, a new biopsy was performed. Radiological studies included chest films, postero-anterior and lateral, skeletal survey including hands and feet, intravenous pyelogram, and lymphanglogram, provided there was no massive mediastinal lesion or pleural effusion. When a primary lesion was located in the face, tomograms were done to assess the extent of bone destruction and to assist in de-

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et

al.

termining the radiation field. Upper GI series and barium enema were done only when abdominal disease was present or suspected or in cases of abdominal complaints without clinical findings. Radioactive liver (with 99m Tc sulfur colloid), bone (with F-18 sodium fluoride), and brain (with 99m Tc pertechnetate) scans, as well as a soft tissue gallium scan (with 67Ga citrate form), were done in most cases. In patients with neurological symptoms related to the extremities, a brain scan, myelogram, and electroencephalogram, as well as a lumbar tap, were performed. Baseline electrocardiograms (64) were done and repeated periodically for follow-up of drug-related toxicity (9). Staging laparotomies were not performed in these patients because of the rapid, widespread dissemination of disease and the necessity to start early, intensive chemotherapy. The role of surgery was primarily in intra-abdominal lymphoma, where resection of the primary tumor and regional nodes was carried out. Biopsy of other enlarged nodes in the abdomen was then performed, but splenectomy and ovarian transposition were not recommended. Definitions

Certain definitions are needed at this point for both better understanding of these disease entities and future comparison with other treatment protocols. Primary site. Although some patients had readily identifiable primary tumor sites (by clinical and/or radiological examination), frequently disease was multifocal and difficult to characterize. In this study a site, organ, or system was considered primary when the disease in that area was bulky and correlated with initial symptomatology. When complaints were nonspecific, and when, after the initial work-up, multiple sites were found to be involved, the system with greatest involvement was considered t o be the primary (for example, a case with multiple bone lesions, one of which was very large and palpable clinically, but with only moderately enlarged nodes, would have been considered a skeletal primary because, from radiological appearance, the bone lesions appeared to have been present longer than those in the lymph nodes.

Marrow involvement. Marrow involvement consists of immature cell clusters or isolated abnormal cells in sufficient number to make their presence in the marrow suggestive of early involvement. (The definition of sufficient number is difficult to establish by percentage. The unquestionable presence of these cells in an otherwise normal marrow, however, warrants consideration for staging purposes.) This type of replacement can be partial or total, with or without peripheral blood involvement. Nervous system involvement. Three different clinical and laboratory manifestations of nervous system involvement have been found in these patients. The first one, purely meningeal, was associated with headache, vomiting, irritability, and papilledema in earlier cases where no routine spinal taps were performed. Now most cases of this variety of disease are discovered by routine spinal taps. Neurological examination in most of these patients reveals little except for papilledema and positive Babinsky’s signs, with or without other deep tendon reflex abnormalities. Spinal taps reveal pleocytosis of varying degrees with positive cytology (a cell count in the spinal fluid of greater than 5 cells/mm3 with positive cytology by Giemsa or Papanicolaou stains), increased opening pressures, and normal or abnormal sugar and protein (elevation of protein, for example, above 38 mg/100 ml). The second type, a focal lesion, presents single or multiple cranial

24 1

Non-Hodgkin’s Lymphoma in Children

nerve involvement, lumbar or brachial plexus involvement, cord compression by extradural involvement at different levels, and cerebellar and cerebral involvement, all without cerebrospinal fluid malignant pleocytosis. The third type shows mixed meningeal and focal disease. “Old“ staging. The staging for nodal and extranodal Hodgkin’s disease, used today for non-Hodgkin’s lymphoma, using either the Rye or Ann Arbor system, is cumbersome and does not apply well to children’s non-Hodgkin’s lymphoma. In a review of the patient population at Memorial Hospital pripr to use of the LSAz LZ protocol, patients with stage I single-site or single-nodal (localized) disease fared better than those with regional disease; this has been confirmed by Freeman et al. (5,65). The latter, therefore, should be stage I1 and not stage I. Also, patients with either extensive mediastinal disease (50% or more of the thoracic cavity involved) or extensive intraabdominal disease (inoperable or incompletely resectable surgically) had a poor prognosis accompanied by early recurrences and metastases to the bone marrow and CNS. This is compatible with stage I11 disease (Ann Arbor or Rye), even though the tumor might be localized within a cavity. Finally, in stage I11 or IV (Rye or Ann Arbor) patients, there was a similar clinical course and survival time (prior to use of the LSAz -Lprotocol), the only difference appearing in those with initial marrow or CNS involvement. These patients did poorly in the length and quality of their survival and the duration of their responses. Jones et al. (25) and Sullivan (30) have both reported that survival time in their patients with marrow involvement was better than in those without it, but this difference may be due to the fact that those patients were treated with more intensive chemotherapeutic regimens and supportive care. “New” staging. Because of the above observations, a simplified staging system for both nodal and extranodal disease is presented (Table I). No distinction in therapy is made between nodal and extranodal presentations. All staging used in the remainder of this study and in the tables will adhere to that found in Table I. Patient Population

One-hundred and four children with non-Hodgkin’s lymphoma were studied at Memorial Sloan-Kettering Cancer Center from 1964 through June 1974 (Table 11). The male to female ratio was 2.3/1. Forty-six patients (44%) had nodaldisease (peripheral nodal and mediastinal primaries), and 58 patients (56%)had extranodal disease. Of the 85 children (86%)with diffuse histology, approximately 41%were D U D , 24%DU, 14%DH, 4%DLWD, and 1 % DM. Most patients with the nodular classification (1 1/14) were male. Twenty-five percent of the patients had early (stages I and 11) disease, and 75% had stage I11 and IV, or advanced, disease. Patients with symptoms of a short duration prior to definitive diagnosis comprised 80%of this group. Almost all patients were referred to Memorial Hospital after the diagnosis was made and biopsy or primary surgery was done elsewhere. The vast majority of patients had primary disease in the peripheral nodes, mediastinum, bowel, or skeleton. No patients with mediastinal primaries had stage I or I1 disease; by the time these patients were diagnosed, disease in the chest was not only extensive (90% had bilateral pleural effusions), but other organs, such as the kidneys, paraaortic nodes, other distant peripheral nodes, and bone marrow, were also frequently involved. All girls with ovarian primary sites had advanced disease. In primary bowel disease

5 14 8

8

8 6 6 9

8

8 8 8

Sex

3 3 1 1 1 1

73

1

104

18 15 19 11

M

.~

25 21 21 17 6 3 5 3 1 1

Median Age (hyears) Total

31

2 2

7 6 2 6 6

F

13

1

13

1

4

I1

I11

Stage

45

7 14 2 3 1 2 3 1 4 5 1 1 1 3 1 2

5

I

33

1

1

9 7 4 9 1 1

IV

*1964-June 30,1974. ?Slides on 5 patients were unavailable for histological classification and are not included.

Peripheral nodal Mediastinal Bowel Skeletal Ovarian Renal Nasopharyngeal Subcutaneous Liver Thyroid Central nervous system Total

Primary Site

Number of Patients

14

1

2

1

1

9

2 3 2 1 1 1 85

6

15 19 18 17

H ist ologyt Nodular Diffuse

TABLE 11. Total Patient Population: Distribution According to Primary Site, Age. Sex, Stage, and Histology*

Non-Hodgkin’s Lymphoma in Children

243

stages 111 and IV were encountered three times more often than stages I and I1 (1 6 / 5 ) . For those with skeletal primaries stages 111 and N were also three times more common than I and I1 ( 13/4). The predominance of diffuse histological types in the mediastinal, bowel, skeletal, and ovarian presentations (the latter two without any cases of nodular histology) is especially noteworthy. RESULTS

Group I

- Non-Protocol Patients

Forty-three patients received therapy on a nonscheduled basis in accordance with specific needs of the patients and/or progression of the disease. The treatment philosophy at the time was similar to that used for Hodgkin’s disease in the past - that is, in early stages the combined use of nitrogen mustard, Thio-TEPA, and radiation therapy, and in those showing disseminated disease or marrow metastases, the use of antimetabolites (either alone or in combination). Table I11 shows the NP population distributed according to primary site, age, sex, histology, stage, and their correlation to survival. Of interest in the table is the predominance of extranodal sites (24/19) and the predominance of stage 111 patients. No stage IV patients had complete marrow involvement nor circulating blast cells in the peripheral blood; at the time these patients began therapy they would have been considered leukemic. None of the 10 children with mediastinal primaries (all diffuse histology) survived; they all had extensive disease in either the thoracic cavity or other sites. In the bowel primary group the only patient who survived was a stage I (no slides available for histological review and typing), in whom complete removal of the primary was possible. The other 6 had inoperable lesions and only biopsies were performed. In summary, only five (1 1%) of the 43 NP patients survived, none of whom had complete marrow involvement or evidence of peripheral blood disease; 4 had stage I disease. The last survivor had stage 111 disease in a peripheral nodal primary and is alive after 45 months, having recurred after 16 months of treatment with various chemotherapeutic agents. This patient is presently off the LSA2-Lprotocol without recurrent disease. (This patient is not considered an LSA2-L2 patient because he received treatment, albeit unsuccessful, prior to receiving the LSA2-Lregimen. This was the case with a patient on the LSAl protocol, as well. Only previously untreated patients are included in the LSA2-Lgroup and survival figures.) In tlus group the high incidence of diffuse histology and far advanced disease, with early recurrences and dissemination to the bone marrow and nervous system leading to early death, were frequently seen and may be peculiar to childhood non-Hodgkin’s lymphoma (40-42,66). The number of patients with nodular histology was too small to compare with the diffuse type, stage by stage, primary by primary, as far as survival and recurrences are concerned. Thus, analysis of these NP patients shows that minimal and sporadic therapy has little effect on the natural course of these disorders. Early recurrences, metastases, and bone marrow and nervous system involvement occurred within the first year after diagnosis. Fifty percent of the patients died within the first 6.5 months, 42% expired withn the next 6 months to a year, and less than 11% 6f the patients are free of disease after more than 5 years. Patients who did not recur ordisseminate within the first 12-15 months usually did well overall.

6 5 5 14

Renal Nasopharyngeal Thyroid Central nervous system Total

3 1 1 1 31

4

21

4

3

Diffuse 12) Nodular [ l ] Diffuse [ 11 Diffuse [ l ] 1381

Diffuse [4]

Diffuse [ 7 ]

Nodular [ l ] Diffuse [4] DH DU DH DLPD DU DLPD NU DLPD DU

NLWD DLPD

NLPD DLPD DH DLPD DU

Subtyping

7 161

(12) (94+)

(7)(30)

(118+)** (77+)

I

I11

(10) (16) ( 5 ) (6) (8)

(5)

(8) (45+) (4) ( 5 ) (9) (9) (2) (5) (21) (4) (1) (1) (2)

(11) (35)

Stage

3 131 24 1211

(13)

(12)

(9)

I1

Histology, Stage, and Survival

*43 patients total; 1964-June 30, 1974. Slides were unavailable for review on 5 NP patients as follows: Stage I - (1 18+), stage 111 - (3) (4) (lo), stage IV - (2). ?Brackets indicate the number of patients in each histological classification. **Parentheses represent the survival in months for 1 patient; + indicates patient alive as of June 30,1974.

8

4

7

Ovarian 3 1 1 1 43

7

9

Skeletal

1

6

7

8

Bowel

Diffuse 191

3

7

10

9

Mediastinal

Nodular [ 3 ] t Diffuse [S]

1

9

8

8

Sex Histology

M F

Median Age (in years) Total

Peripheral nodal

Primary Site

No. of Patients

(4) 9 IS1

(3) (6)

(5) (12)

(13) (13)

( 3)

IV

TABLE 111. Nonprotocol Patients: Comhtion Between Primary Site, Age, Sex, Histological Classification, Stage, and Survival*

t 4 P P

245

Group Il

Non-Hodgkin’s Lymphoma in Children

- Patients Receiving the LSAl Protocol

Eighteen previously untreated children with non-Hodgkin’s lymphoma received the LSAl treatment. No patients had peripheral blood involvement, even when their marrow was partially or completely replaced by extrinsic cells. Table IV shows the patient distribution according to primary site, age, sex, histology, stage, and their correlation to survival. Two-thirds of these children had primary extranodal presenting sites. The male to female ratio in this small group was 3/1. Of note are the low incidence of both early disease (only 34%)and nodular histology (16%).Of the 3 patients with nodular disease, only 1 stage I1 patient is surviving after 48 months; after a recurrence she received the LSAz -btreatment and is now off therapy following 2 years of additional treatment. Five of the patients with diffuse disease are alive, ranging from 69-92 months after diagnosis; 3 of these patients were stage I. Thus, of the 6 surviving M A l patients, 4 have remained free of disease for extended periods of time. Although high-dose cyclophosphamide effectively reduces the bulk of the disease within a short time (in 90% of the cases), alone it is not the therapy of choice. Most of these patients received either no or inadequate concomitant radiation, and the rates of recurrence and dissemination remained high. In all 4 patients who are currently alive without recurrence, radiation therapy was given simultaneously to one or more areas in doses of 3,500 rads or more. In at least 2 of these patients previous experience shows that radiation therapy alone would not have cured them, but that the combination of adequate irradiation to bulky sites of disease (mass or masses 5 cm in diameter or larger) plus highdose cyclophosphamide was more effective. Study of the NP group illustrates that recurrences in the radiation field were high when radiation therapy was less than 3,000 rads, especially when delivered in more than 3.5 weeks. The LSA, study of a single drug in frequent high doses, associated with radiation therapy, provided an improvement in the median survival time from 6.5 to 11 months. There were, however, equal numbers of recurrences and metastases to other nodal or extranodal sites plus bone marrow and CNS involvement within the first 6 months. Again, the majority of patients were dead within 1-1.5 years; only 4 patients have survived free of disease for more than 5 years (22%). It was also observed that in the NP patients, bone marrow involvement preceded CNS involvement in most patients by 1-2 months. In the LSAl study, though, nervous system metastases occurred first, and when cyclophosphamide had to be interrupted for the treatment of central nervous system disease, marrow involvement occurred within 1-2 months. This suggests that although cyclophosphamide may be an effective agent in protecting the marrow, its inability to permeate to the CNS allows the emergence of nervous system disease - even in the absence of local peripheral recurrence or dissemination to other peripheral sites. Therefore, this single drug, whether alone or in combination with radiation, did not improve survival significantly. In the LSA, group, however, there were patients who survived having had stage 111 or IV disease, an improvement over the exclusively stage I survivors in the NP patient group. Because of these poor results and because recurrences and metastases to bone marrow and the nervous system occurred early in these children, a new protocol was designed to attempt the following: (1) Administer an effective initial agent to promote fast and maximum decrease in all bulky disease. I

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( 2 ) Provide simultaneous radiation therapy to one or more sites early in the disease with the same objective as above. (3) Initiate an intensive treatment using several combination and sequential agents to avoid marrow involvement, such as that designed at Memorial Hospital for the treatment of acute leukemia (59). (4) Allow for maximum protection of the CNS during the entire treatment. Group Ill

- PatientsTreated with the LSA2-L2 Protocol

Forty-three previously untreated patients were included in this study from March 197 I , through June 30, 1974. Table V shows the patient distribution according to primary site, age, sex, histology, stage, and their correlation.to survival. The male to female ratio was 211. Twenty-one patients had nodal disease (12 peripheral nodal and 9 mediastinal); the remaining 22 patients had extranodal primaries. Twenty-three percent of the patients had stage I and 11 disease, and 77% had far advanced disease. Only 6 patients (14%) presented with Rappaport’s nodular histology, while 37 (86%) had the diffuse variety. Eight of the nine children with primary mediastinal disease are surviving, with only 1 recurrence in the primary site 10 months after diagnosis. In the bowel primary category the 4 patients who expired had 1 feature in common: From the time of diagnosis at another institution to their transfer to Memorial Hospital ( 1 -2 weeks). there was a marked increase in the size of the primary tumor with rapid dissemination to other sites not previously involved. This indicates that when there is evidence of rapid progression of disease, and the time lapse between diagnosis and the onset of therapy is considerable, the prognosis is poor and nervous system involvement is almost certain - even in the face of intrathecal therapy. If these children had received concomitant radiation therapy to one or more sites of bulky disease as an adjuvant to chemotherapy, it is possible that some of them might have achieved long-term survival. Six patients presented with nodular disease, and all 6 are alive and free of disease. Thirty-seven patients presented with diffuse disease. The majority of these patients had either DLPD (1 7 patients) or DH (10 patients) disease. One stage 1 and 9 stage 11 patients are currently alive. and 9 of the 13 stage Ill patients are alive. Of those with stage IV disease, 1 1 also had peripheral blood involvement, 9 of whom are alive and free of disease. In all who expired, recurrences and dissemination to the CNS occurred within 1-5 months from diagnosis, the same as for the previous studies. There were only 2 late recurrences (10 and 1 1.5 months after diagnosis). and 1 of these is alive. with disease, 16 months after diagnosis. Thus, for the LSAz-Lz patients, the majority of whom presented with extensive disease of the diffuse type, the intensive LSA2 -L2 therapy was successful, yielding complete responses at the end of 1 month from the onset of therapy in 40 of 43 patients. The importance of this complete response - that is, the elimination of all measurable tumor within 1-2 months from the start of treatment - cannot be stressed too strongly. In cases where this was not accomplished, regrowth and dissemination were the rule. Of the three patients who failed to achieve complete responses at the end of induction. 1 responded later and is alive, free of disease. 12 months from diagnosis, and the other 2 went on t o dis. seminate and expire. Only a few patients with bulky disease in multiple sites and initial marrow replacement, to whom no concomitant radiation therapy could be given. had an

18

8

14

1

1

3

1 4

1

2

F

Diffuse [ I ] Diffuse [ l ] Diffuse [ I ] Nodular [ I ] 1181

Diffuse [3]

Diffuse [ 2 ] Diffuse [S]

Diffuse [2]

Nodular [ 2 ] t

Histology

I1

**Parentheses represent the survival in months for 1 patient; + indicates patient alive as of June 30, 1974.

NM

DU

NLPD NLWD DU DH DLPD DLPD DU DLPD DH DH DU

I

111

Stage

Histology, Stage, and Survival

Subtyping

t Brackets indicate the number of patients in each histological classitication.

*18 patients total; 1966-1971.

1 1

8 5

I

Ovarian Nasopharyngeal Ljver Subcutaneous Total 1

3

13

Skeletal

12

5

8

10

2

2

6

Mediastinal Bowel 5

2

4

8

Peripheral nodal

Primary Site

Median Age (in years) Total M

Sex

No. of Patients

TABLE 1V. LSAl Patients: Correlation Between Primary Site, Age, Sex, Histological Classification, Stage, and Survival*

IV

5

a

1

t D

5

2

f'

W

=r

a

3

Y

r

ul"

1

m.

x

wa

11

9

1

4

8

6

8

1 2

3

1

3

4

Diffuse [ l ] Nodular [ l ] Diffuse (21

Diffuse [7]

Diffuse [9]

Nodular [ l ] Diffuse [8]

Diffuse [ 8 ]

Nodular [ 4 ] t

Histology

DLWD DH DU DLPD NLPD DH DU DH

NLPD NLWD NM DLPD DLWD DH NLPD DLPD DLWD DM DU DLPD DH DU DLPD

Subtyping ___

(35+)

I -

(13+) (33+) (15+)

I1

8

(19+) (39+) (24+)

(21+)

(28+)**

111

(33+) (11+) (29+) (24) $ (34+) 13

(5-1/2) (19+)

(15-1/2) (25+) (17+) (8+)(25+) (33+) (5-1/2)

__

2 1 1 Diffuse [ 2 ] 43 28 15 1431 1 9 *43 patients total; March 1971-June 30,1974. ?Brackets indicate the number of patients in each histological classification. **Parentheses represent the survival in months for 1 patient; + indicates patient alive as of June 30, 1974. $ Expired without lymphoma.

Subcutaneous Total

9, 13

5

1 3

5

Skeletal

Ovarian Nasopharyngeal

7

7

Bowel

9

8

Mediastinal

12

Stage

Sex Median Age (in years) Total__ M F - --

9

- .- -

Histology, Stage, and Survival

No. of Patients

IV

(9+)

( 34+) (7+) (21+) (28+)

(21+) (13+) (24+) (9+) (36+) (9+)

20

(11+) (9-1/2) (21+) (34+) (16+) (16+)

(10-1/2) (12-1/2) (7-1/2)

LSA2-L2 Patients: Correlation Between M a r y Site, Age, Sex, Histological ClassiTication, Stage and Survival*

Peripheral nodal

Primary Site ---

TABLE V.

P

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rn

r

m

a z

3

I

W

249

Non-Hodgkin’s Lymphoma in Children

initial good response but showed early recurrence and then dissemination to the nervous system with a fatal outcome. Thus, the time of onset of therapy is critical. This disease grows and disseminates so fast that once the initial studies for staging are finished, treatment should be initiated immediately. At this point it is appropriate to introduce the incidence of bone marrow and nervous system metastases in these three treatment groups and their relation to protocol. Incidence of Bone Marrow Metastases

Table VI illustrates the incidence of bone marrow metastases, relationship to therapy, and respective survivals. Bone marrow involvement occurred in 62 (59%) of the total 104 patients, but if the marrow involvement present at diagnosis is excluded, this incidence drops to 33 patients (32% of the total). Generally marrow metastases developing during the course of the disease indicated a fatal prognosis. In contrast, with the LSA2-L protocol - where treatment is aimed at preventing this type of complication - only one patient developed this involvement after therapy was begun; the patient expired thereafter. It should be emphasized that with the LSA2-L treatment, where many patients presented with this type of involvement initially, the survival rate and disease-free interval are very encouraging. TABLE VI.

Bone Marrow and Nervous System Involvement in Relation to Therapy and Survival*

Appearance oi Involvement None At diagnosis After diagnosis Alone Total with involvement Neither CNS nor BM Total

Number of Patients with Involvement Type of NP LSA, LSAz-Lz Involvement Total Alive Total Alive Total Alive BM CNS BM CNS BM CNS BM CNS BM CNS

13 22 7 4 23 17 18 2 30 21 10 43

5 5 0 0

0 0 0 0

0 0 5 5

5 6 4 0 9 12 2 1 13 12 4 18

4 6 1 0 1 0 2 0 2 0 4 6

24 34 18 2 1

7 13 3 19

9 21 43

21

33 14 1 0 1 13 1 14 2 20 35

*1964-June 30.1974.

Incidence of Nervous System Metastases

Table VI also illustrates the frequency and appearance of nervous system involvement. Forty-two patients (40%) had this type of metastases, but if patients presenting nervous system involvement at diagnosis are excluded, the incidence falls to 3 6 (35%). The nervous system is distinguished here from the CNS because metastases in the peripheral nerves did occur without central involvement. Table VII illustrates the distribution of the three types of nervous system involvement according to protocol. One-half of the NP patients exhibiting nervous system

250

Wollner et al.

TABLE VII. Types of Nervous System Involvement in Relation to the Three Protocols* Number of Patients Type of Involvement

Total NP

LSA

LSAZ-L~

No.

q .___

Meningeal Focal Combined Total

5 5 11

21

4 4 4 12

2 5 2 9

11 14 17

42

26 34 40 40

*1964-June 30. 1974

involvement had the combined focal and meningeal variety, the 12 LSA, patients were evenly distributed, and the majority of the LSAz -L2 patients had focal disease. Purely meningeal involvement occurred only in those patients who had marrow metastases, and of 17 patients with combined meningeal and focal involvement, in only 2 children was this combined variety not preceded by marrow replacement. In the majority of patients with nervous system metastases, bone marrow involvement either preceded or accompanied them. Of the 42 patients with nervous system metastases, 28, or two-thirds, had meningeal with or without focal signs of central or peripheral involvement. Not only is the clinical picture different in those without exclusively meningeal involvement, but their response to treatment (radiation, IT methotrexate, prednisone, and IT Ara-C) is also usually poor, and recurrences develop repeatedly within short periods until death. The total percentage of patients with total or partial cord involvement cannot be correctly estimated because only those with complete cord block could be established either clinically or radiologically. In the others with possible partial cord involvement (by extradural involvement) or focal lesions of the brain. the percentages were not substantiated either by myelographic or more sophisticated radiological studies until after 1966. The median duration of nervous system involvement for the entire group was 3 months, with a slight variation o f ? 1 month in the NP group. If the 43 patients in the LSA2-Lprotocol are excluded, 33 of the remaining 61 patients had nervous system disease. Survival

It is now appropriate t o compare the survival curves for these three groups (Fig. 3). The lowest curve represents the NP patients with a survival rate of 11%. Four patients are free of disease after 5 years, all of whom were stage I. One stage I11 patient, alive after 45 months, had recurrent disease on two occasions but has completed therapy on the LSA2-L protocol. The median survival for this group was 6 months. For the few who survived for more than 12 months, the clinical course was marked by recurrence and multiple episodes of CNS involvement. Usually bone marrow involvement in this group occurred within the first 2-3 months, and CNS metastases occurred within 3 4 months after diagnosis. The middle curve shows the survival of the LSA, patients, for whom the median survival time increased to 1 1 months. Six patients (33%) survived for more than three years, 2 of whom had recurrences and were treated with the L S A 2 - L protocol. Four patients are without evidence of disease after 69-92 months. All of these patients had their therapy discontinued after 6 months. and all but one received concomitant radiation

25 1

Non-Hodgkin’s Lymphoma in Children

Fig. 3. Actuarial survival for 104 children with non-Hodgkin’s lymphoma (January 1964, through June 30, 1974), treated with 3 different protocols: nonprotocol therapy, LSAl therapy, and LSA2-L2 therapy.

therapy in the range of 3,500 rads or more. In these patients bone marrow metastases occurred within 3-4 months and CNS involvement within 4-5 months from diagnosis. The upper curve represents the 43 patients treated on the LSA2-L regimen. On this protocol there is an 81% survival rate, free of disease, and there has been a median observation time of 2 1+ months for the entire group. DISCUSS ION

From the above analysis we will attempt to determine what factors may be considered of genuine prognostic value. Nodal and Extranodal Presentation

Figure 4 shows the actuarial survival of NP,LSAl ,and LSAz -L2 patients with nodal and extranodal primary sites. The difference between the 15% nodal and 10%extranodal survival rates in NP patients is not significant, because only stage I patients have remained alive and free of disease in this group. Of the 6 LSAl patients with primary nodal disease, only one stage I patient is still alive. The survival for this group of patients was only 16%, against 42%for the LSAl extranodal primaries with a larger grbup of patients. The 21 LSA2-L2 patients with nodal presentations had a 94% survival, with only 1 patient showing evidence of disease. The survival for the 22 patients with extranodal primaries was 62%. Two facts are apparent here: (1) The period of risk for the majority of patients, with either nodal or extranodal primaries and independent of the;apy given, is up t o 15 months. This and the following survival curves show that patients who survive for 12-15

252

Wollner et al.

t

0

0

8

0

Fig. 4. Actuarial survival for the entire patient population according to nodal and extranodal primary sites.

months or longer without recurrent disease will probably continue to do so if treatment is continued for 2-3 years, as explained above. In most cases these survival curves hold steady at the point reached between 12 and 15 months. (2) The survival rates for nodal and extranodal primary sites are clearly dependent upon the treatment given. Reticulum Cell Sarcoma and Lymphosarcoma

For historical reasons these patients have been analyzed according to the lesions once termed lymphosarcoma and reticulum cell sarcoma. This nomenclature is no longer used at Memorial Hospital. Histologically, children with non-Hodglun's lymphoma in this study were almost equally distributed between lymphosarcoma and reticulum cell sarcoma (Fig. 5). The actuarial survival curves for the three protocols show that NP and LSAz-b patients with reticulum cell sarcoma fared worse than those patients with lymphosarcoma. In the LSAl patients the reverse was true, even though the number of patients with lymphosarcoma was twice as great as for those with reticulum cell sarcoma. These differences in survival are due to many factors, including primary site, initial staging, amount of bulky disease, and the feasibility of giving maximal and effective combined radiation therapy and chemotherapy. It is these factors, more than histological distinctions or cell resistance, plus individual susceptibility to therapy that will prove to be the determining influences on a child's chance for survival and a normal life. Nodular and Diffuse Histological Classifications

The incidence of nodular subtyping (37) in this population is too small to draw conclusions about its significance as a prognostic factor. The actuarial curves for the NF' patients (Fig. 6) show a 40% suMval, free of disease, for children with nodular disease. Only 33%of the LSAl patients (Fig. 7) showing nodular histology survived. For the LSAz-Lz patients with nodular histological subtyping (Fig. 8), there was a 100%survival

Non-Hodgkin's Lymphoma in Children

253

5

10 15 20 25 30 35 40 Months ofter dioqnosis

5

6 7 0 Y e m oftef dlqnoss

9

Fig. 5. Actuarial survival for the entire patient population if lesions are classified by previously used lymphosarcoma and reticulum cell Sarcoma categories.

I

. 5

.

,

.

. -

,

,

,

10 15 20 25 x) 35 40 Months ofter diogmis

Fig. 6. Actuarial survival for 38 NP patients divided into Rappaport's histological classification (slides were not available on 5 patients).

Wollner et al.

254

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30-

L.

I ,

---. ---

/ I

0

--_--. -*- - - - - - - - ,,-- n

20-

IO-

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Fig. 7. Actuarial survival for 18 LSAl patients divided into Rappaport’s histological classifications.

I

1

5

I

1

I

1

I

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10 15

20 25 30 35 40 Months after dagnosis

Fig. 8. Actuarial survival for 43 LSAz-Lz patients divided into Rappaport’s histological classifications.

Non-Hodgkin’s Lymphoma in Children

255

rate. Five of these last patients are off therapy, 2 are still at risk (less than 12 months from diagnosis), and 1 has recurrent disease. Of those NP patients with diffuse subtyping the DU and DLPD fared poorly (Fig. 6). The DH ranged from 14%survival for the NP patients to 68% for the LSAz -Lz , while the improvement in the survival rates for patients with DLPD disease is even more striking. The DLWD and DM categories had too few patients t o allow conclusions. Although 4 LSA2-b patients presented with DU histology, the extent and sites of their disease prevented early radiation therapy and thus preclude final statements about prognosis for this subtyping (Fig. 8). These results with the LSAz -hprotocol show, therefore, that histological classifications definitely should not be deterrents to equal and aggressive therapeutic approaches for all patients. Staging

The actuarial survival for stage I disease has varied from 57% for NP patients t o 100%for LSAz-L patients (Fig. 9). Stages 11,111, and IV showed early recurrences, dissemination, and death for the NP patients (Fig. 10). In the LSAl group the difference between stages 111 and IV is not significant, considering the larger numbers of patients with stage 111 disease. For the LSAz -Lz protocol this staging clearly defines differences in survival. Ten stage I and I1 children had a 100% survival rate, without recurrences, and 13 stage 111 children had a 65% survival rate (one patient expired without evidence of recurrence from an unrelated cause). Of the 20 LSA2 -bpatients with stage IV disease (initial marrow or CNS involvement), 75% are alive without disease.

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Of the N p and LSAl stage 1's who disseminated and went on to die, 4O-s0% would, in time, have behaved as stage 111 or IV. It is thus proposed that all patients, stages I through IV,should receive equal and aggressive treatment. The absolute necessity for this is borne out by comparing the survival curves for the LSAz-b protocol for the different stages of disease. It is possible and important, however, to improve these survival rates even further. This can be accomplished if chemo- and radiotherapists can be convinced that patients with far advanced disease (stages 111 and IV) deserve the same attention and care as those with early disease. The combination of today's chemotherapeutic agents and radiotherapy techniques, as well as the appearance of more daring surgeons, could improve considerably the future lives of children with these malignant disorders. The role of radiation therapy in t h i s disease should be to concentrate irradiation to areas of bulky disease - that is, those areas with tumors larger than 5 cm in diameter or in which recurrence has taken place shortly after the removal of the primary (as in primary bowel disease). This holds true regardless of whether the recurrence is small or the bone marrow is already involved. Radiation must be-partnered with effective chemotherapy, however, to ensure that the disease-free survival continues, perhaps, indefinitely. Because irradiation to large areas is incompatible with an intensive chemotherapeutic regimen, and because of previously held notions that irradiation is an all-or-nothing proposition (37), we have had no choice but to treat several stage I11 and N patients with chemotherapy alone, with complete initial responses; there have been early recurrences in the areas of primary bulky disease, however, followed by dissemination to other sites and demise. Whether radiation therapy to those patients who are poor risks should be done

257

Non-Hodgkin’s Lymphoma in Children

early in the induction or after induction is completed is still under study. It is obvious from this experience, though, that if irradiation is given in adequate doses, there is no recurrence in the irradiated area. The criteria for diagnosis of stage IV non-Hodgkin’s lymphoma - rather than leukemia -when the marrow is replaced, with or without circulating abnormal cells, are: (1) disease located primarily in extranodal sites; (2) if in nodal sites, evidence of bulky disease in one area, such as the mediastinurn or neck, which should be markedly predominant over other sites involved; (3) multifocal areas of disease (usually nodal and extranodal), with a rapid and extensive spread in the involved areas, suggestive of a sarcomatous process, with partial or total marrow replacement, with or without hepatosplenomegaly, and with or without peripheral blood involvement. In leukemias with bulky disease, the nodes of all involved areas are often of uniform size. In some cases, however, distinction between the two by bone marrow smears or biopsy alone is impossible, and the patient should then be considered leukemic unless the pathologist and/ or radiological findings can be of further assistance. Although often too late for effective therapy, the clinical course in these difficult cases can distinguish between the two diseases: (1) Although non-Hodgkin’s lymphoma with marrow involvement is as responsive as leukemia to treatment used in the latter disease, it usually recurs within 1-3 months and rapidly becomes resistant to most agents. (2) Using “old” methods of treatment, the median survival time in non-Hodgkin’s lymphoma with marrow replacement was 6 months, a much shorter period than for leukemia with marked initial involvement and/or initial high white count. (3) In non-Hodgkin’s lymphoma with bone marrow involvement, CNS metastases usually occur within 1-3 months from diagnosis. The median survival for a non-Hodglun’s lymphoma after CNS involvement is usually 4-5 months, quite different from the median survival of leukemia after CNS disease (67). In general, those patients whose disease progresses slowly and who are very early stages at diagnosis fare better than those who have a short onset of disease but more advanced staging by the time they are first seen. Even in far advanced disease the existence of bulky tumor holds a poor prognosis only if chemotherapy is given alone. In these cases a combination of radiation and chemotherapy will yield better results when given in maximum possible doses within short time periods. However, nervous system involvement is one area in which all modalities of therapy available have failed and is, thus, a poor prognostic sign. Once established, CNS involvement cannot be completely erradicated but rather only palliated for short periods. The goal must be to treat the disease aggressively from diagnosis in an attempt to avoid early dissemination. Spread to this area occurs in incompletely treated patients within 2-3 months after the onset of therapy. CNS prophylaxis is, therefore, built into the LSAz-L protocol. A 100% cure rate for any malignant tumor is not yet possible. There are and will continue to be individual differences in response and in the growth rate of the same types of tumor in different patients. Nevertheless, with a concerted multidisciplinary effort a survival rate of 80%or better can and should be obtained. Primary Sites

Figures 11 through 13 show the actuarial survivals for the most common primary

Wollner e t al.

258

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Sheleial, 7 patients

-_-.

Alive.frec of diseose. on therapy

0

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o

Eapired

Yeon after diagnosis

Months after diagnosis

Fig. 11. Actuarial survival for 33 NP patients with peripheral nodal, mediastinal, bowel, or skeletal primary sites.

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100

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Years after diagnosis

Fig. 12. Actuarial survival for 14 LSAl patients with peripheral nodal, mediastinal, bowel, or skeletal primary sites.

259

Non-Hodgkin’s Lymphoma in Children

i.._...._.A . . _ _ . . . . . _0..._..__..... .. D.... Peripheral nodal,12 pat#lts Mediostinal,9 patients Bowel, 9patients - Skeletal, 7 patients Aliie,free d disease, on Wapy A l i , f r e e d dkeose,offfherqy Alive,with disease, on themw Expired

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Fig. 13. Actuarial survival for 37 L S A Z - L ~patients with peripheral nodal, mediastinal, bowel or skeletal primary sites.

sites for the different protocols, NP, LSAl ,and LSA2 -L, respectively. There are three points of special importance: (1) Prior to development of the LSA2-hprotocol, no patients with primary mediastinal disease survived. In the 9 LSA2 -hpatients with this type of involvement, all had extensive local lesions, 90%had uni- or bilateral pleural effusions, and 60%had disease outside the thoracic cavity. None of these patients received radiation therapy because of the fear that severe marrow depression would interfere with systemic chemotherapy. Only 1 of these children expired with disease, while all others remain free of disease. Two patients are at risk, and 2 are off therapy. (2) In the primary bowel group survival has been increased from 20% in N p and LSAl patients to 54%in the LSAz -L.In this group, especially, local radiation and more aggressive surgery might improve survival even further. The continued development of surgeons who, when faced with a stage IV bowel primary with bone marrow involvement, no longer shy away from surgical removal of the primary (because marrow involvement had been accepted as fatal in the past) is of critical importance. (3) For patients with primary skeletal involvement, the survival has risen from 0% for NP children to 72% for those on the LSA2 -L2 regimen. These jesults are encouraging indeed, in view of the fact that there were more advanced cases among those on the LSA2 -L2 protocol.

260

Wollner et al.

Questions have been raised as to whether disease with a primary site in the bone should be considered different from diseases with nonosseous primaries (68-70). Physicians have believed bone disease to be a different entity because most cases were stage I disease and had, therefore, a better prognosis and cure rate than those with more advanced nonskeletal primary involvement. Detailed analysis of these cases with treatment failure has shown that their clinical course and survival did not, indeed, differ from other primaries. The distinction between non-Hodgkin’s lymphoma of the bone and Ewing’s sarcoma can be extremely difficult. Points of similarity between these two disorders include: (1) the fact that they are rare and, until recently, had a very short median survival time; (2) the presenting clinical and radiological pictures; (3) multiple initial bone lesions or bony metastases during the clinical course; (4) histology showing “small cell” neoplasms. In spite of the above congruences, two distinguishable features should be stressed: (1) Ewing’s sarcoma produces nodular pulmonary metastases early in the disease, while non-Hodgkm’s lymphoma rarely does so (13). In this study minute pulmonary metastases were found at postmortem in only one instance (clinically and radiologically unsuspected) without other evidence of systemic disease except for CNS involvement. When there are pulmonary lesions in non-Hodgkin’s lymphoma, they are usually a finding of terminal disease, characterized by diffuse lesions associated with mediastinal and hilar involvement, lymphangitic spread, or direct extension from pleural or diaphragmatic disease. ( 2 ) Central nervous system involvement in Ewing’s sarcoma is usually due to solid mass implants in the calvarium or direct extension to the spinal canal from paraspinal or vertebral masses, but it is seldom meningeal (71). In each of these four primary sites - peripheral nodal,mediastinal, bowel, and skeletal - the L S A l - L treatment has made a drastic improvement in the length and quality of survival obtained for these children. Combined with effective and aggressive surgery and prompt irradiation to sites of concentrated disease, this multi-drug regimen is making strong progress in a fight that was once almost invariably met by defeat. ACKNOWLEDGMENTS

The authors wish to gratefully acknowledge the editorial assistance and help in manuscript preparation of Mrs. Claudia Seymour. This work was supported in part by grants CA-05826 and CA-08748 from the National Cancer Institute. REFERENCES 1. Aur, R. J. A., Hustu, H. O., S h o n e , J . V., Pratt, C. B., and Pinkel, D. Therapy of localized and

regional lymphosarcoma of childhood. Cancer 27: 1328-1331 (1971). 2. Bailey, R. J., Burgert, E. O., and Dahlin, D. C. Malignant lymphoma in children. Pediatrics 28~985-992(1961). 3. Bloomfield, C. D., Goldman, A., Dick, F., Brunning, R. D., and Kennedy, B. J . Multivariate analysis of prognostic factors in the non-Hodgkin’s malignant lymphomas. Cancer 33:870-879 (1974). 4. Coles, W. C., and Schulz, M. D. Bone involvement in malignant lymphoma. Radiology 50:458-462 (1948). 5. Freeman, C., Berg, J. W., and Cutler, S. J. Occurrence and prognosis of extranodal lymphomas. Cancer 29:252-260 (1972).

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