Br. J. Cancer (1975) 31, Suppl. II, 441

ADVANCED LYMPHOSARCOMA TREATED BY TOTAL BODY IRRADIATION J. T. CHAFFEY, D. S. ROSENTHAL, G. PINKUS AND S. HELLMAN

From the Joint Center for Radiation Therapy, 1'eter Bent Brighan Hospital, and the Departments of Radiation Therapy, Medicine and Pathology, Harvard Medical School

Summary.-Twenty-five cases of clinical Stage III and Stage IV lymphosarcoma primarily treated by total body irradiation (TBI) are reported. Fifteen cases demonstrated nodular histology and 10 demonstrated diffuse histology by the Rappaport criteria. Treatments were 15 rad given twice weekly, calculated to midpelvis, to a total dose of 150 rad. Toxicity was confined to thrombocytopenia, one-third of patients requiring interruptions in the treatment course to allow platelet count recovery. Five patients had additional local irradiation. Complete responses were seen in 80% of patients and partial responses in 20%. Sixteen patients (64%) have been in continuous, unmaintained remission since treatments for variable periods to 39 months. Of 9 patients with clinically recurrent disease, 3 received further TBI and are in remission, 3 are in remission on chemotherapy, one patient has died, failing on all therapy, and 2 have not been treated. One patient died of pneumonia at 12 months, without clinical evidence of disease. Overall, actuarial survival is 87% at 2 years and compares well with survival in a sequential combination drug treated group of patients matched for age, sex and histology, though differences are not statistically significant in these small groups. Total body irradiation is an effective systemic agent in the management of advanced lymphosarcoma and should be considered in treating this disease.

ONLY TWELVE years after the dis- for more than a generation. Johnson, O'Conor and Levin deserve body irradiation were described (Dessauer, credit for rekindling interest in this old 1907) but not until 1923 was the first form of therapy, and in 1970 published series of 12 cases of Hodgkin's disease their results in 25 cases of advanced treated by total body irradiation (TBI) lymphosarcoma, demonstrating prolonged published (Chaoul and Lange, 1923). unmaintained remissions and encouraging In the next decade the technique came survival in patients without visceral into wider use, known as the " Teschen- disease. dorf method'" in Europe (Teschendorf, We began using TBI in selected cases 1927) and " Heublein therapy" in the in 1969, when it became apparent that United States (Heublein, 1932). Ten multiple drug chemotherapy consisting years' experience using "Heublein ther- of cyclophosphamide, vincristine and predapy" in 270 cases was reported by nisone (COP) was exacting a heavy toll Medinger and Craver in 1942, who found in morbidity and toxicity, even in favoura doubling in average survival time follow- able cases which might be expected to ing TBI in disseminated lymphosarcoma. respond well to a less drastic form of That same year nitrogen mustard was treatment. In this report we record the first used in the treatment of human experience of giving TBI in 25 cases malignancy and TBI was nearly forgotten without previous systemic therapy. covery of x-rays the principles of total

Stupportedi in part by ITSPHS Grant No. CA 12662. 29

442

J. T. CHAFFEY, D. S. ROSENTHAL, G. PINKUS AND S. HELLMAN PATIENTS AND METHODS

The 25 patients accepted were either Stage III or Stage IV as determined by clinical examination, lymphangiogram (in nearly all cases), bone marrow biopsy and liver function tests. A palpably enlarged liver with abnormal liver function tests was considered sufficient to categorize a patient as Stage IV, as was bone marrow infiltration. Two patients had laparotomies, one of these demonstrating lymphomatous involvement of the bowel in addition to multiple nodal areas. Two patients demonstrated other extranodal disease in breast and lacrimal glands. Bone marrow biopsies were considered positive in 8 patients, with involvement ranging from one or 2 collections of abnormal " fissured " lymphocytes to sheets of lymphoid cells replacing 40% of the marrow. Nodular foci of lymphoid cells in themselves were not considered abnormal. Although 4 patients had grossly enlarged livers clinically, only one of these had abnormal liver function tests and was classified as Stage IV on that basis. Histology was reviewed by one of us (G.P.) and all cases classified by the Rappaport criteria (Rappaport, Winter and Hicks, 1956). Eleven of the 25 patients originally demonstrated diffuse histology, the remaining 14 presenting with nodular disease. On review, 3 patients originally classified as having diffuse histology were felt to have " vague nodularity" when the slides were submitted for special stains. Another patient had diffuse disease on initial biopsy, while a second biopsy showed nodular disease. Five patients, on review, changed from well differentiated to intermediate or poorly differentiated categories. In order to preserve comparability with a matched COP treated group for whom unstained slides were not available, the original histological designations for both groups are maintained in this report. Patients were treated on a 4 MeV linear accelerator without a beam stopper at a distance of 306 cm from the target to skin. The beam was nearly horizontal, directed to include the entire lateral projection of the patient, who sat on a stool in the position of Rodin's " The Thinker ". A calculated dose of 15 rad was delivered to the midplane of the pelvis. For most of these patients, treatment sides were alternated. However, recently we have treated both sides of the

patient at each session for better uniformity.

The dose distribution of the treatment set-up has been examined using thermoluminescent dosimeters in an Alderson Phantom and on patients. These measures indicate that the calculated dose to the pelvis is correct but that the head receives 21 rad per treatment. Treatment was planned for twice weekly to a total dose of 150 rad to the midplane of the pelvis; however, doses actually delivered ranged from 105 rad to 210 rad in a single course, depending on clinical response. Nine patients had treatment terminated or temporarily interrupted due to thrombocytopenia. The WBC remained adequate in all cases. Five patients were given additional local irradiation either before or after TBI. In order to compare TBI with drug treatment, a group of COP treated patients was matched for age, sex and histology to the TBI treated group. These patients were treated in the period immediately before the TBI treated group, beginning in early 1968. The treatment regimen consisted of cyclophosphamide 10 mg/kg plus vincristine 2 mg given i.v. weekly for 2 weeks, followed by a 2-week rest. Prednisone 50 mg orally/day was administered throughout the 4-week cycle. Cycles were repeated until 6 cycles were completed, following which patients were usually placed on single agent, oral maintenance therapy. RESULTS

The pattern of disease in the 25 TBI treated patients can be seen in Fig. 1. The 17 Stage III patients include 2 with extranodal disease, 5 patients with palpable spleens and 1 with an enlarged liver. In 8 Stage IV patients, 5 had palpable spleens and 3 had enlarged livers. Except for 3 patients with grossly palpable abdominal masses, most patients' para-aortic regions were assessed primarily by lymphangiography. Although 3 patients had disease present for one to 5 years before treatment, most had relatively short clinical courses. Evidence for progression and/or symptomatic disease was considered essential for treatment, and some patients were watched for several months before initiating treatment. All survivals were cal-

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culated from the day of first treatment, Survival not the date first seen. The treatment experience and survival of all patients can be seen in Fig. 2. Toxicity The longest survivor is now nearly 40 The toxicity of treatments was con- months in unmaintained remission, with fined to platelet depression. Nine of 25 no evidence of disease. Two patients patients had their treatment temporarily are dead, one without clinical evidence of withheld or permanently curtailed due disease. In 3 patients the disease has to thrombocytopenia. In 3 cases the recurred and they have been placed on platelet count dropped to 15,000/mm3 COP and are in remission. Three patients or below, and one of these patients was have had herpes zoster at some course in given platelet transfusions. Two of these their disease. Five additional patients, 3 patients demonstrated bone marrow who are either partial responders or have infiltration by lymphoma. The third recurred, have received a second course patient, however, had a negative bone of whole body irradiation. Altogether, marrow biopsy, yet has continued to be 18 of the 25 patients are living in remission thrombocytopenic for several months without clinical evidence of disease and following his therapy. In general, the without maintenance therapy. the one nadir of the platelet counts for all the Stage IV patient with documented liver patients was reached between 30 and disease underwent splenectomy for hyper46 days following the first treatment. splenism and an enlarged spleen and has This meant that the platelet low was remained in remission for the last 10 usually reached 2-3 weeks following months. completion of treatment, after which the Bone marrow involvement did not platelet count generally rose rapidly appear to confer an ominous prognosis toward normal. There were no instances and there was no clear-cut association of haemorrhagg secondary to thrombo- between stage and survival in these cytopenia in these patients, although advanced cases. More significant appear2 patients temporarily developed pete- ed to be the histology, with the nodular chiae. lymphomata performing better as a group The white blood cell count generally than the diffuse. Thirteen of 14 patients reached its low point somewhat later than with nodular histology demonstrated a the platelets but was not a significant complete response to treatment, the problem in any case. It tended to also fourteenth patient responding to a second return rapidly towards normal following course of TBI. Twelve of these patients a low reached about a month after the are in continuous, unmaintained remission end of therapy. Erythrocyte counts were for periods ranging from 2 to 39 months. very little affected and in only a few One failed at 22 months and has been in patients was a trend toward a decrease remission on COP for 4 months; the other noted 3 or 4 months following completing failed at 17 months and received a second therapy. Of the 25 patients, 17 reached course of TBI and remains in remission the planned dose of 150 rad or more. 5 months later. One patient was carried to 210rad and Of 11 patients exhibiting diffuse histoyet showed no depression in any of her logy, 7 were complete responders while haematological parameters. Eight pa- 4 partially responded to treatment. Three tients had their dose curtailed due to of these were placed on COP therapy at low platelets, at levels of 105-135 rad. 2, 3, and 7 months and 1 continues at Two of the 8 were given additional 10 months with active disease untreated radiation, bringing their dose total above due to low platelets. One of the partial 150 rad following recovery of the platelet responders failed promptly on COP and count. died at 7 months. Another patient died

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J. T. CHAFFEY, D. S. ROSENTHAL, G. PINKUS AND S. HELLMAN

of pneumonia at 12 months without clinical evidence of disease. Only 1 patient with diffuse disease had a prolonged disease-free survival, but the disease has recently recurred at 33 months. Figure 3 demonstrates the actuarial survival for all patients as well as diseasefree survival. Overall, survival is 87 % at 2 and 3 years. Disease-free survival can be seen to be 74% at 1 year and 55%

at 2 years. Patients who were re-treated

following relapse and are now continuing in unmaintained remission are considered as initial treatment failures despite their current status. Disease-free survival, therefore, means continuously free of disease since initial TBI. Disease-free survival as a function of stage can be seen in Fig. 4. Note that in these patients bone marrow infiltration

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did not influence the disease-free survival. Thus, patients with bone marrow involvement appear to enjoy survival comparable with patients with uninvolved marrow. On the other hand, when the disease-free survival is compared by histology, it can be seen that the nodular histology appears to be superior (Fig. 5). In this plot, disease-free survival among nodular patients remains at 65% through 3 years, whereas with diffuse histology diseasefree survival drops to 45 % by 8 months although, due to the small number of patients, these differences do not reach statistical significance. A comparison was made of those patients undergoing local boost irradiation in addition to the TBI versus those patients not undergoing such local irradiation. The numbers are small, since only 5 patients initially underwent boost therapy, but it appears that this sub-set may have a better survival, with all 5 patients disease-free at one year. Whether this is chance, patient selection or the result of treatment needs to be investigated further.

We have compared our group of selected patients with lymphosarcoma with a group of patients matched for age, sex and histology who were treated by multiple drug chemotherapy (COP). The result of this comparison can be seen in Fig. 6. Differences between these survival curves are not statistically significant due to the small numbers of patients involved, but it appears that TBI treated patients fare no worse and perhaps better, especially at the longer times, than COP treated patients.

Analysis of relapse An attempt was made to correlate the time to relapse following TBI with either the stage or the histology of the disease. Of the 9 patients who relapsed, 6 had Stage III disease while 3 had Stage IV disease. Six patients had diffuse disease, and relapsed at 1, 3, 7, 7, 7 and 34 months respectively. Three patients with nodular disease relapsed at 6, 18 and 22 months. With this small number of cases no clear pattern emerged. It did

448

J. T. CHAFFEY, D. S. ROSENTHAL, G. PINKUS AND S. HELLMAN

appear that diffuse disease relapsed more frequently and earlier than nodular disease. Nevertheless, some patients with diffuse disease enjoyed long disease-free survivals. Of the 9 patients who failed, 4 received a second course of TBI. Three of these are well at 2 months, 5 months and 7 months respectively. One patient died after failing on all treatment modalities. Platelet counts were noted to drop to lower levels and stay depressed for a longer period of time following a second course of total body irradiation; however, no patients have shown signs of bleeding or required transfusions. Three other patients were placed on COP after radiation failure and are well at 5 months, 8 months and 16 months. One patient with thrombocytopenia has had no further therapy and the remaining failure is currently on a second course of total body irradiation. DISCUSSION

The clinical course of lymphosarcoma is extremely variable, with a spectrum ranging from patients whose disease is manifest by only localized nodes present for many years without significant enlargement, to patients with a very rapid clinical course poorly responsive to treatment and resulting in death in a few weeks. The Rappaport classification appears to correlate more closely with the clinical course of the disease than older classifications; however, a really satisfactory and uniformly acceptable histological classification has yet to be achieved (Rappaport etal., 1956). Differences in the method of reporting make comparisons with older series suspect; nevertheless, it is of interest to see that there has been little, if any, improvement in survival in 30 years. Medinger and Craver in 1942, reviewing 10 years' experience with total body irradiation of the Heublein type, report a 50% survival at 38 months following onset of disease and 17 months following treatment in 30 cases classed as lymphosarcoma. They report an average survival in all patients of 1 18 months, with a

survival in those treated by local irradiation alone, a more selected group, of 12-4 months. However, the group receiving total body irradiation with or without irradiation, had an average survival of 24-2 months. This figure compares favourably with figures obtained in the ensuing 30 years and suggests either excellent selection of cases or perhaps some increased efficacy of the treatment. Bagley et al. (1972) have recently reported 35 patients (32 without previous therapy) treated by a COP programme. There were 57% complete and 34% partial responses, with 73% survival at 2 years. Four patients remain in complete remission, one for more than 32 months, and 4 unmaintained remissions relapsed between one and 2 years. Of the 35 patients, 29 had nodular disease. Reported toxicity in this COP treated group included hair loss, neuropathies, nausea and vomiting, and 5 patients with severe infections, one patient dying of bilateral pneumonitis. By comparison with these patients, our own 25 patients showed an 80% complete and 20% partial response rate. A 95% survival was seen at one year and 87% survival at 2 years. In all, 55 % of patients have remained disease-free since beginning of treatment. All survivals are calculated from onset of treatment. The lack of toxicity is a major potential advantage of body irradiation. In these patients it was confined to platelet depression and in only one case was transfusion given. There was no hair loss or nausea, and patients were able to continue working while on treatment. The total treatment time was generally 5-7 weeks, with patients making a total of 10-15 visits. One can only speculate at the mechanism of action of irradiation which demonstrates such dramatic effectiveness against lymphosarcoma cells at doses ordinarily considered to be homoeopathic. Lymphocytes are known to be an extremely sensitive class of cells and to die an intermitotic death, in sharp contrast to nearly all other classes of cells. The

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ADVANCED LYMPHOSARCOMA

mechanism of this event is unknown and literature in this area is scanty. Recent work in our own laboratory suggests that inability to repair intracellular sublethal or potentially lethal damage may play a significant role in lymphocyte sensitivity to irradiation (Helman and Timberlake, unpublished data). Schrek et al. (1962) have noted that the sensitivity of normal human lymphocytes to x-irradiation in vitro is somewhat variable using their technique of phase contrast morphological assessment as a measure of viability. Even greater variations in sensitivity were observed in human lymphocytic leukaemia cells, in which patients with " radioresistant " lymphocytes exhibited a median survival of only 4 months in contrast to those with " radiosensitive " cells who showed a median survival of 22 months. The varied clinical response in our group of TBI treated patients suggests that similar variations in sensitivity to x-irradiation may be found. While the response to multiple drug therapy and to x-ray therapy is generally parallel in patients, we have noted in several instances a marked disparity in response to drugs compared with irradiation, or vice versa. Perhaps by using TBI as one of the agents in a multiple drug programme advantage could be taken of differing sensitivities to such totally different kinds of systemic agents and a net gain in the therapeutic ratio could be realized. We are encouraged by the result in this small series of patients primarily treated by total body irradiation and are increasingly adding extended field and total nodal irradiation in those patients in whom there seems a reasonable prospect for long-term control. In the more disseminated cases, we are investigating ways of combining irradiation and drugs. CONCLUSION

It appears that total body irradiation is a highly effective agent in treatment of lymphosarcoma. Results in percentage

of remissions and duration ofunmaintained remissions and total survival compare favourably with results by other treatment modalities, including multiple drug chemotherapy (COP). Toxicity and morbidity experienced by the patient appear appreciably less when total body irradiation is used than with multiple drug chemotherapy. Low dose total body irradiation thus appears to be a highly effective and relatively non-toxic therapy and should be considered in the management of advanced nodular lymphosarcoma. Its effectiveness as a systemic agent makes it worth investigation as part of combination therapy in advanced lymphomatous diseases and perhaps in other diseases as well.

REFERENCES BAGLEY, C., DE VITA, V. T., BERARD, C. W. & CANELLOS, G. P. (1972) Advanced Lymphosarcoma: Intensive Cyclical Combination Chemotherapy with Cyclophosphamide, Vincristine and Prednisone. Ann. intern. Med. 76, 227. CHAOUL, H. & LANGE, K. (1923) Ueber Lymphogranulomatose und ihre Behandlung mit Rontgenstrahlen. Munch. med. Wschr., 70, 725. DESSAUER, F. (1907) Eine neue Anordnung zur Rontgenstrahlung. Arch. phy8. Med. Techn., 2, 218. HEUBLEIN, A. C. (1932) Preliminary Report on Continuous Irradiation of Entire Body. Radiology, 18, 1051. JONES, S. E., FUKS, Z., BULL, M., KADIN, M. E., DORFMAN, R. F., KAPLAN, H. S., ROSENBERG, S. A. & KIM, H. (1973) Non-Hodgkin's Lymphomas IV. Clinico-pathologic Correlation in 405 cases. Cancer, N. Y., 31, 806. JOHNSON, R. E., O'CONOR, G. T. & LEVIN, D. (1970) Primary Management of Advanced Lymphosarcoma with Radiotherapy. Cancer, N. Y., 25, 787. MEDINGER, F. G. & CRAVER, L. F. (1942) Total Body Irradiation. Am. J. Roentg., 48, 651. RAPPAPORT, H., WINTER, W. J. & HICKS, E. B. (1956) Follicular Lymphoma: Re-evaluation of its Position in the Scheme of Malignant Lymphomas, Based on Survey of 253 Cases. Cancer, N.Y.,9, 792. ROSENBERG, S. A., DIAMOND, H. D. & CRAVER, L. F (1960) Lymphosarcoma: A Review of 1269 Cases. Ann. intern. Med., 43, 877. SCHREK, R., LEITHOLD, S. L., FRIEDMAN, I. A. & BEST, W. R. (1962) Clinical Evaluation of an in vitro Test for Radiosensitivity of Leukemic Lymphocytes. Blood, 20, 432. TESCHENDORF, W. (1927) Uber Bestrahlung des ganzen menschlichen Korpers bei Blutkrankheiten. Strahlentherapie, 16, 720.

Advanced lymphosarcoma treated by total body irradiation.

Br. J. Cancer (1975) 31, Suppl. II, 441 ADVANCED LYMPHOSARCOMA TREATED BY TOTAL BODY IRRADIATION J. T. CHAFFEY, D. S. ROSENTHAL, G. PINKUS AND S. HEL...
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