TREATMENT OF CANCER WITH INTERFERON AND RADIOTHERAPY

Abstract: Radiation-sensitive human cancers are treated with combined interferon and radiation therapy. Use of the interferon for the manufacture of an appropriate medicament is disclosed.

Description: " TREATMENT OF CANCER WITH INTERFERON AND RADIOTHERAPY!' BACKGROUND OF THE INVENTION The interferons represent a group of ' biologically active glycoproteins with proven anti-viral and anti-neoplastic properties. Several subtypes of interferon have been defined based upon differences in antigenic and biological properties. The interferon subtypes are alpha interferon, beta interferon and qamma interferon. Advances in biotechnical research in the past 10 years have resulted in the production of highly purified recombinant D A interferons. Clinical studies have shown that when used as a single agent, the interferons have antitumor activity in e.g. renal cell carcinoma, melanoma, indolent forms of non-Hodgkin's lymphoma, Kaposi's sarcoma and hairy cell leukemia. Other tumors including ovarian carcinoma and glioblastoma multiforme appeared to be less responsive to interferon. All subtypes of interferon are not active against all the listed tumors. Radiation therapy is a mainstay in modern cancer treatment with proven efficacy in many human tumors. There is, however, always a need for continued improvement in ef ectiveness of such treatment. Among the attempts to improve the efficacy of radiation treatment are efforts to develop radiation sensitizers or potentiators which enable the radiation to cause increased tumor destruction. Despite numerous laboratory and clinical studies, no sinqle agent has, to date, emerqed as the optimal radiation sensitizer. There have been a small number of studies in the laboratory involving interferon and radiation therapy, however, the results were inconclusive. Dritschilo et al., Am. J. Clinic. One. 5_ 79 (1982) studied the effect of IFN on the radiation response of mouse 3T3 cells in tissue culture. A soecies specific enhancement of radiation killinq of 3T3 cells irradiated in the presence of mouse L-cell interferon was observed as a reduction in the shoulder portion of the cell survival curve. Split-dose experiments designed to test for chanπes in sub-lethal radiation injury repair failed to demonstrate an inhibitory interferon effect. Dritschilo et al., postulate that interferon potentiates radiation injury possibly by inhibiting the ability of the cultured cells to accumulate sub-lethal radiation injury. Namba et al., Cancer 54, 2262 (1984) confirmed the Dritschilo et al., observations in a study of the combined use of interferon and radiation therapy using HeLa cells. Gould et al., J. Interferon Research _4_ 123 (1984) observed in vitro radiosensitization of human bronchogenic carcinoma with beta interferon but not with alpha interferon. Gould et al. noted that the deqree of radiosensitization of the various interferons paralleled their anti-proli rative effects when used alone on the bronchogenic cell lines. Nevertheless, Gould et al . concluded that the ant-neoplastic effects of the combined use of interferon and radiation were supra-additive indicating radiosensitization. eder an et al., Acta Radioloqica Oncology, 21 , 231 (1982) observed enhanced growth retardation in human qlioma cell cultures followinq combined therapy in comparison to interferon and radiotherapy used alone. ederman et al. attributes their results to the additive antineoplastic effect of the radiation and interferon but could not confirm radiosensitization. Combined radiation and interferon studies have not been reported in animal model systems, rimarily because of the species specificity of interferon; Lvovsky et al., Int. J. Rad. One. o. Phys. _l_l_, 1721 (1985) observed enhanced tumor control usinq the interferon inducer, ooly ICLC and radiation, and radiation in the mouse Lewis lung tumor model. A delay in tumor reqrowth and a prolonged duration of survival were observed in the inducer plus radiation animals as compared to either inducer or radiation alone. Mahalev et al . , J. Bio. Res .Modifiers _3_ 19 (1984) reported a phase I study of t'->e combined use of interferon and radiation therapy in ine patients with anaplastic glioma followinα subtotal resection. Patient survival was comparable to that for a matched πrouo with combined RC U and radiation therapy. Other reports show unexpected increases in toxicity when combined therapv is used. Real et al., J. Bio. Resp. Modifiers, _4_, 141 (1985) reported severe oral cavity mucositis in two patients with Kaposi's sarcoma reouirinq cessation of radiotherapy. Mattson et al., J. Biol. eso. Modifiers __, 18 (1985) reported that the concomitant use of interferon and radiotherapy has been associated with an increased incidence of radiation pneumonitis in patients with small cell carcinoma. SUMMAPY OF THE INVENTION This invention relates to a method of treating radiation sensitive human cancers such as carcinomas and sarcomas by concomitantly administering radiation with an interferon radiation sensitizer. The method comprises administering to a patient with a radiation sensitive cancer sufficient amount of an interferon radiation sensitizer to effectively sensitize the cancer to radiation, then administer radiation in standard amounts. As used herein "interferon" includes natural and recombinant alpha (leucocyte) and beta (fibroblast) interferons, but alpha interferons are preferred. As used herein, "alpha interferon" means a natural or recombinant interferon exhibiting biological properties similar to those of human leucocyte interferon. A number of alpha species are known which are usually designated by a numeral after the Greek letter designation, and all are contemplated for use in this invention as radiation sensitizers. Preferred forms of alpha interferon for use in this invention are alpha-1 and alpha-2 interferons. Particularly preferred is alρha-2 interferon and most preferred is alpha-2 interferon prepared by reco binant- DNA methods, the so-called recombinant-DMA alnha-2 interferon. Recombinant-DNA alpha-2 inter f eron may be prepared, for example, as disclosed bv Naqata et al., Nature, 284, 316 (1980) and in European Patent 32,134. DETAILED DESCRIPTION This invention provides a method for concomitantly treating radiation sensitive cancers such as sarcomas and carcinomas with radiation sensitizing interferon and standard radiation in a regimen which reguires shorter radiation treatment times, thus amelioratinq side effects ordinarily associated with radiation treatment. The invention will hereafter be described usinq as an example the preferred recombinant DNA alpha-2 interferon, desiqnated IFN. I have found that three-times-per-week administration of from 2x10° to 5x10 International Units of IFN per square meter of tumor followed by administration of standard amounts of radiation to a patient with a radiation sensitive cancer is well tolerated and results in reduction and elimination of tumors. The preferred mode of administration of IFN is by injection, preferably subcutaneously, administered approximately two hours before radiation. The radiation is administered according to this invention by standard techniques with standard meqavoltaqe eαuioment, such as AECL Theratron 80, Varian Clinac 4 or Varian Clinac. The maximum size of the radiation portal should be no qreater than 300 cm . A suitable does is between about 15 Gy and 35 Gy, with the specific dose dependent on the area of the body treated. Thus, a dose to the spinal cord would be about 35 Gy, whereas a dose to the bilateral kidneys would be about 15 Gy and to the whole liver 20 Gy. Breaks in the therapy are at the discretion of the clinician takinq into con ideration the patients tolerance for radiation therapy. The injectable compositions of I^N are made by conventional means. Thus, they can be made with sterile distilled water or buffered solutions and the like containinq, e.g. Preservatives. Tests in the clinic demonstrating this invention were conducted as follows: METHODS AND MATER IALS Patient Population Sixteen patients were enrolled in the study of the combined use of aloha-2 recombinant interferon and radiation therapy conducted at the Georgetown Universitv Hospital. Patients were declared eliσible for participation if they had histoloqical confirmation of an advanced unresectahle or etastatic carcinoma or sarcoma and a life expectancy of at least three months. Of the 16 patients, 8 were male. The mean aqe was 51 years with a ranσe of 43 to 76. Fifteen of the 16 patients had histoloqical diaqnosis of epithelial carcinoma with primaries located in the lung, esophaqus, pancreas, cervix, and kidney. One patient had bony metastasis and a soft tissue mass secondary to multiple myeloma. Of the 16 patients, 14 are available for analysis. Two patients were declared inevaluable because they were unable to complete the rari -.therapeutic course. All patients were removed r m prior hormonal therapy or chemotherapy two to four weeks prior to beqinninq the protocol. Study Design Prior to enrollment, all patients were throuqhly examined and their disease clinically staqed usinq chest x-rays, computerized tomoσraohv, EKG, he atoloqic and blood chemistries. Clottinq studies includinq total fibrinoαen determination, D T , PT, IT, and fibrin deqradation products, were conducted. Thereafter, each patient was seσuentially assioned to qroups consistinq of six subjects each which was then further subdivided into two suboroups of three patients each (Subgroups A and B). Each group of six patients received the same dose of alpha-2-interferon which was escalated in each succeedinq group. The doses studied were 2.0χlO β IU/m 2 and 5.0xl0 6 IU/m 2 . Doses higher than 5.0xl0 α u/m were not used because they are toxic. Within a given groun, one subqrouo (Subgroup A) received the αiven interferon dose subcutaneouslv five times per week in conjunction with the radiotherapy. The re g aining subgroup (Subqroup B) received the same IFN dose subcutaneouslv three times per week (M,W,F). The daily dose of interferon was administered two hours prior to radiation therapy in order to allow for adeαuate serum levels at the time of radiation administration. The combined usaqe of interferon and radiation was continued unless interrupted by siqnificant treatment toxicitv or patient resignation from the protocol. The interferon dosage was adjusted in the event of granulocytopenia less than 1500 cells per m depending on the platelet count with reduction in dosaπes ranginq form 15 to 25%. interferon administration was temporarily stopped in all cases involving a qranulocytopenia count of less than 1000 or a platelet count of less than 50,000. Adminis ration of interferon was resumed when the involved patient showed evidence of hematologic recovery. Radiation therapy was administered usinq standard radiation technique and meqavoltaqe equipment (AECL Theratron 30, Varian Clinac 4 or Varian Clinac 13). All fields were simulated and "shrinkinq field technique" was used, when possible in accordance with established radiotherapeutic principles. The maximum size of the radiation portal was limited to 300 2 c with appropriate shieldinq to surrounding normal tissue using individually manufactured blocks. The dose to the spinal cord was limited to 35 Gy, to the whole liver to 20 Gy, and to the bilateral kidneys 15 Gy, respectively. Radiotherapeutic breaks in treatment lastinq at least one week were instituted at the discretion of the radiotherapist in accordance with the patient's overall tolerance to treatment. Toxicity Evaluation and Response Criteria Each patient was viqorously monitored for earlv siqns of toxicity as well as radioqraphic evidence of clinical e ectiveness throuπhout the treatment course and on a regular basis thereafter. Methods of evaluation included frequent physician examination, a reqular scheduled performance of laboratory procedures includinq hematoloqic, serum chemical, and clottinq studies. Radioqraphic studies included chest x-ravs and CT scans as appropriate. Toxicity was qraded in accordance with the World Health Orqaniza on's recommendations for gradinq of acute and subacute toxicity. Performance status was graded from zero to four with complete disability beinq defined as four. Tumor response was determined by means of serial radioqraphic studies. Areas of referenced tumors were determined by multiplication of the lonqest diameter by the qreatest perpendicular diameter. Complete response was then defined as the disappearance of all measurable disease determined bv observation separated bv at least four weeks with the appearance of no new lesions within the radiation portal. Partial response was a 50% decrease in the referenced tumor mass and stable ϋsease was defined as a less than 50% decrease in tumor size, or less than 25% increase. A tumor αrowth larπer than 25% was declared proqressive disease. Results No specific differences in patient tolerance was noted at IFN doses between 2xlO G and 5xl0 6 IU/m 2 . The three-day-per-week reqi en was better tolerated as evidenced by treatment related toxic side effects and the ability of the patients to complete the planned irradiation course. The treatment related toxic side effects in the patients on the five-day-a-week reqi en resulted in unsatisfactory patient tolerance of both I^M and radiation therapv. The patients on the tri-weekly regimen were able to tolerate 100% of the planned dosaqe of IFN and 86% of the planned radiation treatment dose, whereas the patients on the five days per week reqimen were able to tolerate only 22% of the oriqinally planned IFN dosaqe and only 44% of the planned radiation treatment dosaqe. Tumor response was determined one month followinq completion of therapy. Complete and partial responses were observed in six patients and no chanqe was observed in eiqht patients. No patients had tumor proqression. Thus, the results of the clinical study indicate that the combined IFN and radiation therapy approach is feasible. Maximum tolerated dose and schedule of recombinant DNA alpha-2-interferon given subcutaneously in conjunction with daily radiation was 6 three-times-per-week at 5.0x1 IU/m . This is superior to daily administration of IFN in conjunction with daily radiation treatment.

Claims: CLAIMS ; -10- 1. A method of treating radiation-sensitive human cancers in patients in need of such treatment which comprises concomitantly administering to such patients a radiation-sensitizing interferon and radiation. 2. The method of claim 1 wherein each dose of interferon administered is between 2.0x10° IU/m 2 and 5.0xl0 6 IU/m 2 . 3. The method of claim 2 wherein the interferon is administered subcutaneously three days a week at a time on those days prior to radiation therapy. 4. The method of claim 3 wherein the radiation in doses from 15 to 35 Gy is administered five days a week including those days on which interferon is administered. 5. The method of any of claims 1 to 4 wherein the interferon is alpha-2-interferon, preferably recombinant DNA-alpha-2-interferon. 6. Use of a radiation-sensitizing interferon for the manufacture of a medicament for effective combined therapeutic treatment of radiation-sensitive human cancers by administration of said radiation-sensitizing interferon and radiation. 7. Use as claimed in claim 6, characterized by administration of individual doses of interferon containing between 2.0xl0 6 IU/m 2 and 5.0xl0 6 IU/m 2 . 8. Use as claimed in claim 7, characterized by the subcutaneous administration of interferon three days a week at a time on those days prior to radiation therapy. 9. Use as claimed in claim 8, characterized by administration of radiation in doses from 15 to 35 Gy five days a week including those days on which interferon is administered. 10. Use as claimed in any of claims 5 to 9, characterized in that the interferon is alpha-2- interferon, preferably recombinant DNA-alpha-2- interferon.

Inventors: BONNEM ERIC M, BONNEM, ERIC, M.
Applicants: SCHERING CORP, SCHERING CORPORATION
Application year: 1987
Main classification: A61K45
IPC codes: A61K38, A61P35