STAGES IIB AND IIIB HODGKIN'S DISEASE Results of Combined Modality Treatment

ROBERT GOODMAN, MD, PETER MAUCH, MD, ANTHONY PIRO, MD, DAVID ROSENTHAL, MD,

MICHAEL GOLDSTEIN, MD, JAMES TULLIS, MD, AND SAMUEL HELLMAN, MD

Between April 1969, and December 1974,23 IIB and 26 IIIB surgically staged patients with Hodgkin's disease were treated at the Joint Center for Radiation Therapy. Stage IIB patients received either mantle and para-aortic-splenic pedicle, o r total modal irradiation (TNI) alone or with the addition of combina- tion chemotherapy. Relapse-free survival is 83% and overall survival 88%. Eleven patients received combination chemotherapy in addition to mantle and para-aortic irradiation, and both the relapse-free and overall survival are 100%. Of the stage IIIB patients, seven received TNI alone with four relapses, and 19 were treated with TNI and MOPP with two relapses. These relapse rates are significantly different ( p less than 0.05). The relapse-free and overall survival for all stage IIIB patients is 66% and 84% respectively. These data imply that irradiation alone is not adequate treatment for stage IIIB Hodgkin's disease, and that with the addition of combination chemotherapy both the disease-free and overall survival is similar to that of early stage Hodgkin's disease without systemic symptoms. The ideal management of stage IIB Hodgkin's disease is less certain; it is our plan to study the efficacy of combined modality treatment.

Cancer 40:84-89, 1977.

HE RELAPSE-FREE AND OVERALL SURVIVAL OF T patients with stages IIB and IIIB Hodg- kin's disease treated with radiation therapy alone is not sufficiently high to recommend con- tinuation of irradiation as the sole modality of treatment. 14 "A major advance in improving the survival of patients with advanced disease has been the use of combination chemotherapy re- sulting in increased survival in those patients previously thought to have a poor p rogn~s i s . ' ~~ Although survival has improved since the in- troduction of combination chemotherapy, there is as yet no generally agreed upon method of treatment Stages IIB and IIIB disease. Chemo- therapy alone, chemotherapy with the addition of a low dose irradiation to areas of previous involvement, high dose irradiation followed by chemotherapy and hepatic radiation in addition

Presented at the Eighteenth Annual Meeting of the Amer- ican Society of Therapeutic Radiologists, October 13-16, 1976, Atlanta, Georgia.

From the Joint Center for Radiation Therapy, the Depart- ments of Medicine of the Peter Bent Brigham Hospital, Beth Israel Hospital, the New England Deaconess Hospital and the Departments of Radiation Therapy and Medicine, Har- vard Medical School, Boston. MA.

Address for reprints: Robert Goodman, MD, joint Center for Radiation Therapy, 50 Binney Street, Boston. MA 02115.

Accepted for publication February 4, 1977.

84

to chemotherapy and/or radiation have all been advocated. ~ 3 7 * 4 1 0 9 1 8 1 4 1 6 - 1 8 It is the purpose of this study to report the results of the treatment of stages IIB and IIIB Hodgkin's disease pa- tients at the Joint Center for Radiation Therapy to determine whether any conclusion regarding therapy can be reached.

METHODS A N D PATIENT CHARACTERISTICS

All pathologically staged IIB and IIIB pa- t i e n t ~ ' ~ seen at the Joint Center for Radiation Therapy between April 1969, and December 1974 are included in this evaluation. Staging included chest radiography, whole lung tomog- raphy (if hilar nodes enlarged), bipedal lym- phangiography, biochemical evaluation, lap- arotomy and splenectomy. Staging was according to the Ann Arbor classification.6 Twenty-three patients were classified as stage IIB and 26 as stage IIIB. Three patients were subclassified as (E) because of a single area of extranodal disease contiguous to an involved lymph node region. There were 31 males and 18 females. Histologic types included two lym- phocyte predominance, 25 nodular sclerosis, 18 mixed cellularity, and four lymphocyte deple- tion. The median age of the combined group was 23 years (8-56). During this period of time,

No. 1 COMBINED MODALITY TREATMENT FOR HODCKIN'S DISEASE Goodman et a/ . 85

the treatment policy was not standardized and a TABLE 1. Evaluation of Chemotherapy

variety of reGmens was used. When patients received both radiation and combined chemo- therapy, in general, two to three cycles of chemotherapy (MOPP) was administered prior to the initiation of radiotherapy and was contin- ued after the completion of the irradiation until a total of six cycles was reached or toxicity pre- vented continuation. Of the 23 stage IIB pa- tients, l l received combined modality treat- ment, including radiation to the mantle and para-aortic-splenic pedicle regions in eight, while three received total nodal irradiation (TNI). Six patients received TNI only, and one received mantle and para-aortic-splenic pedicle irradiation only, five recieved TNI only, and one received mantle irradiation only with the addi- tion of combination chemotherapy.

Of the 26 patients with stage IIIB disease, 19 received TNI in addition to combination chemo- therapy. Six patients received TNI alone and one received mantle and para-aortic-splenic ped- icle irradiation alone. The radiation dose in all groups was 3500-4000 rad to each region ad- ministered at 150-200 rad per day, five days per week. Technical factors included simulation, di- vergent blocks, thermoluminescent dosimetric monitoring, the arms up position, and one field of treatment per day. A total of 14 patients had the mantle irradiation prior to laparotomy be- cause of bulky mediastinal disease. 's Of the en- tire group of patients recieving chemotherapy, seven received maintenance MOPP for varying periods of time up to one year following the completion of the initial six cycles. As of July 1976, the median follow-up period from the in- itiation of therapy was 32 months (22-73) in patients with IIB disease with a median follow- up from the end of drug therapy of 17 months (12-31). In those patients with stage IIIB dis- ease, the median follow-up from the initiation of therapy was 50.5 months (28-76) and a median follow-up from the end of chemotherapy was 30.5 months (1 1-47). Actuarial survival curves were calculated using the Cutler modification of the Rerkson-Gage technique.

RESULTS

Eleven patients with stage IIB disease re- ceived TNI or mantle and para-aortic-splenic pedicle irradiation in addition to combination chemotherapy, and none of these patients has relapsed (Table 1). One patient received mantle and combination chemotherapy, developed an extension of disease into the para-aortic and

Treatment Total number Number relapsed

Stage I I B hlANTLE + M O P P 1 1 KAD* + M O P P 11 0 KAD* ALONE 11 2

Stage I l I B KADt + M O P P 19 2 K AD' ALONE 7 4

* Mantle plus para-aortic and splenic pedicle irradiation

' Total nodal irradiation. or total nodal irradiation.

pelvic regions and subsequently died of active disease. Eleven received either TNI or mantle and para-aortic-splenic pedicle irradiation but no prophylactic combination chemotherapy; two of these patients developed relapsing disease and were placed on MOPP chemotherapy at the time of relapse. One has subsequently died of pneumocystis carinii pneumonia, and the other is presently alive without any evidence of disease 32 months after the initiation of MOPP chemo- therapy and 58 months after the initiation of all treatment (Table 2). Thus, of the 11 IIB pa- tients who were treated with MOPP in addition to mantle and para-aortic or TNI, the relapse- free and overall survival rates are 100%. Of the entire group of IIB patients, the relapse-free sur- vival is 83% (Fig. 1) with an overall survival of 88% (Fig. 2). There were no obvious determi- nants to predict the likelihood of relapse in pa- tients who did not receive prophylactic MOPP chemotherapy. Age, sex, histologic type, or bulk of disease did not appear to be associated with a worse prognosis (Table 3). Only the addition of combination chemotherapy was associated with the absence of relapsing disease, although with the small numbers analyzed, the difference be- tween the two groups of patients did not reach statistical significance.

Of the 26 patients with stage IIIB, eight failed to be cured of this disease after initial treatment. There were four true recurrences, two extra- nodal disseminations (one liver, one lung), and two patients who died without having relapsed, but of disease-related causes (one disseminated herpes zoster, one acute myelomonocytic leu- kemia). Both patients who died of disease- or treatment-related causes had received TNI as well as combination chemotherapy (Table 4). Of the six patients who relapsed, three are pres- ently alive without any evidence of disease, and one alive with evidence of disease after retreat-

86 CANCER J u l ~ 1977 Vol. 40

26 44 13 33 50 41 19 30 44

Sex Stage Histology

F F M M M M M M M

IIB IIB IIB IIIB IIIB IIIB IIIB IIIB IIIB

N.S. M.C. N.S. N.S. M.C. M.C. N.S. M.C. M.C.

TABLE 2. Relapses

Relapse Total survival Initial treatment (months) Location Type (months)

Rad 26 Pre-auric. Exten. 58 (NED)* Rad,' MOPP 20 Pelvis Exten. 21 (D. cd.): Rad 4 Breast E.N.I 9 (D. drd.)" Rad, MOPP 35 S.C.' True 64 (A. cd.)** Rad 33 Retroperit. True 60 (NED) Rad, MOPP 28 Infrahilar True 52 (NED) Rad 34 Mediastinum Hilum True 48 (NED) Rad 10 Lung E.N. 25 (D. cd.) Rad 4 Liver E.N. 6 (D. cd.)

* Alive without evidence of disease t Received only mantle irradiation * Dead with disease 0 Extranodal

'I Dead, disease related death, pneumocystis carinii q Supraclavicular

** Alive with disease

ment with MOPP. Those who relapsed have had a median follow-up since relapse of 15 months (2-29) (Table 2). There was only one significant determinant regarding risk of re- lapse; of the 19 patients who received TNI and MOPP, there were only two relapses whereas

there were four relapses out of a group of seven patients who had received TNI but no MOPP (p less than 0.05). There was a suggestion that age was associated with a greater risk of relapse; of six patients greater than 40 years of age, three relapsed. However, only two of the patients over

118 83%

' 40 It w

L 18 13 I I 8 3 2 I

I I IB 66%

2ol 1 I 1 I I I I 0 12 24 36 48 60 72

MONTHS

I oc

I-%

2ol t I I I I I I I

0 12 24 36 48 60 72 MONTHS

FIG. 1. Probability of relapse-free survival in months after FIG. 2. Probability of overall survival in months after the the initiation of treatment in all Stage IIB and IIIB patients. initiation of treatment in all Stage IIB and IIIB patients.

No. 1 COMBINED MODALITY TREATMENT FOR HODGKIN'S DISEASE Goodman et al. 87

40 had received prophylactic MOPP (Table 3). There was no difference in prognosis in relation- ship to clinical stage prior to laparotomy. There was no relationship between sex, timing of chemotherapy, or bulk of disease above or below the diaphragm and the risk of relapse (Table 3).

Similarly, histologic type did not influence prognosis; two of the 11 patients with nodular sclerosis histology and four of 14 with mixed cellularity failed. Of the two patients who died without evidence of relapse, the patient who de- veloped acute myelomonocytic leukemia did so 17 months after the initiation of her treatment and four months after the initiation of MOPP which had been given prophylactically. The sec- ond patient developed disseminated herpes zos- ter during the first cycle of prophylactic MOPP following the completion of TNI (Table 4).

Of the entire group of IIIB patients then, there was a 66% relapse-free survival (Fig. 1) and 84% overall survival (Fig. 2). In those pa- tients treated with combined modality, there was an 83% relapse-free survival and a 95% over- all survival. If one combines the 30 patients with stages IIB and IIIB who were treated with mantle, para-aortic or TNI as well as pro- phylactic MOPP, the disease-free survival in this group is 87% (Fig. 3) and the overall sur- vival, 97% (Fig. 4).

Hematologic tolerance to the chemotherapy in the patients receiving wide field irradiation was somewhat diminished. It was the philoso- phy of the medical oncologists to deliver a re- duced dose of the nitrogen mustard and pro- carbazine if there was leukopenia or thrombocytopenia rather than to delay treat- ment to await the return of the blood counts to higher levels. In those patients who received TNI, 75% of the anticipated dose of nitrogen mustard and procarbazine was delivered, 90% of the vincristine, and 100% of the prednisone. In those patients who had not had radiation to the pelvis, 90% of the anticipated dose of nitrogen mustard and procarbazine was delivered in ad- dition to 90% of the vincristine and 100% of the prednisone.

TABLE 3. Prognostic Factors Stage IIB + IIIB

IIB IIIB

Number Number Factor Number relapsed Number relapsed

Age <40 20 2 20 3 240 3 1 6 3

Yes 16 4 No 7 1

Yes 7 1 7 1 No 16 2 19 5

Yes 2 0 1 1 2 No 10 1 8 0

Bulk disease below diaphragm (IIIB alone)

Bulk mediastinal disease

MOPP split course

DISCUSSION Review of published data does not clearly in-

dicate the most effective treatment for Stages IIB and IIIB Hodgkin's disease. In the present series, there was no statistically significant dif- ference in either relapse-free or overall survival in stage IIB patients whether treated by radi- ation alone or in addition to combination chemotherapy. Nevertheless other series suggest that radiation therapy alone is associated with a sufficiently high relapse rate to suggest that it is not adequate as the sole form of therapy.'41' Several recent studies have grouped patients with IIB, IIIA, IIIB and IV disease, and some have included patients relapsing from previous therapy as well, making it difficult to evaluste the efficacy of combined modality treatment in stages IIB and IIIB specifically.

The introduction of combination chemother- apy for advanced Hodgkin's disease by DeVita et al. in 1965 was associated with an increased survival.'*8 The majority of those patients had Stage IV disease. A more recent report of pa- tients with Stage I11 (both A and B) treated by chemotherapy alone has a five-year survival of 68% and for all stages of patients with B symp- toms, 60%.g It is important to note that these patients were not staged by formal laparotomy and may then have elements of both under and

TABLE 4. Disease Related Deaths

Time Age Sex Stage Histology Initial treatment (months) Cause

40 F IIIB N.S. RAD, MOPP 5 Dissemenated Herpes zoster 56 F IIIU N.S. RAD, MOPP 19 Acute leukemia

88 CANCER JULY 1977 Vol. 40

80 18 1 2 9 5 3 2 I

- 07%

401

I 0 12 24 36 48 60 72

MONTHS FIG. 3. Probability of relapse-free survival in months after

initiation of treatment in Stage I I B and IlIB patients treated with combined modalities.

over staging when compared to series in which laparotomy is used for staging.

Prosnitz et al. have reported the results of combination chemotherapy employing five drugs in conjunction with 1500-2500 rad to re- gions where disease had existed initially in 80 patients with either advanced or relapsing dis- ease. Fifty-four patients out of the entire group remain in complete remission with a follow-up of 1-6 years, representing a survival of 68%. Only 17 of the 80 patients were previously un- treated Stage IIIB, and 13 of the 17 or 76% achieved a complete remission. It is not clear whether any of this particular group sub- sequently relapsed or died.

Moore et a/. reported 102 patients with pre- viously treated Hodgkin's disease stages I B through IIIB who were randomized to receive either TNI or TNI followed by six cycles of MOPP. '* '' One out of the 48 patients receiving sequential therapy relapsed, while 10 of the 45 receiving only radiation therapy relapsed. The median duration of follow-up from the end of combination chemotherapy was only 375 days. Thus far, the survival probabilities of the two groups are not statistically different.

Kun et al. have recently reported a series of 28 previously untreated IIB and IIIB Hodgkin's disease patients who were treated with all cycles of MOPP delivered prior to wide field irradia- tion. l2 The disease-free survival was only 61%' and the combined true and marginal recurrence rate was 14%. There was considerable morbidity associated with the treatment. Such results are quite dissimilar to those reported from Stanford where MOPP was given following the radi- ation'* l7 or in this report where the MOPP was divided both before and after the irradiation.

Two groups of investigators have observed a high incidence of relapse in sites of previous involvement in patients with advanced Hodg- kin's disease treated by chemotherapy alone. lql' It is the recommendation of these groups to consider the use of radiation therapy to sites of previous involvement but the results of such treatment are not yet available.

There are two reports describing the risk of second tumors in patients treated with a combi- nation of chemotherapy and irradiation.%' We have one patient with acute myelomonocytic

I00

80

v 60

%

$ 40

20

2 2 9 2 4 19 14 I I 7 3 2 I

97 %

0 12 24 36 48 60 72

Moms FIG. 4. Probability of overall survival in months after the

initiation of treatment in Stages IIB and IIIB patients treated with combined modalities.

No. 1 COMBINED MODALITY TREATMENT FOR HODGKIN’S DISEASE Goodman et al. 89

leukemia. Such a low incidence of leukemia may be quite acceptable considering the morbidity and mortality from advanced Hodgkin’s disease, although a longer period of follow-up is neces- sary to assess the true risk of second malignancy. It may be that the risk of second tumors is low when chemotherapy is initiated after only a short interval following the completion of irra- diation rather than when given at the time of relapse. ‘

We continue to perform staging laparotomy and splenectomy in patients who clinically ap- pear to have Stages IIB and IIIB Hodgkin’s disease. Aside from establishing the presence or absence of disease in the liver, we feel that sple- nectomy allows smaller radiation fields, result- ing in less morbidity associated with in- fradiaphragmatic irradiation. Since we believe that pelvic irradiation need not be delivered in patients with supradiaphragmatic Stage IIB dis- ease, the information resulting from laparotomy is necessary before omitting the pelvic field.

It is our current policy to continue lap- arotomy, mantle and para-aortic-splenic pedicle irradiation or TNI with the addition of combi- nation chemotherapy in pathologic stages IIB and IIIB Hodgkin’s disease, respectively. Since our patients were not randomly allocated to the different treatment alternatives, we have ques- tioned the comparability of the treatment groups. Those treated with combination chemo- therapy did not appear to have less disease. However, a large number of the patients over 40 received no chemotherapy. Thus, these results must be interpreted with caution. However, the very high relapse-free and overall survival prob- abilities have resulted in all current IIB and IIIB patients being treated in this combined fashion. Because the relapse-free survival results are equal to those obtained in early stage Hodgkin’s disease“ and are better than those seen for Stage IIIA patients in our institution treated with TNI alone, we have adopted this plan of combined treatment for Stage IIIA patients as well.

REFERENCES

1 . Aisenberg, A., and Qazi, R.: Improved survival in Hodgkin’s disease. Cancer 37:2423-2428, 1976.

2. Arseneau, .J., , Sponzo, R., Levin, D. el al.: Non- lymphomatous malignant tumors complicating Hodgkin’s disease. N . Engl. J . Med. 287:1119-1122, 1972.

3. Bonadonna, G., Uslenghi, C., and Zucali, R. : Recent trends in the medical treatment of Hodgkin’s disease. Eur. J . Cancer 1 1 :251-266, 1975.

4. Canellos, G., Arseneau, J., DeVita, V. el al.: Second malignancies complicating Hodgkin’s disease in remission. I,ancet 1 :947-949, 1975.

5. Carbone, P., Kaplan, H., Musshoff, K. et a f . : Report of the committee on Hodgkin’s disease staging and classifica- tion. Cancer Res. 31:1860-1861, 1971.

6. Cutler, S. J., and Ederer, F.: Maximum utilization of the life table method in analyzing survival. J . Chron. Dzs. 8:699-711, 1958.

7. DeVita, V., Serpick, A., and Carbone, P.: Combina- tion chemotherapy in the treatment of advanced Hodgkin’s disease. Ann. Intern. Med. 73:881-895, 1970.

8. DeVita, V., Canellos, G., and Moxley, J. : A decade of combination chemotherapy of advanced Hodgkin’s disease. Cancer 30:1495-1504, 1972.

9. DeVita, V., and Canellos, G. : Personal cornmunica- tion.

10. Frei, E., Luce, J. et al.: Combinationchemotherapy in advanced Hodgkin’s disease. Ann. Intern. Med. 79:376-382, 1973.

1 1 . Goodman, R., Piro, A., and Hellman, S.: Can pelvic irradiation be omitted in patients with pathologic stages IA

and IIA Hodgkin’s disease? Cancer 37:2834-2839, 1976. 12. Kun, L., DeVita, V., Young R., Johnson, R.: Treat-

ment of Hodgkin’s disease using intensive chemotherapy followed by irradiation. Int. 3. Radiat. Oncol. Biof. Phys. 1 :619-626, 1976.

13. Lowenbraun, S., DeVita, V., and Serpick, A,: Combi- nation chemotherapy with nitrogen mustard, vincristine, procarbozine and prednisone in previously treated patients with Hodgkin’s disease. Blood 36:704-716, 1970.

14. Moore, M., Bull, J., Jones, S., Rosenberg, S., and Kaplan, H. : Sequential radiotherapy and chemotherapy in the treatment of Hodgkin’s disease. Ann. Intern. Med. 77:l-9, 1972.

15. Piro, A., Weiss, D., and Hellman, S.: Mediastinal Hodgkin’s disease: A possible danger for intubation anes- thesia. Int. J . Radial. Oncol. Biol. Phys. 1:415-419, 1976.

16. Prosnitz, L., Farber, L. et al.: Long term remissions with combined modality therapy for advanced Hodgkin’s disease. Cancer 37:2826-2833, 1976.

17. Rosenberg, S., Moore, M. et al.: Combination chemo- therapy and radiotherapy for Hodgkin’s disease. Cancer 30:1505-1510, 1972.

18. Rosenberg, S., and Kaplan, H.: The management of Stages I, I1 and I11 Hodgkin’s disease with combined radio- therapy and chemotherapy. Cancer 35:55-63, 1975.

19. Young, R., Canellos, G., Chabner, B., and DeVita, V. : Patterns of relapse after complete remission in Hodgkin’s disease treated ‘with MOPP chemotherapy. Prac. Am. Sac. Clin. Oncol. 16:249., 1975.

.