The integration of radiotherapy into the primary treatment of non-Hodgkin's lymphoma

Critical Reviews in Oncology/Hematology, 1992; 12:211-229 0 1992 Elsevier Science Publishers B.V. All rights reserved. 1040-8428/92/$15.00

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ONCHEM 023

The integration of radiotherapy into the primary treatment of non-Hodgkin’s lymphoma

Mansoor Raza Mirzaa, Hans Brinckerb and Lena Specht’ “The Aga Khan University, Faculty of Health Sciences. Medical College, Karachi, Pakistan, ‘Department of Oncology and Hematology, Odense

University Hospital, Odense. Denmark and ‘Department of Oncology, Herlev University Hospital, Herlev. Denmark

(Accepted 13 January 1992)

Contents

I. Introduction

II. Localized lymphomas A. Stage I-II lymphomas B. Extensive disease limited to the abdomen C. Primary brain lymphomas D. Cutaneous T-cell lymphomas (mycosis fungoides)

III. Generalized lymphomas ................................... A. Bulky tumor ....................................... B. Stage III low-grade lymphomas ......................... C. Total body irradiation ................................

IV. Summary and recommendations

V. References . 226

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I. Introduction

While the integration of radiotherapy into the primary treatment of Hodgkin’s disease is well-estab- lished, it is still being debated if and to what extent radiotherapy should be integrated into the primary treatment of non-Hodgkin’s lymphomas. Obviously, the crux of the matter is the difference in biological behaviour between these two different types of lymphomas. While Hodgkin’s disease behaves like a primarily localized disease with an orderly and pre-

dictable type of spread, non-Hodgkin’s lymphomas are most often generalized when first seen due to the in- herent migratory nature of the lymphoma cells. Accord- ingly, it may be argued that radiotherapy - which is essentially a local and not a systemic treatment-has no individual curative potential in the latter kind of lym- phomas.

Nevertheless, in a subset of lymphoma cases where the disease appears to be truly localized there is convincing documentation that a number of such cases can be cured by radiotherapy alone. Although the same or a

Mansoor Raza Mirza received and M.D. degree from 2nd Moscow State Medical Institute, U.S.S.R. He is currently senior registrar at the Department of Medicine, the Aga Khan University, Karachi, Pa- kistan. Hans Brincker received an M.D. degree from the University of Aarhus, Denmark. He is currently associate professor of oncology at the University of Odense, and senior consultant in oncology and hematology at the Department of Oncology and Hematology, Odense

University Hospital, Denmark. Lena Specht received an M.D. degree at the University of Copenhagen. She is currently senior registrar at the Department of Oncology, Herlev University Hospital, Denmark.

Correspondence: Hans Brincker, M.D., Department of Oncology and Hematology, Odense University Hospital, 5000 Odense C, Denmark.

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superior cure rate may be achieved with chemotherapy alone in such cases, it is conceivable that the combina- tion of both treatment modalities might lead to even better results.

Further, radiotherapy would be definitely indicated in the treatment of localized lymphomas in sites not easily accessible to chemotherapy, such as the central nervous system.

Lymphoma cells are among the most radiosensitive of mammalian cells due to the apparent lack of repair mechanisms for sublethal and potentially lethal damage [l]. Thus, radiotherapy might provide a useful addi- tional cytoreductive effect in conjunction with chemo- therapy, at least in localized disease but perhaps also in generalized lymphomas. In the latter patients it is con- ceivable that radiotherapy might lead to a decreased recurrence rate in disease locations with bulky tumor when used as post-chemotherapy consolidation treat- ment. Radiotherapy might also have a systemic effect in generalized lymphomas when administered in the form of total body irradiation.

Clearly, treatments given with a curative intent often lead to temporary palliation rather than cure. There- fore, when evaluating the effect of integrating radio- therapy into the treatment of non-Hodgkin’s lymphomas it is necessary to consider data on relapse free survival (RFS) as well as data on total survival (TS). In the present review the main emphasis has been on randomized and retrospective studies comparing dif- ferent treatments, but pertinent data from single-treat- ment studies has also been considered. In publications where 5- and IO-year survival rates have not been given specifically in the text, these rates have been read as accurately as possible from the included survival graphs.

The great variety of histopathologic classifications of non-Hodgkin’s lymphomas makes comparisons be- tween different studies extremely difficult, even when an attempt is made to use the so-called Working Formula- tion. For this reason it has been necessary to make only a very general distinction between ‘favorable’ ‘low- grade’ and ‘unfavorable’ ‘high-grade’ lymphomas. In studies with lymphomas subdivided according to no- dular or diffuse histology, the former type has been considered as ‘low-grade’ and the latter type as ‘high- grade’. In general, lymphomas of intermediate grade have been grouped together with high-grade lymphomas.

Although this division may be debatable, it is neces- sary to make a general distinction between low- and high-grade lymphomas, not only because of differences in tendency to systemic disease and prognosis, but also because of significant differences between these two

main groups of lymphoma as regards mechanism of action of radiotherapy and dose levels necessary to achieve local control. Since a reasonably clear distinc- tion between low-grade and high-grade lymphomas has been made only in studies after the beginning of the 70s long-term rates on RFS and TS are not yet available for most studies. This makes it particularly difficult to evaluate the effect of any therapy in low-grade lymphomas because of the indolent natural history of this subset.

In addition to difficulties of histological classification there are, obviously, difficulties of a multitude of che- motherapy regimens when comparing different treat- ment studies. Although debatable, it will be assumed for this review that the activity of CHOP and ‘2nd and 3rd generations’ of CHOP-like regimens are roughly com- parable.

The following possible indications for radiotherapy as part of the primary treatment will be discussed:

Section II. Localized lymphomas

A. Stage I-II lymphomas B. Extensive disease limited to the abdomen C. Primary brain lymphomas D. Cutaneous T-cell lymphomas (mycosis fungoides)

Section III. Generalized lymphomas

A. Bulky tumor B. Stage III low-grade lymphomas C. Total body irradiation

II. Localized lymphomas

II-A. Stage I-II lymphomas

Historically, localized lymphomas represented the only disease category in which radiotherapy con- sistently led to long-term survival in the pre-chemo- therapy era. Thus, it would be natural to ask the ques- tion: ‘what are the 5-year and IO-year rates of relapse- free survival and total survival following radiotherapy of localized low-grade and high-grade lymphomas, re- spectively’. Somewhat surprisingly, in spite of a fairly large number of studies a clear answer to this simple question cannot be given since most of the available survival rates have been calculated either for low-grade and high-grade cases combined, or for a multitude of patient subsets rather than for the two main groups of cases. Nevertheless, more recent data, summarized in table 1, show that 5-year TS in high-grade lymphomas varies from 26682%, while the corresponding IO-year figures varies from 18-68%. As might be expected, 5- year TS for low-grade lymphomas and for unspecified mixed histologies tends to be higher.

The available data on localized low-grade lymphomas are insufficient to determine to what extent radiotherapy may be curative in these cases. However, the lo-year follow-up data of Bush and Gospodarowicz [7], the 15year follow-up data of Lawrence et al. [20], and the 17-year follow-up data of Rosenberg [1 1] sug- gest that radiotherapy may be curative in about half of all such patients, and particularly so in patients below the age of 40. As can be seen from Table 1, the 5- and 1 O-year TS-data on localized high-grade lymphomas suggest that about half of all such cases may be curable with radiotherapy alone. Obviously, these conclusions are very general, since the prognosis may be better or worse in various subsets defined by stage, site, histol- ogy, age, radiotherapy technique, etc. However, the ex- pectation of a 50% cure rate with radiotherapy alone in localized non-Hodgkin’s lymphomas of all histologies appears to be confirmed by the results of Sutcliffe et al. [lo] in their very large series of 496 patients with all histologies (Table 1).

TABLE 1

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The appearance of effective chemotherapy in non- Hodgkin’s lymphomas made it logical to ask whether the addition of chemotherapy to radiotherapy might improve RFS and TS. To answer this question 7 ran- domized studies have been performed. They are sum- marized in Table 2. In 4 of the studies a significant prolongation of RFS was found, but only one study showed a prolongation of TS. In the first 3 studies including both grades only the high-grade lymphomas appeared to benefit from the addition of chemotherapy. However, in the two studies comprising patients with high-grade lymphomas only, there was no indication of any benefit from the added chemotherapy, and in the last study including both grades the value of adjuvant chemotherapy appeared to be similar in low-grade and high-grade lymphomas.

As shown in Table 3, the value af adjuvant chemo- therapy has also been assessed in patients with high- grade lymphomas in five retrospective studies. Three of these studies showed a significant benefit in terms of af

Studies of primary radiotherapy in localized non-Hodgkin’s lymphoma in which information is available on rates of 5-year and IO-year relapse-free survival and total survival, respectively

Ref. N Subset

-

121

131

141 [51

[61

171

PI

62 152

23

67 12 35

53 11

54

130 201 113 (Waldeyer)

26 28

496

LG _ 65 HG 26 LG 55 90 HG 40 55

LG+HG 75 100 LG 83 100 HG 37 59 LG _ 100 HG _ 52 LH 55 HG 47

LG+HG 36 47

191

[lOI

[]‘I

t121 P31 u41 [I51

26 98

31 14

148

15

[I61 1171 [I81 [I91

91 50 42 45 27 27 21

LG HG 143 LG

353 HG LG, ~40 yr

LG. 240 yr HG HG HG

LG+HG (thyroid) LG+HG LG

LG+HG,st.I HG, st. I HG, st. II LG, st. I LG, st. II

5-year

RFS TS

IO-year

RFS TS

15-year

RFS TS

-

47 91

35 45 54 62

82 82

55 75 78 80 75 82

51 63 78

40 31 14 53 85 52 68 35 56 70 49

40 18

53

39 26 32

49 49

82 82

48 55 54 58

34 40

82 82 39 23

48 68 35 44 65 65 35 35

Abbreviations: RFS, % relapse-free survival; TS, % total survival; LG. low-grade; HG. high-grade; St.. stage; yr, year

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TABLE 2

Randomized studies of primary radiotherapy in localized non-Hodgkin’s lymphomas with or without the addition of chemotherapy

Ref. N Subset CT RT alone 5-year

RFS TS

RT + CT 5-year

RFS TS

p value RFSITS

VI 55 LG+HG CVP

1221 96 LG+HG CVP

1231 80 HG CVP [241 73 LG+HG CVPS [I41 46 HG CVP 1251 21 LG BMCVP

[I81 124 LG+HG CVP

41* 92* 86* 91* o.o2/Ns 46 56 72 83 0.005/0.03

_ 68 _ 48 -INS 49 58 90 71 0.00110.13 68 62 54 60 NS/NS _ _ _ NSJNS 55 86 75 84 0.002/0.5

*30-month figures only. Abbreviufions (see also Table 1): RT, radiotherapy; CT, chemotherapy; CVP, cyclophosphamide, vincristine, prednisone; CVPS, CVP + strepto- nigrin; BMCVP, BCNU, mechlorethamine + CVP; NS = not significant

prolongation of 5-year RFS and/or TS, but in 3 of the 5 studies the latter rates were unusually low in the radio- therapy-alone patients. Taken together, the results of the 12 studies may be used in support of the addition of chemotherapy to radiotherapy in localized non- Hodgkin’s lymphomas. On the other hand, a significant prolongation of TS was found only in 3 of the 12 stud- ies, and two of these were not randomized. Thus, when assessed critically, the value of adjuvant chemotherapy in this situation remains uncertain. However, it should be mentioned that the type of chemotherapy employed in 5 of the randomized studies (CVP) would not be considered optimum therapy today.

Obviously, the question of adjuvant chemotherapy may be turned around, and it may then be asked whether the addition of radiotherapy to chemotherapy results in any survival benefit in localized non- Hodgkin’s lymphomas. Since the concept of chemo- therapy as the sole treatment in such cases is relatively new, only limited data are available on the long-term results of this strategy [9,28-301, and there are no ran- domized studies comparing chemotherapy alone with chemotherapy followed by radiotherapy. As shown in

Table 4, three retrospective studies have addressed this problem (However, some of the patients from the first study were included in the last). Although there may be a trend in favor of the combined treatment, the results are not conclusive. Thus, until more data become avail- able the value of adjuvant radiotherapy appears to be almost as debatable as that of adjuvant chemotherapy in localized non-Hodgkin’s lymphomas.

In spite of these uncertainties there appears to be a fast-growing consensus that the treatment of choice in localized high-grade lymphomas is short-term polyche- motherapy (3 courses), followed by involved-field ra- diotherapy to moderate doses (30004000 cGy) [32]. No doubt the success of this idea is due to the proven ef- ficacy of chemotherapy in advanced disease, combined with the experience that the success-rate of radiotherapy is highest in small tumors. This strategy resulted in a 85% 5-year TS in a pilot study of 78 patients [33]. An- other study of 49 stage I patients produced a 5-year RFS of 96% and a TS of 94% [34]. These results need to be confirmed, preferably in prospective comparative studies.

In the above discussion no distinction has been made

TABLE 3

Non-randomized studies of primary radiotherapy in localized non-Hodgkin’s lymphomas with or without the addition of chemotherapy

Ref. N Subset CT RT alone 5-year

RFS TS

RT + CT 5-year

RFS TS

p value RFSITS

1261 [91

1151

1271 1191

33 40 34 28

42 61

HG HG, St.1 HG, St.11 LG+HG (Thyroid)

HG HG

var. 90 _ 82 0.3 var. 52 61 81 96 0.03/0.03 var. 9 18 44 56 0.001/0.003 var. 78 _ I? _ NSI-

var. 26 _ 84 -/0.003 var. 35 41 58 65 0.05/o. 19

Abbreviations (see also Tables I and 2): var. = various types of combination chemotherapy.

between nodal and extranodal lymphomas, since there is no evidence of significant overall prognostic differ- ences between these presentations [3,5,14,16,26]. Be- cause of a general lack of conclusive data, special topo- graphic presentations will also not been considered. However, as regards localized gastric lymphomas it should be mentioned that it is still being debated whether primary resection may be substituted with che- motherapy plus radiotherapy. Some of the available data support primary resection [36-401, while other data indicate that resection may be omitted [41-43].

For the optimum use of radiotherapy, it is necessary to consider such problems as dose in relation to histol- ogy and bulk of disease, tissue volume to be treated, and interaction with concomitant chemotherapy.

It has been recognized for decades that relatively small radiation doses may lead to local control in low- grade lymphomas in contrast with high-grade lymphomas where larger doses are needed. This observation correlates well with the progressive reduc- tion in sensitivity of lymphocytes as they are trans- formed by antigenic stimulation, and therefore with the proposal that non-Hodgkin’s lymphomas are neoplasms of cells arrested at different stages of lym- phocyte transformation [44]. Normally, the interplay between radiation dose, total treatment time and num- ber of fractions makes it questionable to compare radi- ation doses alone as a measure of treatment intensity. However, in non-Hodgkin’s lymphomas a ‘threshold dose’ appears to exist with relatively little dependency on time or number of fractions [45], proba- bly due to minimal repair of sublethal damage [l]. This makes it permissible to compare doses directly between various studies.

Most dose-response studies have been conducted re- trospectively in series of lymphomas of all stages by assessing the rate of local control in the various ir- radiated regions and relating this rate to the given dose of radiation. Unfortunately, this procedure is associated with a certain type of bias. Stage III and IV lymphomas have a higher risk of relapse, both within and outside

TABLE 4

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the irradiated field than stage 1 and II lymphomas. At the same time significantly higher doses have generally been given in localized lymphomas than in advanced lymphomas, simply because radiotherapy of small fields is better tolerated than radiotherapy of large fields. Thus, by disregarding this linking of low dose with high relapse rate, dose-response studies in lymphomas of all stages tend to result in the finding that higher doses have a better probability of local control than lower doses.

Because of this problem, particular weight must be attributed to the findings of Sutcliffe et al. [lo] in a very large study of 496 patients, exclusively with stage I and II lymphomas of all histologies, treated with doses from ~2000 cGy to >4000 cGy. In low-grade lymphomas local control was not improved by increasing the dose beyond 2000 cGy, and no correlation existed between dose, local control and tumor bulk. In high-grade lymphomas local control was not improved by increas- ing the dose beyond 3000 cGy, and if the tumor bulk was very small 2500 cGy was sufficient. In an earlier analysis of the same data Bush and Gospodarowicz [7] found additionally that in patients over the age of 60 a dose of 35004000 cGy was necessary to obtain local control in cases with bulky disease.

In an analysis of 62 patients with all stages Seydel et al. [46] found dose levels necessary for local control to be similar to those found by Sutcliffe et al. [lo]. In another analysis of 13 1 patients with all stages Cox et al. [45] found that doses necessary for control of low- grade and high-grade lymphomas were 2200 cGy and 4200 cGy, respectively. However, lymphomas arising in bone and brain needed higher doses for control than lymphomas arising in Waldeyer’s ring, the gastrointes- tinal tract and lymph nodes.

Others have concluded that doses larger than 3000 cGy are necessary for local control of high-grade lymphomas [4749]. In contrast, in an analysis of 198 patients with all stages Fuks & Kaplan [50] could not find a dose/response relationship at all in diffuse histiocytic lymphomas, while it was concluded that

Non-randomized studies of primary chemotherapy in localized non-Hodgkin’s lymphomas with or without the addition of radiotherapy

Ref. N Subset CT CT alone S-year _

RFS TS

CT + RT 5-year

RFS TS

p value RFSITS

~-

1281 45

[91 71

1311 142*

HG LG+HG HG

CHOP var. CHOP

76 81 88 94 0.1310.66 43 56 75 80 0.00710.04 77 _ 85 0.21/p

*45 of these patients are identical with the patients in the study by Miller 1983. Abbreviafions (see also Tables I and 2): CHOP. cyclophosphamide + doxorubicin + vincristine + prednisone; var., various types of combination chemotherapy.

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doses as high as 4400 cGy were necessary for optimum control of other types of diffuse as well as nodular lymphomas.

In spite of somewhat contradictory findings, a balanced evaluation of the data on optimum radiation dose indicates that in low-grade lymphomas 2500 cGy will suffice for local control, regardless of tumor bulk. In high-grade lymphomas the corresponding figure is 3500 cGy, unless the tumor is small in which case 3000 cGy is sufficient. However, for patients over the age of 60, doses of up to 4000 cGy may be necessary for local control in cases with bulky tumor. In special sites like brain (see below) and bone [47] higher doses of 4500- 5000 cGy seem to be indicated.

For stage I and II disease the usual treatment volume will be an ‘involved field’, encompassing the site of the lymphoma with a wide safety margin. Usually this margin will be larger for nodal than for extranodal presentations [51]. Attempts have been made to increase RFS and TS by using ‘extended fields’ encompassing either all supradiaphragmatic lymph-nodes (‘Mantle field’) or all infradiaphragmatic lymph-nodes (‘Inverted Y-field’), or both. In one retrospective study of 121 patients with high-grade lymphomas the 5-year survival rate with ‘extensive’ radiotherapy was 67% but only 35% with ‘limited’ radiotherapy [14]. However in an EORTC controlled trial of 57 patients with all histolo- gies 5-year survival was similar in patients given ex- tended field versus extended field plus prophylactic trans-diaphragmatic lymph-node irradiation [I 81. Further, in a small trial of 20 patients with low-grade lymphomas randomized between involved field radio- therapy and total lymphoid irradiation there was also no survival difference [52]. Finally, comparison of the fairly large patient materials of Stanford and Princess Margaret Hospital seemed to indicate no difference in outcome between patients with low-grade lymphomas treated with involved-field and extended-field irradia- tion [53].

The concomitant use of chemotherapy and radiother- apy enhances the effect of the latter treatment, re- sulting in increased damage to the normal tissue with late sequelae [54,55]. This interaction has been demon- strated clinically in breast cancer [56], but it may also be relevant to radiotherapy in lymphoma although radi- ation doses are usually lower here. For this reason it would seem prudent to separate the application of chemotherapy and radiotherapy in lymphoma. The necessary duration of this separation is unknown, but recovery from the acute effects of radiotherapy usually takes from 2-3 weeks and from chemotherapy 3 weeks, suggesting that an interval of about 3 weeks may be necessary between the two treatment modalities in order

to avoid untoward interactions. However, this interval may be too long for the optimum effect on the tumor of the combined treatment. Thus, in animal experiments an interval of only 7 days between each treatment mo- dality was followed by the highest cure rate [57].

II-B. Extensive disease limited to the abdomen

In a subset of lymphoma patients extensive abdom- inal disease is found without evidence of lymphoma outside the abdominal cavity. In such patients adjuvant radiotherapy to the whole abdomen might be consid- ered after primary tumor-reducing chemotherapy. Calvo et al. [58] reported a series of 29 patients treated with whole abdominal radiation, 19 of whom also had chemotherapy. lo-year TS was 63% regardless of fa- vorable or unfavorable histology. Velasquez et al. [59] reported a 5-year TS of 79% in 18 patients with exten- sive abdominal involvement treated with CHOP-bleo plus abdominal radiation. Unfortunately, there is very little additional data in the literature on the results of such a treatment policy although the use of whole ab- dominal radiation (‘abdominal bath’) in this situation was worked out many years ago following the advent of megavoltage therapy [60]. Thus, it is feasible to de- liver 2500 cGy to the whole abdomen in 5 weeks pro- vided that the kidneys are shielded during part of the course of treatment [51,61]. It would seem that prospec- tive studies of adjuvant radiotherapy are justified in patients with extensive abdominal disease, in particular in patients with intermediate-grade histology of the dif- fuse small cleaved cell type in whom the long term re- sults are poor with chemotherapy [62].

II-C. Primary brain lymphomas

Brain lymphomas constitute less than 1% of all ma- lignant lymphomas, but like stage I and II lymphomas they represent a type of localized disease in which radio- therapy has been the mainstay of treatment for decades. The concept of an impenetrable blood-brain barrier has hampered attempts to develop effective chemotherapy for this location until recently, even though there is evidence that the blood-brain barrier may often be dis- rupted in CNS-lymphomas [63.64].

The behaviour of brain lymphomas differs markedly from that of other lymphomas in a number of ways. For example, brain lymphomas arise in an organ without lymphatics, and they are almost always of high grade. Further, the response to radiotherapy is poorer than in any other types of localized disease, and for the few long-term survivors (>5 years) the frequency of late relapse is almost 50% [65], in contrast with non-CNS

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high-grade lymphomas. Finally, in contrast with other types of lymphomas, the incidence of brain lymphomas has increased almost threefold from 1973 through 1984 [66,67].

In a very comprehensive review of the literature Murray et al. [65] found that only 56 out of 693 reported cases survived more than 3 years, and only 21 survived for more than 5 years. A total of 308 patients had radio- therapy to their CNS-lymphoma, and in 198 cases sur- vival could be related to the radiation dose. In this subset the 5-year survival rate was 42% in patients who had more than 5000 cGy, but only 13% for those who had less than 5000 cGy, suggesting a surprisingly high degree of radioresistance. Median survival was about 24 months regardless of dose level. Since radiation doses of more than 5700 cGy to the whole brain with conven- tional fractionation schedules is associated with a certain risk of late brain necrosis [68], dose escalation beyond this level is not a practicable means of increas- ing survival rates in brain lymphomas.

In order to explain the origin of CNS-lymhomas it was proposed recently [67] that some B-lymphocytes in a lymph node or extranodal site may carry a CNS- specific binding marker. Such a cell may become ac- tivated, caused to proliferate, and transformed to be- come neoplastic. Subsequently it may migrate into the bloodstream and become bound at sites within the CNS where it multiplies and present as a ‘primary’ tumor. In the meantime the true primary site remains obscure and undetected.

Such a scheme would explain how lymphomas may develop in the CNS, why they are often multifocal, and

TABLE 5

Studies of primary CNS-lymphoma in which radiotherapy was supple- mented with polychemotherapy

Ref. N CT Median survival (months)

(351 3 4 2

1691 5 [701 9

[711 II [721 IO I641 21

1731 10

CHOP VEMP

ACNU var. var.

CHOP HU/POC HDARAC + MTX i.v./i.t. MACOP-B

15 12

29 44

6Oi

20+ 30 551

I4

Abbreviufions (see also Tab/es 1 und 21: CHOP, cyclophosphamide + doxorubicin + vincristine + prednisone; VEMP. vincristine + cyclo- phosphamide + 6-mercaptopurine + prednisolone; ACNU, methylni- trosurea + 5-fluorouracil + prednisolone; HU/POC, hydroxyurea + procarbazine + vincristine + CCNU; HDARAC, high-dose cytosine arabinoside; MTX, methotrexate: MACOP-B, methotrexate + doxoru- bicin + cyclophosphamide + vincristine + prednisone: var.. various types of combination chemotherapy.

why they do not result in extra-CNS spread. Although not mentioned by Hochberg and Miller [67], this scheme also suggests that the ‘recurrences’ after radiotherapy may in fact represent re-seeding of the CNS with the original transformed lymphocytes. In this way a new rationale is established for adjuvant chemotherapy, directed against the ‘sleeping’ transformed lymphocytes in peripheral sites rather than against the tumor cells within the CNS.

No randomized trials have tested this hypothesis, but in 7 small pilot studies radiotherapy to the brain has been supplemented with various types of chemotherapy. These studies are reviewed in Table 5, and in 4 of them median survival exeeds the median survival of 24 months observed after radiotherapy alone [65,72]. Al- though the tatter results look promising they need to be confirmed in larger series of patients.

II-D. Cutaneous T-cell lymphoma (mycosis fungoides)

Ionizing irradiation is the most effective single agent for the treatment of mycosis fungoides, and permanent local control of lesions may be achieved with doses as low as 700 cGy [74,75]. For palliative treatment of indi- vidual lesions orthovoltage irradiation has been used successfully since the turn of the century [76]. With the development of electron beam therapy it has become possible to treat the entire skin [76.77], concentrating the dose of radiation in the epidermis and upper dermis while limiting the dose to the deep dermis and sub- cutaneous tissue. The total dose is generally 3600 cGy, and tumorous lesions will often receive boost treatment initially to reduce their thickness, usually with doses of 1500-2000 cGy. Only a few larger series have been reported in the literature. They are summarized in Table 6. Complete response is attained in 71-100% of patients with plaque disease but less often (3671%) in patients with tumorous disease [76,78,79]. The majority of

TABLE 6

Studies of cutaneous T-cell lymphoma treated with total skin electron beam irradiation

Ref. N Subset CR% 5-year

RFS TS

[76] 43 limited plaques 98 50 80 I04 generalized plaques 71 25 45 47 tumors 36 25

[791 50 plaques 96 32 87 56 advanced 71 7 42

[801 90 generalized plaques 47 54 tumors 35

1811 30 mixed 90 71

Ahhrrviufions (see also Tuble 1): CR, complete remission rate.

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patients relapse within 3 years after treatment 1801. 5- year RFS in patients with plaque disease ranges from 25-50% [76,79], but in patients with tumorous disease it is less than 10% [79]. Systemic chemotherapy is less active in mycosis fungoides whereas total skin electron beam irradiation offers significant palliative benefit and, in some cases, long-term RFS for patients with both progressive plaque disease and with tumorous dis- ease [76].

III. Generalized lymphomas

tensive abdominal disease (TS 79%) was attributed to radiotherapy [59]. In one of the studies with low-grade lymphomas it was noted that the sites of relapse were predominantly in unirradiated areas [90]. However, an analysis by Shipp et al. [91] of the relapse pattern in 81 patients with high-grade lymphomas and bulky disease revealed that very few patients relapse only in previous sites of bulky disease after chemotherapy. Conse- quently, they would be unlikely to benefit from ad- juvant radiotherapy. Thus, the question of the value of adjuvant radiotherapy in bulky disease remains unset- tled, but the prospects do not look promising.

III-A. Bulky tumor III-B. Stage III low-grade lymphomas

In a number of studies the analysis of failure patterns in high-grade non-Hodgkin’s lymphomas has shown that a poor prognosis is associated with the presence of ‘bulky’ or ‘ex-tended’ disease, defined either as high total tumor volume [59,82-851 or as circumscript lymphoma masses > 10 cm in diameter [9,14,86,87]. This finding has suggested the use of adjuvant radiotherapy to areas of bulky tumor in stage III and IV patients with high-grade lymphomas, following chemotherapy.

The possible benefit of such a treatment policy has only been tested in one randomized study where patients were randomized to + consolidation with in- volved field irradiation after induction chemotherapy. Preliminary analysis showed a prolongation of RFS in patients with stage III disease [88]. Table 7 shows the results from five single-treatment studies. two of which comprised patients with high-grade lymphomas and three patients with low-grade lymphomas only. The rates of RFS and TS show a considerable spread, parti- cularly in high-grade lymphomas, but the rates appear to be within the range of results seen with chemotherapy alone.

In one of the two studies with high-grade lymphomas the reasonably good prognosis of 18 patients with ex-

TABLE 7

Studies of post-chemotherapy adjuvant radiotherapy to bulky tumor, in stage III and IV lymphomas

Ref. N Subset CT 5-year

RFS TS

[59] 41 HG, St.111 CHOP-B 53 64 [I81 99 LG. st.III+IV AVCP 38 66

;: HG, st.III+IV AVCP 18 30

[89] LG, st.111 CHOP-B 52 75 [90] 84 LG, st.III+IV CVP 32 60

In the absence of any proven curative regimen of chemotherapy in advanced low-grade lymphomas [11,92] there have been some attempts to employ irradiation of all major lymphoid regions in such patients with stage III disease to doses of 3000 to 4000 cGy. In two studies, summarized in Table 8, the results appears to be better than those obtained with chemo- therapy. In the study reported by Paryani et al. [52] the RFS curve showed a plateau at 38% from 10 to 19.5 years, suggesting that a substantial subset of the patients may actually have been cured. A recent ran- domized study of stage III and IV low-grade lymphomas showed a significant improvement of both RFS and TS by the addition of irradiation to chemo- therapy [95]. Obviously, these results need to be con- firmed in other studies with long follow-up times.

III-C. Total body irradiation

The first large series of low-dose total body irradia- tion (TBI) in lymphoma was published in 1942 [96], but this type of treatment was temporarily abandoned until the middle 1960’s, probably due to the advent of chemo- therapy. Since then, a number of studies have evaluated the effect of TBI in generalized non-Hodgkin’s lymphomas of both low and high grade, and Table 9 summarizes studies in which 5-year and some IO-year survival figures are available. It appears from these data

TABLE 8

Studies of total lymphoid irradiation in stage III low-grade lymphomas

Ref. N S-year IO-year 15-year

RFS TS RFS TS RFS TS

Abbreviations (see also Table I and 2): CHOP-B, cyclophosphamide + doxorubicin + vincristine + prednisone + bleomycin; AVCP, doxoru- bicin + VM-26 + vincristine + prednisone; CVP. cyclophosphamide + vincristine + prednisone.

1931 61 57 75 38 48 38 34 [941 29 61 78 - -

Abbrrviutions: see Table 1.

225

TABLE 9

Studies of total body irradiation in stage III and IV lymphomas

Ref. N Subset 5-year I O-year _

RFS TS RFS TS

1971 22 LG 14 84 _ _ 13 HG 0 27 _

[98] 43 LG 23 65 15* 57+

[99] :; HG 10 42 HG 0 0

PO01 [loll** :;

LG 34 95 LG 31 30*

15 HG 0 _

[IO21 25 LG 32 48 27 35

20 HG 0 I5 0 0

PO31 21 LG 28 56 I2 32 I7 HG 0 I7 0 0

*7.5 years. **I 3 patients had received previous treatment. Abbreviations: see Table I

that the results with TBI are so poor in high-grade

lymphomas that chemotherapy remains the treatment

of choice in this subset. Poor results are also seen in pretreated patients, some of whom have probably end- stage transformed low-grade lymphomas [ 102,104]. In primary low-grade lymphomas 25-30% of the patients remain in complete remission at five years, and about 15% at 10 years. These results are similar to those ob- tained with chemotherapy in low-grade lymphomas [ 11,921, and this conclusion is supported by the results of two trials in which patients were randomized to re- ceive either TBI or chemotherapy. No significant dif- ferences were found as regards RFS and TS [97,100].

If it is accepted that TBI and chemotherapy give sim- ilar results in low-grade lymphomas, the choice between the two treatments may depend on differences of side effects, on the availability of radiotherapy, or treatment costs. Although TBI results in moderate bone-marrow depression of lo-12 weeks’ duration [105$107] there were fewer infectious complications among the TBI patients than among the chemotherapy patients in the two randomized studies mentioned above. However, in a few patients TBI may result in permanent thrombocy- topenia which may complicate treatment with chemo- therapy after a subsequent relapse. ANNL or myelo- dysplastic syndromes have also been observed in a few patients after TBI [ 100,103].

The standard technique of TBI involves treatment to the entire body with 15 cGy twice weekly to a total dose of 150 cGy in 5 weeks [98,100,103]. Since this total dose corresponds to about 1120 of the cumulative dose of a standard course of radiotherapy in lymphoma. it is nat- ural to ask how such a small dose can result in long- term remissions in some patients.

To explain this paradox, Rees [44] proposed that pe- ripheral (non-marrow) masses of non-Hodgkin’s lymphoma may not necessarily be truly malignant and autonomous neoplasms as far as the innate capacity for continued cell replication is concerned, in that the divid- ing cells responsible for their growth are situated else- where, in the marrow. The converse would tend to apply in high grade lymphoma, with a continuous spectrum of variation in autonomy. Thus, the discrepancy be- tween doses required for local control and effective whole body doses may be explained by a combined effect of the latter on radiation sensitive cells situated in the marrow, and on circulating radiosensitive ‘virgin’ lymphocytes which had been destined to undergo par- tial transformation to a more resistant stage before hav- ing their maturation arrested in a mass of peripheral lymphoma.

IV. Summary and recommendations

IV-A.1. Stage I and II lymphomas

About 50% of stage I and II non-Hodgkin- lymphomas of high grade appears to be curable with radiotherapy alone. Although some studies indicate that similar cure rates may be achieved with chemo- therapy alone, this has not yet been shown conclusively in randomized trials. As regards the combination of radiotherapy followed by chemotherapy. both random- ized and retrospective studies indicate that RFS is pro- longed by this combination, but it is yet uncertain whether there is also a prolongation of TS. The reverse sequence of chemotherapy followed by radiotherapy has not been tested in randomized trials, but in re- trospective comparisons with chemotherapy alone there may be a trend in favor of the combination. Since high rates of TS have been observed with chemotherapy fol- lowed by radiotherapy in several pilot studies, there appears to be a growing consensus that the optimum treatment of stage I and II high-grade lymphomas is a relatively short course of chemotherapy (34 cycles) fol- lowed by radiotherapy to moderate doses (3000-4000

~GY).

For stage I and II lymphomas of low-grade radio- therapy may result in prolonged RFS and possibly in cure in about 50% of the cases, particularly in younger patients. There is no indication that chemotherapy alone may lead to better or even similar results, and no indication that the addition of chemotherapy to radio- therapy leads to improved results. In low-grade lymphomas the majority of dose-response studies indi- cate that doses of 2500 cGy are sufficient for local con- trol except in cases of bulky tumor.

226

In high-grade lymphomas doses of 3500 cGy are sufficient for local control in the majority of cases when radiotherapy is used alone. Doses up to 4000 cGy may be necessary in patients over the age of 60 with bulky tumors. Further, doses up to 5000 cGy may be necessary in lymphomas localized to bone. When radio- therapy is used after chemotherapy, minimal residual disease will be present, and doses of 3000 cGy are suffi- cient.

Both in high-grade and low-grade lymphomas stage I patients should be treated with involved fields and stage II patients with extended fields.

IV-A.2. Extensive disease limited to the abdomen

Although there are few data to support this, it would be logical to treat patients with extensive lymphomas limited to the abdomen with chemotherapy to maxi- mum response followed by radiotherapy to the whole abdomen to a dose of 2500 cGy. This strategy might be particularly useful in lymphomas with intermediate- grade histology of the diffuse small cleaved cell type with a poor prognosis from chemotherapy alone. It is necessary to shield the kidneys after 1800-2000 cGy in order to avoid radiation nephritis.

IV-A.3. Primary CNS-lymphomas

Brain lymphomas have a poor prognosis but a small proportion is curable with radiotherapy, provided that radiation doses of 5000 cGy to the whole brain are employed. Doses of more than 5700 cGy carry a certain risk of late brain necrosis, and in cases with relatively small solitary tumors it may be sufficient to give 4000 cGy to the whole brain plus an additional 1000-1500 cGy to the tumor site.

In some studies adjuvant chemotherapy appears to have resulted in improved survival results, and recent theories on the origin of brain lymphomas provide a rationale for such a combined treatment in spite of the presence of the blood-brain barrier.

IV-A.4. Cutaneous T-cell lymphomas

Total skin electron beam irradiation to a dose of 3000-3600 cGy, supplemented with initial boost to tumorous lesions with doses of 1500-2000 cGy, con- stitutes effective treatment for patients with mycosis fungoides with progressive plaque disease or with tumo- rous disease. Treatment results are superior to those of systemic chemotherapy, offering significant palliation, and in some cases long-term RFS.

IV-B.1. Bulky tumor

The analysis of failure patterns in lymphoma patients has consistently shown the presence of bulky tumor to be associated with a poor prognosis. Nevertheless, it appears that recurrences in patients with bulky tumors do not particularly appear in previous sites of bulky disease. Thus, the rationale for adjuvant radiotherapy to sites of bulky tumor is questionable, and only one study to date has indicated any benefit from this strategy.

ZV-B.2. Stage III low-grade lymphomas

In a few studies radiotherapy to all major lymphoid regions in patients with stage III low-grade lymphomas has produced 5-year rates of RFS that appears to be higher than similar rates following chemotherapy alone. In one study the curves for both RFS and TS showed a prolonged plateau, indicating a possible curative potential for this type of radiotherapy in some patients with stage III low-grade lymphomas. As stated above, a tumor dose of 2500 cGy should be sufficient, except, perhaps, in sites with very bulky disease.

IV-B.3. Total body irradiation

TBI is indicated only in the primary treatment of generalized low-grade lymphomas. It is not useful in high-grade lymphomas or in transformed low-grade lymphomas. When given in fractions of 15 cGy twice weekly for 5 weeks to a total dose of 150 cGy TBI produces rates of RFS and TS comparable to that of chemotherapy with fewer complications. Although a small fraction of patients obtain long-term RFS, TBI should not be considered as curative therapy.

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