,nt.,.&&,ti,,n OncdogyBiol.Phys.. 1976,Vol. 1.p~.803-801. PemamonPrrSs. ~~~~U.~.A.

RADIATION DOSES FOLLOWING INTENSIVE CHEMOTHERAPY IN THE TREATMENT

OF HODGKIN’S DISEASE

LEONARD R. PROSNITZ, M.D. Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar

Street, New Haven, CT 06510, U.S.A.

The combination of radiation therapy and multiple agent chemotherapy is becoming increasingly popular, particularly in the man- agement of Hodgkin’s disease and other lymphomas, but also in a wide variety of malignancies-childhood cancers, carcinoma of the ovary, testicular carcinoma, to name a few. The evidence is increasing, however, that such combined modality treatment has to be carried out with considerable caution to avoid untoward effects on normal tissues.

The subject recently has been reviewed extensively by Phillips and Fu.’ Radiation injury may be enhanced by a variety of cancer chemotherapeutic agents; however, the worst offenders appear to be the antineoplastic antiiiotics, particularly actinomycin D and adriamycin. Such enhancement may occur whether drugs are given before, concurrently, or after radiotherapy. It is impossible to predict on theoretic grounds the extent to which radiation injury may be augmented by specific drugs, but a variety of animal and clinical data show an increase in the dose effect from 10 to 80% in normal tissues. When the normal tissues in question are vital ones such as the heart, lungs and intestine the radiotherapist should be especially cautious. Wara and Phillips have suggested, for exam- ple, a maximum whole lung does of 1500 rad (g-10 fractions) when chemotherapeutic drugs have been or will be used, as opposed to 2500 rad when no drug therapy is contemplated.’ In addition the combination of drugs and radia- tion appears to increase considerably the risk of a second malignancy.’

Unfortunately, little data are available con-

cerning the enhancement of radiation effect on human tumors by antineoplastic agents. Whether or not the therapeutic ratio is altered favorably remains to be seen.

In the present issue of this Journal Kun et al. present additional evidence for the en- hancement of normal tissue radiation injnry by chemotherapeutic agents. In a small series of patients with Stage IIB and IIIB Hodgkin’s disease, MOPPt chemotherapy followed by full dose radiotherapy resulted in serious radiation injury, including 4 deaths, in 15 of 28 patients. There were 5 patients who developed radiation pneumonitis, 2 with pericarditis, 2 with severe intestinal injuries (one of whom had a transverse myelitis also), 3 patients with excessive subcutaneous fibrosis, 2 patients with disseminated herpes xoster (one of whom subsequently developed acute leukemia as well) and one patient with a broncho- esophageal fistula. This contrasted with 2 patients with radiation pneumonitis (both of whom had massive mediastinal disease) and no other serious complications in 55 patients who were treated with radiation alone at the same institution.

Apart from the risks involved in the treatment of Hodgkin’s disease with full doses of both chemotherapy and radiation, conven- tional doses of radiation probably are not necessary. Since the demonstration 10 years ago that approximately 4OOOrad in 4 weeks’ time was required to produce 95% local control,3 radiotherapists have given this amount in most instauoes when they were treating a patient with Hodgkin’s disease, no matter what the stage. In advanced Hodgkin’s

tMOPP = Nitrogen mustard, vincristine, procarbazine, prednisone.

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804 Radiation Oncology 0 Biology 0 Physics 1976. Vol. 1, Number 7 and Number 8

disease, however, when both chemotherapy and radiotherapy are planned, it would seem reasonable to assume a certain cell kill with drugs and accordingly use a smaller dose of radiation. A patient with Stage IIIB disease, for example, presumably has disease in extranodal sites and is therefore not suitably treated with radiation alone. If cure is to be achieved, chemotherapy must eradicate these occult extranodal foci. At the same time, the number of cells in clinically evident foci of disease wil3 be reduced, but one would amicipate chemotherapeutic failure in these sites of bulk disease, as has, in fact, been demonstrated.z Here radiotherapy can be quite helpful, but since we are potMating a certain cell kill by chemotherapy, the doses of radiation m are far less than the usual 4000 rad; 1500-2000 rad will su5ce. Further- more such doses can be given safely to organs such as lungs or liver if they are the sites of bulk disease.

kin’s disease who were treated with combina- tion chemotherapy and low dose radiation at Yale, 60 achieved complete remission, but more impormnt, only 5 of the 60 have relapsed. The cumulative survival of the complete responders is 90% at 5 years. No serious radiation toxicity of the type described by Kun was encountered with the exception of 1 patient who developed acute myelocytic leukemia.6 Relapse within the irradiated field after these low doses has not been a significant problem.

The detailed rationale and cellular kinetics behind this argument have recently been pub- lished.’ Of 80 patients with advanced Hodg-

The principles descriid apply to other situations besides lymphomas. If both chemotherapy and radiation are being given because of a very high risk of disseminated disease and if the chemotherapy is effective, the dose of radiation can be reduced below that which is necessary for local control with radiation alone. We would like to urge both radiotherapists and medical oncologists to consider these data in the phuming of combi- nation chemotherapy-radiotherapy treatment programs for Hodgkin’s disease as well as other mabgmmcies,

REFERENCES 1. Camlbs, G.P.. Amenau, J.C., DeVita, V.T., et 5. Pros&x, L.R., Farber, L.R., Fischer, JJ., et al.:

d: !3ecoad malipnancici? compiicatjng Hodg- Low dose radiation therapy and combination kinb di8eam in remission. L.ancct 947-949, chemotherapy in the treatment of advanced 1975. Hodgkin’s dimease. Radiology NV: 187-193,

2. Frci, E., Lute, J.K., Gambie, J.F., et d: 1973. Co&in&on chemotherapy in advanced Hodg- 6. Prosnitz. L.R.. Farber, L.R., Fischer. J.J., et al.: kin’s disease. Ann. Intern Med. 19: 376-382, Long term remissions with combined Jnodality 1973. therapy for advanced Hodgkin’s disease. Cancer

3. Kaplan, H.S.: Evidence for a tua~oricidal dose to be published. level in the radiothcmpy of Hodgkin’s disease. 7. Wara WM., Phillips, T.L., Margob, L.W., et Cancer Res. 26: 1221-1224, 1966. 1: Radiation pneumonitis-A new approach to

4. Phillips, T.L., Fu, K.K.: Quantilkatioa of the derivation of time-dose factors. Cancer 32: combined radiation therapy and chemotherapy 547-a& 1973. effects on critical aormal tissues. Cancer 37: 11861200,1976.