Br. J. Cancer (1975) 31, SuppI. II, 450
MANAGEMENT OF GENERALIZED MALIGNANT LYMPHOMATA WITH " SYSTEMIC " RADIOTHERAPY R. E. JOHNSON From the Radiation Branch of the National Cancer In8titute, National Institutes of Health, Bethesda, Maryland, U.S.A.
Summary.-The natural history of lymphocytic lymphomata is such that anatomical generalization of disease is usually present at the time of diagnosis. Tumour infiltration of extralymphatic sites such as the liver and bone marrow is identifiable with particular frequency in those cases presenting with lymph node manifestations of disease. Even in the absence of detectable extralymphatic dissemination, the lymphatic involvement is often sufficiently diffuse to mitigate against extensive lymph node irradiation " ala Hodgkin's disease" as appropriate or technically feasible form of treatment. Rather, systemic treatment must be recognized as imperative for the majority of newly diagnosed patients and we have investigated " systemic " radiotherapy as an alternative to chemotherapy during the past decade. Our experience with 57 consecutive patients with lymphocytic lymphoma has been reviewed. Total body irradiation (TBI) has been found to yield high remission rates despite a lack of serious toxicity or constitutional reactions. Rigorous diagnostic staging was not employed but despite the advanced stage of disease which was clinically obvious in most cases, survival rates have been strikingly high. Actuarially calculated 5-year survival rates for the well differentiated (diffuse and nodular combined), nodular poorly differentiated and diffuse poorly differentiated subtypes are 85%, 69% and 51% respectively. Furthermore, initial management with radiotherapy as described has not negated with effective use of subsequent chemotherapy when selectively required.
THE MALIGNANT lymphomata display protean clinical manifestations and exhibit an extremely wide range of biological behaviour. Among other determinants, there is a wide disparity between those lymphomata primary in lymph nodes as contrasted with primary extranodal lymphomata. The latter are truly local or regional with considerable frequency and are thereby amenable to definitive management with local treatment such as surgical extirpation and/or tumouricidal radiotherapy (Freeman, Berg -and Cutler 1972). Conversely, nodal presentations of malignant lymphoma are usually anatomically diffuse when the diagnosis is established and conventional radiotherapy or surgical techniques are seldom relevant. Although rigorous diagnostic evaluation was not employed consistently in the past, there has long been an appreciation
that relatively few patients with nonHodgkin's lymphomata have anatomically limited involvement by disease. More recent prospective staging has further emphasized the disseminated extent of tumour in the vast majority of newly diagnosed patients (Johnson et al., 1975). This situation has increasingly relegated conventional radiotherapy to a minor role in terms of primary management. There has consequently been a virtual absence of published articles concerning the radiotherapeutic management of generalized lymphoma during the last decade, aside from our own reports. Renewal of interest in the potential for radiotherapy in advanced lymphoma began in 1964 and the progress of our experience has been serially described (Johnson, 1966; Johnson et al., 1967; Johnson, 1969a; Johnson, O'Conor and Levin, 1970; Johnson, 1972;
451
MANAGEMENT OF GENERALIZED MALIGNANT LYMPHOMATA
1973a, b). Our investigations have particularly emphasized total body irradiation (TBI) and the present report summarizes the observations to date, including appraisal of the iatrogenic complications. MATERIALS AND METHODS
The initial pilot studies were confined to previously treated patients who occasionally were nearly terminal with their disease. Multiple uncontrolled variables pertained to these cases, including the type and extent of prior therapy, the degree to which bone marrow function was compromised and other readily definable determinants. Furthermore, those patients with more indolent disease usually continued to receive therapy elsewhere and were not referred for investigational therapy. Contrariwise, cases with extremely virulent progression of disease were usually unable to tolerate transfer to our hospital or were too compromised upon admission to undergo an adequate trial of therapy. Consequently, the present review has been restricted to all consecutive previously untreated patients with a histological subclassification of lymphocytic lymphoma admitted to the Radiation Branch of the National Cancer Institute since 1965. The age and sex distributions are given in Table I and the histology is described in Table II. During the early years of the programme, rigorous diagnostic staging was not utilized so that accurate definition of extranodal dissemination was potentially lacking in some cases. None the less, general-
ized involvement was recognizable in 86% of the series with routine investigation (history and physical examination, biopsy of accessible lesions including cytological examination of effusions, a complete blood count and radiographs of the chest and skeletal system). Only 3 of the total 57 patients were classified as either Stage III or IV as the consequence of exploratory laparotomy (Table III). This latter deserves comment
TABLE Ill.-Basis for Demonstration of Anatomically Generalized Disease for 57
Consecutive Cases of Lymphocytic
Lymphoma
Stage Extent of evaluation Usual clinical tests
Lymphography Bone marrow biopsy Laparotomy
I-II
III-IV
8 4 3 0
49 53 54 57
since reports limited to more recent experilikely to include a substantial fraction of cases staged as " advanced " because of exhaustive diagnostic evaluation. Treatment could be categorized as one of 3 types, namely total body irradiation (TBI), comprehensive lymph node irradiation (CNI), or a combination of TBI and lymph node irradiation administered sequentially. TBI was most frequently given in 10 rad fractions to a total dose of 100-150 rad, altemating the daily exposures from the left versus right sides with patients assuming a semi-foetal position while sitting in a chair. The dosimetric aspects were of minimal complexity TABLE I.-Age and Sex Distributions of and teletherapy units proved of utility equal 57 Consecutive Cases of Generalized to high energy linear accelerators. The individual treatments required only a few Non-Hodgkin's Lymphoma minutes at most and the doses referred to above represent midline absorbed doses (see Age at diagnosis Sex
1-20 1 0
21-40 9 3
41-60 19 15
ence are
Fig. 1).
Following an initial series of TBI exposures, treatment was interrupted for an average of 8 weeks to permit bone marrow recovery and those patients having an TABLE II.-Histological Subclassiftcation objective therapeutic response were often for 57 Consecutive Cases of General- given a second course of TBI. Some patients received TBI using a " hemibody " techized Lymphocytic Lymphoma nique which consisted of 50 rad daily exposNodular Diffuse ures (to a total of 300-600 rad) to either the Well differentiated upper or lower half of the body. After 4 5 Poorly differentiated 30 18 interruption of treatment to permit marrow Male Female
61-99 5 5
452
R. E. JOHNSON
0
0 I-
,2 LATERAL PELVIC DIAMETER (cm) FIG. 1.-The curve provides tumour-air ratios for externally measured transverse hip diameters. Multiple thermoluminescent dosimetry determinations provided the data for this curve, the dosimetry readings being obtained via rectally inserted catheters which remained " in vivo " during the radiation exposures.
regeneration in the treated hemibody, the remaining half was irradiated similarly. This hemibody technique did not produce either a higher remission rate or more durable remissions and the standard TBI method using small daily fractions was subsequently resumed. The technique called CNI consisted of an effort to include not only lymphatic areas which are frequently involved by Hodgkin's disease but additionally to include treatment of the epitrochlear, peri-auricular and Waldeyer's ring areas. Patients with apparent mesenteric node involvement further had the para-aortic field extended to an " abdominal bath" approach. The tumour doses used for CNI varied from 1000 to 4000 rad, the higher range being usual when CNI constituted the only treatment and a lower range when CNI followed a preliminary course of
TBI (here usually 100 rad in 10 rad fractions). Assignment of patients to various therapeutic methods was non-random in nature. Cases with obvious extranodal dissemination were treated routinely with TBI whereas the patients with clinically less extensive involvement tended to receive CNI. An increasing propensity has none the less developed to use TBI routinely for Stage III cases and to extend this concept of " systemic " treatment even to Stage II involvement (with lymph node presentations) in light of the common experience that these latter patients are often if not generally understaged. RESULTS
While long-term survival remains a primary goal in cancer therapeutics, other considerations merit attention. We
MANAGEMENT OF GENERALIZED MALIGNANT LYMPHOMATA
have therefore reviewed other factors together with the usual criteria of remission rates and survival, namely the number of clinic visits and time required to complete treatment, the toxicity experienced with therapy and the ability of patients to sustain semi-normal, if not normal, activities while undergoing treatment. With respect to acute subjective reactions, TBI has proven to incur little, if any, of the toxicity frequently observed with modern chemotherapy. For example, the neurotoxicity, gastrointestinal symptoms, alopecia and steroid effects noted with CVP (cyclophosphamide, vincristine and prednisone combination chemotherapy) did not occur. Patients were generally treated on an ambulatory basis unless their poor medical condition required hospitalization. Although mild fatigue was not uncommon during a course of TBI, the absence of " radiation sickness " permitted the majority of patients to continue ordinary activities on a status quo level. Those patients with disease related symptomatology often experienced a marked improvement in function with remission of disease, even while undergoing treatment. Haematological depression was distinct in all patients but, except for the situation discussed in more detail under Complications, was moderate in degree and transient in nature. However, it must be emphatically stressed that profound bone marrow depression can be readily induced by TBI, even with relatively small daily fractions of 1O rad. It is imperative to recognize the need to restrict the total dose administered in each course and not to await the clinical appreciation of falling peripheral blood counts. Similarly, the interval between successive courses of therapy and the total dose administered in the second course must remain flexible according to the haematological effect observed after the initial series of exposures. The second course of TBI was variably instituted between 6 and 12 weeks of the initial series and
453
effects secondary to treatment were essentially non-existent in the interim. While the overall time for completion of treatment thus ranged from 2 to 4 months, the majority of time was not involved with therapy per se. TABLE IV.-Complete Remission Rates Correlated with Treatment and Histo-
logic Classificaction Therapy , K
Histology WD (diff. & nod.) PD, nodular PD, diffuse
CNI
3/3 13/13 2/2
CNI & TBI 2/2 3/4 1/2
A~~~
TBI 4/4 8/13 9/14
Table IV summarizes the complete response (remission) rates for the treatment approaches and histological classifications. Complete remission is here defined as resolution of all measurable disease, including bone marrow infiltration when such was detectable before initiation of treatment, and disappearance of all disease related symptoms. The 100% complete remission rate observed with CNI compared with the lower remissions rates for TBI or CNI plus TBI clearly reflects the bias of assigning patients with less extensive disease and more favourable histological subtypes to CNI. The median observation time for the entire series is approximately 4 years, providing reasonable stability to the actuarial survival rates depicted in Fig. 2, especially during the initial 3 years. The difference in survival for the various histological groups correlates with the complete remission rates described in Table IV. The implication of this correlation is that therapy sufficiently effective to induce a " remission " will ultimately reflect an increased duration of survival. It is of further interest that those patients eventually not controlled by radiotherapy have been amenable to chemotherapy. Clinically useful chemotherapy (i.e., objective response accom-
R. E. JOHNSON
o45 I.%-
-Jo o)
5 YEARS AFTER FIRST THERAPY FIG. 2.-Actuarially calculated survival curves are shown for patients with lymphocytic Iymphoma of the well differentiated (nodular and diffuse patterns combined), poorly differentiated nodular and poorly differentiated diffuse subtypes. The median observation time is approximately 4 years for the entire series. Only a single patient died from unrelated causes and the survival rates for the first several years are therefore basically absolute survival rates.
panied by subjective improvement) has been observed in 8 of the 14 patients (57%) eventually treated with chemotherapy in this series. These 14 patients are clearly selected in the context of having relatively aggressive disease and the chemotherapy response (i.e., lack of cross resistance) was quite gratifying. It may additionally be noted that chemotherapy has been utilized to a limited degree and for rather short duration in most patients and has not materially influenced the survival data shown in Fig. 2.
Complications While TBI did not evoke significant constitutional reactions, there was a predictable haematopoietic depression, as discussed. The CNI method produced a variety of local normal tissue reactions and systemic effects virtually identical to those already described by many investigators for Hodgkin's disease and so-called " total nodal irradiation ". These radiation effects can be reviewed in detail in the published literature (e.g., Johnson et al., 1969) and do not require reiteration here.
The single major (and unanticipated) complication with the 3 treatment approaches utilized has been development of myeloproliferative disorders consistent with acute myelocytic leukaemia in 3 patients. Two of these cases occurred within a small risk group of 8 patients initially given both TBI and extensive lymph node irradiation as primary treatment. The third instance was a patient initially treated with CNI and subsequently given both TBI and chemotherapy after relapse was observed 4 years following primary therapy. No indication of myeloproliferative disorders has been observed in any of the 31 cases treated with TBI alone despite a comparable risk period. It would appear that TBI combined with CNI is sufficiently carcinogenic and immunosuppressive as to create a highly provocative milieu for iatrogenic leukaemia and one might speculate that a similar potential could also exist by combining intensive radiotherapy and systemic chemotherapy on the basis of recent experiences with Hodgkin's disease (Canellos et al., 1974).
MANAGEMENT OF GENERALIZED MALIGNANT LYMPHOMATA DISCUSSION
The quality of the patient population in the present study is difficult to compare with other reported series. The rigour of the diagnostic evaluation constitutes an important variable, as already mentioned. An ill-defined socioeconomic factor is also present since a substantial fraction of our patients are referred because of lacking financial means to undergo medical care in their home community. Any bias introduced by this type of referral pattern compared with more general practice is clearly
uninterpretable. The ready appreciation of anatomically generalized involvement, usually by physical examination alone, indicates that the series described had macroscopically and not microscopically advanced or systemic involvement. The overall 5year survival rate of 66% is quite impressive when considered in this context. Speculation that this survival rate reflects inherent " indolence " of lymphocytic lymphomata can be readily countered by directing attention to one subgroup in particular, namely those with diffuse poorly differentiated histology. The available literature consistently reports the rather unfavourable response to therapy and survival for these patients. The 51% 5-year survival for this group objectively implies that the treatment effectiveness is an independent factor responsible for the excellence of the overall results. Finally, while it remains to be determined whether " systemic " radiotherapy can produce better results than modern chemotherapy for lymphocytic lymphomata, the ease of administration of TBI and the minimal attendant toxicity are considerations of major importance. The preliminary results of a randomized clinical trial comparing chemotherapy and radiotherapy for Stage III-IV lymphocytic lymphomata has been presented
455
elsewhere in this Symposium (Canellos et al., 1975). Our initial experience has been confirmed in this latter study in that TBI is not only an effective modality which is well tolerated by ambulatory patients but deserves expanded consideration as a first-line method of treatment for patients with generalized lymphocytic lymphomata. REFERENCES CANELLOS, G. P., DEVITA, V. T., ARSENEAU, J. C. & JOHNSON, R. E. (1974) Carcinogenesis by Cancer Chemotherapeutic Agents: Second Malignancies Complicating Hodgkin's Disease in Remission. Ann. N.Y. Acad. Sci. In the press. CANELLOS, G. P., DEVITA, V. T., YOUNG, R. C., CHABNER, B. A., SCHEIN, P. S. & JOHNSON, R. E. (1975) Therapy of Advanced Lymphocytic Lymphoma: A Preliminary Report of a Randomized Trial Between Combination Chemotherapy (CVP) and Intensive Radiotherapy. Br. J. Cancer. 31, Suppl. II, 474. FREEMAN, C., BERG, J. & CUTLER, S. (1972) Occurrence and Prognosis of Extranodal Lymphomas. Cancer, N. Y., 29, 252. JOHNSON, R. E. (1966) Evaluation of Fractionated Total Body Irradiation in Patients with Leukemia and Disseminated Lymphomas. Radiotogy, 86, 1085. JOHNSON, R. E. (1969) Modern Approaches to the Radiotherapy of Lymphomas. Semin. Hemat., 6, 357. JOHNSON, R. E. (1972) Remission Induction and Remission Duration with Primary Radiotherapy in Advanced Lymphosarcoma. Cancer, N. Y., 29, 1972. JOHNSON, R. E. (1973a) Radiation Therapy of Generalized Lymphocytic Lymphomas. Am. J. Roentg., 117, 50. JOHNSON, R. E. (1973b) Radiation Management of the Lymphomas. In Proc. Seventh natn. Cancer Conf. Philadelphia: J. G. Lippincott. p. 375. JOHNSON, R. E., FOLEY, H. T., SWAIN, R. W. & O'CoNoR, G. T. (1967) Treatment of Lymphosarcoma with F'ra.tionated Total Body Irradiation. Cancer, ' Y.,20, 482. JOHNSON, R. E., IX \GAN, A. R., HAFERMANN, M. D. & KEYES, J. W. (1969) Patient Tolerance to Extended Irradiation in Hodgkin's Disease. Ann. intern. Med., 70, 1. JOHNSON, R. E., O'CONOR, G. T. & LEvIN, D. (1970) Primary Management of Advanced Lymphosarcoma with Radiotherapy. Cancer, N. Y., 25, 787. JOHNSON, R. E., DEVITA, V. T., KUN, L. E., CHABNER, B. R., CHRETIEN, P. B., BERARD, C. W. & JOHNSON, S. K. (1975) Patterns of Involvement with Malignant Lymphoma and Implications for Treatment Decision Making. Br. J. Cancer 31, Suppl. II, 237.
MANAGEMENT OF GENERALIZED MALIGNANT LYMPHOMATA WITH " SYSTEMIC " RADIOTHERAPY R. E. JOHNSON From the Radiation Branch of the National Cancer In8titute, National Institutes of Health, Bethesda, Maryland, U.S.A.
Summary.-The natural history of lymphocytic lymphomata is such that anatomical generalization of disease is usually present at the time of diagnosis. Tumour infiltration of extralymphatic sites such as the liver and bone marrow is identifiable with particular frequency in those cases presenting with lymph node manifestations of disease. Even in the absence of detectable extralymphatic dissemination, the lymphatic involvement is often sufficiently diffuse to mitigate against extensive lymph node irradiation " ala Hodgkin's disease" as appropriate or technically feasible form of treatment. Rather, systemic treatment must be recognized as imperative for the majority of newly diagnosed patients and we have investigated " systemic " radiotherapy as an alternative to chemotherapy during the past decade. Our experience with 57 consecutive patients with lymphocytic lymphoma has been reviewed. Total body irradiation (TBI) has been found to yield high remission rates despite a lack of serious toxicity or constitutional reactions. Rigorous diagnostic staging was not employed but despite the advanced stage of disease which was clinically obvious in most cases, survival rates have been strikingly high. Actuarially calculated 5-year survival rates for the well differentiated (diffuse and nodular combined), nodular poorly differentiated and diffuse poorly differentiated subtypes are 85%, 69% and 51% respectively. Furthermore, initial management with radiotherapy as described has not negated with effective use of subsequent chemotherapy when selectively required.
THE MALIGNANT lymphomata display protean clinical manifestations and exhibit an extremely wide range of biological behaviour. Among other determinants, there is a wide disparity between those lymphomata primary in lymph nodes as contrasted with primary extranodal lymphomata. The latter are truly local or regional with considerable frequency and are thereby amenable to definitive management with local treatment such as surgical extirpation and/or tumouricidal radiotherapy (Freeman, Berg -and Cutler 1972). Conversely, nodal presentations of malignant lymphoma are usually anatomically diffuse when the diagnosis is established and conventional radiotherapy or surgical techniques are seldom relevant. Although rigorous diagnostic evaluation was not employed consistently in the past, there has long been an appreciation
that relatively few patients with nonHodgkin's lymphomata have anatomically limited involvement by disease. More recent prospective staging has further emphasized the disseminated extent of tumour in the vast majority of newly diagnosed patients (Johnson et al., 1975). This situation has increasingly relegated conventional radiotherapy to a minor role in terms of primary management. There has consequently been a virtual absence of published articles concerning the radiotherapeutic management of generalized lymphoma during the last decade, aside from our own reports. Renewal of interest in the potential for radiotherapy in advanced lymphoma began in 1964 and the progress of our experience has been serially described (Johnson, 1966; Johnson et al., 1967; Johnson, 1969a; Johnson, O'Conor and Levin, 1970; Johnson, 1972;
451
MANAGEMENT OF GENERALIZED MALIGNANT LYMPHOMATA
1973a, b). Our investigations have particularly emphasized total body irradiation (TBI) and the present report summarizes the observations to date, including appraisal of the iatrogenic complications. MATERIALS AND METHODS
The initial pilot studies were confined to previously treated patients who occasionally were nearly terminal with their disease. Multiple uncontrolled variables pertained to these cases, including the type and extent of prior therapy, the degree to which bone marrow function was compromised and other readily definable determinants. Furthermore, those patients with more indolent disease usually continued to receive therapy elsewhere and were not referred for investigational therapy. Contrariwise, cases with extremely virulent progression of disease were usually unable to tolerate transfer to our hospital or were too compromised upon admission to undergo an adequate trial of therapy. Consequently, the present review has been restricted to all consecutive previously untreated patients with a histological subclassification of lymphocytic lymphoma admitted to the Radiation Branch of the National Cancer Institute since 1965. The age and sex distributions are given in Table I and the histology is described in Table II. During the early years of the programme, rigorous diagnostic staging was not utilized so that accurate definition of extranodal dissemination was potentially lacking in some cases. None the less, general-
ized involvement was recognizable in 86% of the series with routine investigation (history and physical examination, biopsy of accessible lesions including cytological examination of effusions, a complete blood count and radiographs of the chest and skeletal system). Only 3 of the total 57 patients were classified as either Stage III or IV as the consequence of exploratory laparotomy (Table III). This latter deserves comment
TABLE Ill.-Basis for Demonstration of Anatomically Generalized Disease for 57
Consecutive Cases of Lymphocytic
Lymphoma
Stage Extent of evaluation Usual clinical tests
Lymphography Bone marrow biopsy Laparotomy
I-II
III-IV
8 4 3 0
49 53 54 57
since reports limited to more recent experilikely to include a substantial fraction of cases staged as " advanced " because of exhaustive diagnostic evaluation. Treatment could be categorized as one of 3 types, namely total body irradiation (TBI), comprehensive lymph node irradiation (CNI), or a combination of TBI and lymph node irradiation administered sequentially. TBI was most frequently given in 10 rad fractions to a total dose of 100-150 rad, altemating the daily exposures from the left versus right sides with patients assuming a semi-foetal position while sitting in a chair. The dosimetric aspects were of minimal complexity TABLE I.-Age and Sex Distributions of and teletherapy units proved of utility equal 57 Consecutive Cases of Generalized to high energy linear accelerators. The individual treatments required only a few Non-Hodgkin's Lymphoma minutes at most and the doses referred to above represent midline absorbed doses (see Age at diagnosis Sex
1-20 1 0
21-40 9 3
41-60 19 15
ence are
Fig. 1).
Following an initial series of TBI exposures, treatment was interrupted for an average of 8 weeks to permit bone marrow recovery and those patients having an TABLE II.-Histological Subclassiftcation objective therapeutic response were often for 57 Consecutive Cases of General- given a second course of TBI. Some patients received TBI using a " hemibody " techized Lymphocytic Lymphoma nique which consisted of 50 rad daily exposNodular Diffuse ures (to a total of 300-600 rad) to either the Well differentiated upper or lower half of the body. After 4 5 Poorly differentiated 30 18 interruption of treatment to permit marrow Male Female
61-99 5 5
452
R. E. JOHNSON
0
0 I-
,2 LATERAL PELVIC DIAMETER (cm) FIG. 1.-The curve provides tumour-air ratios for externally measured transverse hip diameters. Multiple thermoluminescent dosimetry determinations provided the data for this curve, the dosimetry readings being obtained via rectally inserted catheters which remained " in vivo " during the radiation exposures.
regeneration in the treated hemibody, the remaining half was irradiated similarly. This hemibody technique did not produce either a higher remission rate or more durable remissions and the standard TBI method using small daily fractions was subsequently resumed. The technique called CNI consisted of an effort to include not only lymphatic areas which are frequently involved by Hodgkin's disease but additionally to include treatment of the epitrochlear, peri-auricular and Waldeyer's ring areas. Patients with apparent mesenteric node involvement further had the para-aortic field extended to an " abdominal bath" approach. The tumour doses used for CNI varied from 1000 to 4000 rad, the higher range being usual when CNI constituted the only treatment and a lower range when CNI followed a preliminary course of
TBI (here usually 100 rad in 10 rad fractions). Assignment of patients to various therapeutic methods was non-random in nature. Cases with obvious extranodal dissemination were treated routinely with TBI whereas the patients with clinically less extensive involvement tended to receive CNI. An increasing propensity has none the less developed to use TBI routinely for Stage III cases and to extend this concept of " systemic " treatment even to Stage II involvement (with lymph node presentations) in light of the common experience that these latter patients are often if not generally understaged. RESULTS
While long-term survival remains a primary goal in cancer therapeutics, other considerations merit attention. We
MANAGEMENT OF GENERALIZED MALIGNANT LYMPHOMATA
have therefore reviewed other factors together with the usual criteria of remission rates and survival, namely the number of clinic visits and time required to complete treatment, the toxicity experienced with therapy and the ability of patients to sustain semi-normal, if not normal, activities while undergoing treatment. With respect to acute subjective reactions, TBI has proven to incur little, if any, of the toxicity frequently observed with modern chemotherapy. For example, the neurotoxicity, gastrointestinal symptoms, alopecia and steroid effects noted with CVP (cyclophosphamide, vincristine and prednisone combination chemotherapy) did not occur. Patients were generally treated on an ambulatory basis unless their poor medical condition required hospitalization. Although mild fatigue was not uncommon during a course of TBI, the absence of " radiation sickness " permitted the majority of patients to continue ordinary activities on a status quo level. Those patients with disease related symptomatology often experienced a marked improvement in function with remission of disease, even while undergoing treatment. Haematological depression was distinct in all patients but, except for the situation discussed in more detail under Complications, was moderate in degree and transient in nature. However, it must be emphatically stressed that profound bone marrow depression can be readily induced by TBI, even with relatively small daily fractions of 1O rad. It is imperative to recognize the need to restrict the total dose administered in each course and not to await the clinical appreciation of falling peripheral blood counts. Similarly, the interval between successive courses of therapy and the total dose administered in the second course must remain flexible according to the haematological effect observed after the initial series of exposures. The second course of TBI was variably instituted between 6 and 12 weeks of the initial series and
453
effects secondary to treatment were essentially non-existent in the interim. While the overall time for completion of treatment thus ranged from 2 to 4 months, the majority of time was not involved with therapy per se. TABLE IV.-Complete Remission Rates Correlated with Treatment and Histo-
logic Classificaction Therapy , K
Histology WD (diff. & nod.) PD, nodular PD, diffuse
CNI
3/3 13/13 2/2
CNI & TBI 2/2 3/4 1/2
A~~~
TBI 4/4 8/13 9/14
Table IV summarizes the complete response (remission) rates for the treatment approaches and histological classifications. Complete remission is here defined as resolution of all measurable disease, including bone marrow infiltration when such was detectable before initiation of treatment, and disappearance of all disease related symptoms. The 100% complete remission rate observed with CNI compared with the lower remissions rates for TBI or CNI plus TBI clearly reflects the bias of assigning patients with less extensive disease and more favourable histological subtypes to CNI. The median observation time for the entire series is approximately 4 years, providing reasonable stability to the actuarial survival rates depicted in Fig. 2, especially during the initial 3 years. The difference in survival for the various histological groups correlates with the complete remission rates described in Table IV. The implication of this correlation is that therapy sufficiently effective to induce a " remission " will ultimately reflect an increased duration of survival. It is of further interest that those patients eventually not controlled by radiotherapy have been amenable to chemotherapy. Clinically useful chemotherapy (i.e., objective response accom-
R. E. JOHNSON
o45 I.%-
-Jo o)
5 YEARS AFTER FIRST THERAPY FIG. 2.-Actuarially calculated survival curves are shown for patients with lymphocytic Iymphoma of the well differentiated (nodular and diffuse patterns combined), poorly differentiated nodular and poorly differentiated diffuse subtypes. The median observation time is approximately 4 years for the entire series. Only a single patient died from unrelated causes and the survival rates for the first several years are therefore basically absolute survival rates.
panied by subjective improvement) has been observed in 8 of the 14 patients (57%) eventually treated with chemotherapy in this series. These 14 patients are clearly selected in the context of having relatively aggressive disease and the chemotherapy response (i.e., lack of cross resistance) was quite gratifying. It may additionally be noted that chemotherapy has been utilized to a limited degree and for rather short duration in most patients and has not materially influenced the survival data shown in Fig. 2.
Complications While TBI did not evoke significant constitutional reactions, there was a predictable haematopoietic depression, as discussed. The CNI method produced a variety of local normal tissue reactions and systemic effects virtually identical to those already described by many investigators for Hodgkin's disease and so-called " total nodal irradiation ". These radiation effects can be reviewed in detail in the published literature (e.g., Johnson et al., 1969) and do not require reiteration here.
The single major (and unanticipated) complication with the 3 treatment approaches utilized has been development of myeloproliferative disorders consistent with acute myelocytic leukaemia in 3 patients. Two of these cases occurred within a small risk group of 8 patients initially given both TBI and extensive lymph node irradiation as primary treatment. The third instance was a patient initially treated with CNI and subsequently given both TBI and chemotherapy after relapse was observed 4 years following primary therapy. No indication of myeloproliferative disorders has been observed in any of the 31 cases treated with TBI alone despite a comparable risk period. It would appear that TBI combined with CNI is sufficiently carcinogenic and immunosuppressive as to create a highly provocative milieu for iatrogenic leukaemia and one might speculate that a similar potential could also exist by combining intensive radiotherapy and systemic chemotherapy on the basis of recent experiences with Hodgkin's disease (Canellos et al., 1974).
MANAGEMENT OF GENERALIZED MALIGNANT LYMPHOMATA DISCUSSION
The quality of the patient population in the present study is difficult to compare with other reported series. The rigour of the diagnostic evaluation constitutes an important variable, as already mentioned. An ill-defined socioeconomic factor is also present since a substantial fraction of our patients are referred because of lacking financial means to undergo medical care in their home community. Any bias introduced by this type of referral pattern compared with more general practice is clearly
uninterpretable. The ready appreciation of anatomically generalized involvement, usually by physical examination alone, indicates that the series described had macroscopically and not microscopically advanced or systemic involvement. The overall 5year survival rate of 66% is quite impressive when considered in this context. Speculation that this survival rate reflects inherent " indolence " of lymphocytic lymphomata can be readily countered by directing attention to one subgroup in particular, namely those with diffuse poorly differentiated histology. The available literature consistently reports the rather unfavourable response to therapy and survival for these patients. The 51% 5-year survival for this group objectively implies that the treatment effectiveness is an independent factor responsible for the excellence of the overall results. Finally, while it remains to be determined whether " systemic " radiotherapy can produce better results than modern chemotherapy for lymphocytic lymphomata, the ease of administration of TBI and the minimal attendant toxicity are considerations of major importance. The preliminary results of a randomized clinical trial comparing chemotherapy and radiotherapy for Stage III-IV lymphocytic lymphomata has been presented
455
elsewhere in this Symposium (Canellos et al., 1975). Our initial experience has been confirmed in this latter study in that TBI is not only an effective modality which is well tolerated by ambulatory patients but deserves expanded consideration as a first-line method of treatment for patients with generalized lymphocytic lymphomata. REFERENCES CANELLOS, G. P., DEVITA, V. T., ARSENEAU, J. C. & JOHNSON, R. E. (1974) Carcinogenesis by Cancer Chemotherapeutic Agents: Second Malignancies Complicating Hodgkin's Disease in Remission. Ann. N.Y. Acad. Sci. In the press. CANELLOS, G. P., DEVITA, V. T., YOUNG, R. C., CHABNER, B. A., SCHEIN, P. S. & JOHNSON, R. E. (1975) Therapy of Advanced Lymphocytic Lymphoma: A Preliminary Report of a Randomized Trial Between Combination Chemotherapy (CVP) and Intensive Radiotherapy. Br. J. Cancer. 31, Suppl. II, 474. FREEMAN, C., BERG, J. & CUTLER, S. (1972) Occurrence and Prognosis of Extranodal Lymphomas. Cancer, N. Y., 29, 252. JOHNSON, R. E. (1966) Evaluation of Fractionated Total Body Irradiation in Patients with Leukemia and Disseminated Lymphomas. Radiotogy, 86, 1085. JOHNSON, R. E. (1969) Modern Approaches to the Radiotherapy of Lymphomas. Semin. Hemat., 6, 357. JOHNSON, R. E. (1972) Remission Induction and Remission Duration with Primary Radiotherapy in Advanced Lymphosarcoma. Cancer, N. Y., 29, 1972. JOHNSON, R. E. (1973a) Radiation Therapy of Generalized Lymphocytic Lymphomas. Am. J. Roentg., 117, 50. JOHNSON, R. E. (1973b) Radiation Management of the Lymphomas. In Proc. Seventh natn. Cancer Conf. Philadelphia: J. G. Lippincott. p. 375. JOHNSON, R. E., FOLEY, H. T., SWAIN, R. W. & O'CoNoR, G. T. (1967) Treatment of Lymphosarcoma with F'ra.tionated Total Body Irradiation. Cancer, ' Y.,20, 482. JOHNSON, R. E., IX \GAN, A. R., HAFERMANN, M. D. & KEYES, J. W. (1969) Patient Tolerance to Extended Irradiation in Hodgkin's Disease. Ann. intern. Med., 70, 1. JOHNSON, R. E., O'CONOR, G. T. & LEvIN, D. (1970) Primary Management of Advanced Lymphosarcoma with Radiotherapy. Cancer, N. Y., 25, 787. JOHNSON, R. E., DEVITA, V. T., KUN, L. E., CHABNER, B. R., CHRETIEN, P. B., BERARD, C. W. & JOHNSON, S. K. (1975) Patterns of Involvement with Malignant Lymphoma and Implications for Treatment Decision Making. Br. J. Cancer 31, Suppl. II, 237.
