- Email: [email protected]
Phase I combined modality clinical trial of alpha-2-interferon and radiotherapy
Int. J. Radiation Oncology Bid. Phys.. Vol. 12, pp. 1453-1456 Printed in the U.S.A. Au rights reserved.
Copy&t0
0360-3016/86 $3.00 + .OO 1986 Pergamon Journals Ltd.
0 Session VI
PHASE I COMBINED MODALITY CLINICAL TRIAL OF ALPHA-ZINTERFERON AND RADIOTHERAPY J. TORRISI, M.D.,’ C. BERG, M.D.,’ K. HARTER, M.D.,’ E. LVOVSKY, M.D.,3 K. YEUNG, M.D.,2 P. WOOLLEY, M.D.,2 E. BONNEM, M.D.4 AND A. DRITSCHILO, M.D.’ ‘Department of Radiation Medicine, ‘Department of Medical Oncology, Georgetown University Medical Center, 3800 Reservoir Road, N.W., Washington, D.C. 20007; 3The Genesee Hospital, Rochester, NY 14607; 4Schering Corporation, Kenilworth, NJ 07033 Sixteen patients were enrolled in a Phase I study of the combined use of recombinant DNA alpha-Zinterferon (IFN) and radiation therapy, conducted at the Georgetown University Hospital (GUH) from February 1,1984 to September 20,196 Escalating IFN doses ranging from 2.0 X lo6 IU/m* to 5 X lo6 IU/m* were administered to groups of six patients per IFN dose level. Three patients at each dose level were treated on a S-day-a-week schedule and three patients were treated on a 3-day-a-week schedule. Significant toxicity including dehydration, infection, deep vein thrombosis, and myocardial infarction was noted throughout in patients receiving IFN five times per week, with eight of nine requiring hospitalization during the treatment course. There was one treatment-related death. In the five-times-per-week group, only 22% of patients tolerated the full initially planned IFN dosage and 44% tolerated the full initially planned radiation dosage, compared to 100 and 86%, respectively, in the threetimes-per-week group. A tolerance dose and schedule of 5.0 X lo6 IU/m* of alpha-a-interferon administered subcutaneously three-times-per-week in conjunction with standard radiotherapy has been identified for use in future combined modality trials. Radiotherapy, Interferon, Combined radiotherapy-chemotherapy, INTRODUmION
Radiation sensitizer.
IFN and radiation therapy conducted at the Georgetown University Hospital from Feburary 1, 1984 through September 20, 1985. Patients were declared eligible for participation, if they had histological confirmation of an advanced unresectable or metastatic carcinoma or sarcoma and a life expectancy of at least 3 months. A poor performance status, prior history of cardiac arrhythmia or failure, central nervous system malignancy, previously diagnosed clotting disorder, history of previous irradiation to the spinal axis or previous exposure to IFN were considered grounds for ineligibility. The clinical characteristics of the 16 patients are shown in Table 1.
Radiation therapy and interferon are used in the treatment of cancer. Recent laboratory studies have suggested that IFN has sensitizing properties, when used in combination with radiotherapy. 4,6,9~‘3~14 The clinical efficacy, as well as, the toxicity of the combined use of radiotherapy and IFN in humans have not been well-studied. Case reports of enhanced normal tissue toxicity in patients receiving radiation therapy, incidentally to IFN treatment, suggest that a formal evaluation of patient tolerance to the combined modality treatment is needed.‘*,16 Consequently, a Phase I clinical trial was conducted at the Georgetown University Hospital to study the combined use of radiation therapy and Schering alpha-2 recombinant DNA IFN. Factors including the optimal schedule of administration, dose, toxicity, patient tolerance, and anti-tumor efficacy were addressed.
Study design
Sixteen patients were enrolled in the Phase I study of the combined use of Schering alpha-2 recombinant DNA
Prior to enrollment, all patients were thoroughly examined and their disease clinically staged using chest X rays, computerized tomography, EKG and hematologic and blood chemistries. Clotting studies including total fibrinogen determination, PTT, PT, TT, and fibrin degradation products were screened. Thereafter, each patient was sequentially assigned to groups consisting of six subjects, then further subdivided into two subgroups of three
Presented at the Chemical Modifiers of Cancer Treatment Conference, Clearwater, Florida, 20-24 October 1985. Reprint requests to: J. Torrisi.
Acknotiledgement-We wish to thank Ms. Sandra Hawkins for her contribution in the preparation of this manuscript. Accepted for publication 25 February 1986.
METHODS
AND
MATERIALS
Patient population
1453
1454
I. J. Radiation Oncology 0 Biology??Physics Table 1. Patient characteristics Number enrolled Age (mean) Performance status (mean) Male/female Tumor sites Lung Esophagus Pancreas Cervix Renal Base of skull/orbit
:: (43-76) 0.9 (O-2) 818 9 3 1 1 1 1
patients each (Subgroup A and B). Each group of six patients received the same dose of alpha-Zinterferon, which was escalated in each succeeding group. The doses to be studied included 2.0 X IO6II-I/m*, 5.0 X lo6 III/m*, 10.0 X lo6 III/m*, 20 X lo6 IU/m*, and 30 X lo6 III/m*. Actual patient accrual was terminated at the 5.0 X lo6 III/m* level, because of toxicity. Within a given group, one subgroup (Subgroup A) received the given IFN dose subcutaneously five times per week in conjunction with the radiotherapy. The remaining subgroup (Subgroup B) received the same IFN dose subcutaneously three times per week (M, W, F). The daily dose of IFN was administered 2 hr prior to radiation therapy to allow for adequate serum levels at the time of radiation administration. The combined usage of IFN and radiation was continued unless interrupted by significant treatment toxicity or patient resignation from the protocol. The IFN dosage was adjusted in the event of granulocytopenia or thrombocytopenia. Radiation therapy was administered using standard radiation techniques and megavoltage equipment. The maximum size of the radiation portal was limited to 300 cm* with appropriate shielding of surrounding normal tissue using individually manufactured blocks. Toxicity evaluation and response criteria Each patient was vigorously monitored for early signs of toxicity and radiographic evidence of clinical effectiveness, throughout the treatment course and on a regular basis thereafter. Methods of evaluation included frequent physician examination, a regularly scheduled performance of laboratory procedures including hematologic, serum chemical, and clotting studies. Radiographic studies included chest X rays and CT scans, as appropriate. Toxicity was graded in accordance with the World Health Organization’s recommendations for grading of acute and subacute toxicity. Performance status was graded from zero to four with complete disability defined as four. Tumor response was determined by means of serial radiographic studies using standard perpendicular diameter measurements.
* Schering Corporation,
Kenilworth, NJ.
August 1986, Volume 12, Number 8
Conduct of the study All patients enrolled in the study were informed of the investigational nature of the combined use of radiotherapy with IFN and signed an informed consent form. The study was reviewed and approved by the Georgetown Institutional Review Board. Recombinant DNA alpha-2-interferon was supplied free of charge by the manufacturer.* RESULTS The combined use of alpha-2-interferon with radiotherapy was associated with more toxicity than expected from radiation therapy alone. Ten of 16 patients required hospitalization during the course of their therapy and there was one treatment related death. Accrual to the study was terminated following completion of the group at 5 X lo6 IU/m*, the dose at which hematologic toxicity was observed. Nearly all patients experienced flu-like symptoms, anorexia, fatigue, and mild weight loss previously associated with IFN therapy. Flu-like symptoms characterized by chills, fevers, malaise, and headaches were observed in 88% of the patients, but were noted to decrease in intensity with repeated IFN administration. Acetaminophen was useful in the alleviation of these symptoms. Severe to lifethreatening toxicity attributed to the combined modality approach (Grade III to IV) included significant dehydration, infection, deep-vein thrombosis, myocardial infarction, and psychosis. The one patient who died within the first week of treatment experienced an uncontrollable gastrointestinal hemorrhage thought to be caused by the tumor erosion of a major blood vessel. A post-mortem examination was not obtained. Other milder side effects observed included hypokalemia and exacerbation of psoriasis. Common side effects associated with radiotherapy, such as, radiation dermatitis and esophagitis, appeared earlier and seemed to be enhanced over that expected from radiotherapy alone. Table 2 summarizes the systemic toxicities encountered in the study. Hematological toxicity was milder than expected with only two patients in the study requiring dose modification secondary to granulocytopenia. Both patients received daily IFN at the 5.0 X lo6 III/m* level. There were no significant thrombocytopenia nor clotting abnormalities identified. Table 3 summarizes the hematologic toxicity encountered in the study. Our results provide useful information on the optimal dose and schedule of administration of IFN used in a combined modality setting. No specific differences in patient tolerance were noted between the 2 X 10” and 5 X lo6 III/m* dose levels. The 3-day-per-week (M, W, F) administration schedule, however, was better tolerated in terms of treatment-related toxicity and the ability to complete the planned irradiation course. Treatment related
1455
Combined interferon and radiotherapy trial 0 J. TORRISI et al.
expected with radiation alone. Future Phase II and III trials will be needed.
Table 2. Systemic toxicity Subgroup A
B
8 3 1
6 1
Mild to moderate (Grade I-II) Flu-like symptoms Esophagitis Hypokalemia Radiation dermatitis Exacerbation of psoriasis
1 1
Severe to life-threatening (Grade III-IV) Dehydration Pelvic infection Pneumonia Deep-vein thrombosis Myocardial infarction (same pt with DVT) Psychosis Hospitalizations
DISCUS!SION
6 1 1 1 1 1 required
819 subgroup A 217 subgroup B Treatment-related deaths 1
side effects encountered in the May-a-week (Subgroup A) resulted in this subgroup receiving only 22% of the originally planned IFN dosage. In contrast, patients placed on a 3-day-a-week schedule (Subgroup B) were able to receive 100% of the planned IFN administration. The 3day-a-week subgroup also tolerated radiotherapy better. Delivery of 86% of the originally planned radiation treatment dose was observed versus 44% for those patients receiving IFN 5-days-per-week. These findings suggest that the maximum tolerated schedule of alpha-2-interferon administered subcutaneously in conjunction with radiotherapy is 5 X lo6 IU/m2 administered on a 3-day-perweek schedule. Tumor response was determined 1 month following completion of therapy at the first follow-up visit. Complete and partial responses were observed in six patients and stable disease was noted in eight patients. No patients were noted to have tumor progression in the treated volume. Since this was a Phase I clinical trial designed to study patient tolerance, including patients with extensive local and metastatic disease, it was impossible to determine if the short-term response was different from that
The interferons represent a group of biologically active glycoproteins with proven anti-viral and anti-neoplastic properties.2q7 Anti-tumor efficacy has been shown in human tumors including renal cell carcinoma,5T8 melanoma, indolent forms of non-Hodgkin’s lymphoma,” Kaposi’s sarcoma, l6 and hairy cell leukemiai and other tumors.‘,” Details of the clinical responses of patients to IFN and radiotherapy are lacking and served as the impetus for conducting this study. Our interest in the combined use of IFN with radiation stems from in vitro studies which demonstrate that IFN has radiosensitizing properties. Dritschilo et al. studied the effect of IFN on the radiation response of mouse 3T3 cells in tissue culture.4 A speciesspecific enhancement of radiation killing of 3T3 cells irradiated in the presence of mouse L-cell IFN was observed as a reduction in the shoulder portion of the cell survival curve. Split-dose experiments designed to test for changes in sublethal radiation injury repair failed to demonstrate an inhibitory IFN effect. The authors concluded that IFN potentiates radiation injury, possibly by inhibiting the ability of the cultured cells to accumulate sublethal radiation injury. A recently published study of the combined use of IFN and radiotherapy using HeLa cells appears to confirm the above observations.13 Gould et al6 observed in vitro radiosensitization of human broncho-genie carcinoma with beta IFN but not with alpha-interferon. Nonetheless, he concluded that the anti-neoplastic effects of the combined IFN and radiation program were supraadditive indicating radiosensitization. Enhanced growth retardation (but not radiosensitization) was observed in human glioma cell cultures following combined therapy, in comparison to IFN and radiotherapy used alone.14 Although combined radiation and IFN studies have not been reported in animal model systems, primarily because of the species-specificity of IFN, Lvovsky et al9 have observed enhanced tumor control using the IFN inducer poly ICLC and radiation in the mouse Lewis lung tumor model. A delay in tumor regrowth, as well as, a prolonged duration of survival were observed in the inducer plus radiation animals, compared to either inducer or radiation alone.
Table 3. Hematologic toxicity: Nadir counts during treatment Parameter
Normal range
Average
Range
2.0 X lo6 IU/M2
5.0 X lo6 IU/M2
Hemoglobin White blood cell count Absolute granulocyte count Platelets
12-18 g/d1 4.8-10.8 X 103/mm3 900-4307/mm3 130-400 X 103/mm3
10.2 3.4 1927 206
8.1-14.2 1.3-5.9 900-4307 60-348
10.5 3.66 2242 208
9.8 2.79 1657* 203
Note: No difference in hematologic toxicity between schedule A and B were noted and thus combined data are presented. * Two patients at this dose level required interferon dose modifications for granulocyte counts less than 1000.
1456
I. J. Radiation Oncology 0 Biology 0 Physics
Few reports of the clinical use of combined IFN and radiotherapy exist. Mahaley et al. lo have reported a Phase I study of the combined use of IFN and radiation therapy in nine patients with anaplastic glioma following subtotal resection. No dose limiting or prohibitive toxicities were encountered. Patient survival was comparable to survival for a matched group treated with combined BCNU and radiotherapy. l1 Other reports, however, have suggested an unexpected increase in toxicity using a combined therapeutic approach. Severe oral cavity mucositis was noted in two patients with Kaposi’s sarcoma, requiring cessation of radiotherapy at doses of 11 and 21 Gy, respectively.‘6 Both patients required hospitalization for supportive care. Concomitant use of IFN and radiotherapy has also been associated with an increased incidence of radiation pneumonitis in patients with small cell carcinoma.‘* The results of the present Phase I clinical trial indicate
August 1986, Volume 12, Number 8
that the combined IFN and radiotherapeutic approach is feasible in the clinical setting. The maximum tolerated dose and schedule of alpha-24nterferon given subcutaneously in conjunction with daily irradiation was threetimes-per-week at 5.0 X IO6 IU/m*. This schedule was noted to be superior to daily admininistration of IFN in terms of overall patient tolerance, need for treatmentrelated hospitalization and the ability to deliver the planned full radiation dose. Significant toxicity was identified in this study, particularly, among those individuals in the 5-day-per-week subgroup, which reinforces our contention that the combination of IFN with radiation therapy is a potent modality. The information in this report pertaining to scheduling and dosage of IFN administration will benefit future studies designed to evaluate further the effectiveness of this combined therapeutic approach.
REFERENCES 1. Berek, J.S., Hacker, N.F., Lichtenstein, A., Jung, T., Spina, C., Knox, R.M., Brady, J., Greene, T., Ettinger, L.M., Lagasse, L., Bonnem, E., Spiegel, R., Zighelboim, J.: Intraperitoneal recombinant a-interferon for “salvage” immunotherapy in stage III epithelial ovarian cancer: A gynecologic oncology group study. Can. Rex 45: 4447-53, 1985. 2. Borden, E.: Progress toward therapeutic application of interferon?,, 1979-1983. Cancer 54: 2770-76, 1984. 3. Creagan, E.T., Ahman, D.L., Green, S.J., Long, H.J., Rubin, J., Schutt, A.J., Dziewanowski, Z.E.: Phase II study of recombinant leukocyte A interferon in disseminated malignant melanoma. Cancer 54( 12): 2844-49, 1984. 4. Dritschilo, A., Mossman, K., Gray, M., Sreevalsan, T.: Potentiation of radiation injury by interferon. Am. J. Clin. Oncol. 5: 79-82, 1982. 5. Edsmyr, F., Esposti, P.L., Andersson, L., Steineck, G., Lagergren, C., Strander, H.: Interferon therapy in disseminated renal cell carcinoma. Radiother. Oncol. 4: 21-26, 1985. 6. Gould, M., Kakria, R., Olson, S., Borden, E.: Radiosensitization of human bronchogenic carcinoma cells by interferon beta. J. Interferon Rex 4: 123-28, 1984. 7. Kirkwood, J.W., Ernstoff, M.: Interferons in the treatment of human cancer. J. Clin. Oncol. 2: 336-352, 1984. 8. Kirkwood, J.M., Harris, J.E., Vera, R., Sandler, S., Fischer,
D.S., Khanderkar, J., Em&off, M.S., Gordon, L., Lutes, R., Bonomi, P., Lytton, B., Cobleigh, M., Taylor, S.J.: A randomized study of low and high doses of leukocyte a-interferon in metastatic renal cell carcinoma: The American Cancer Society. Can. Rex 45: 863-71, 1985. 9. Lvovsky, E., Mossman, K., Levy, H., Dritschilo, A.: Response of mouse tumor to interferon inducer and radiation. Int. J. Radiat. Oncol. Biol. Phys. 11: 1721-25, 1985.
10. Mahaley, M.S., Urso, M., Whaley, R., Staab, E., Williams, T.E., Guaspari, A.: Immunobiology of primary intracranial tumors: IX. Phase.I study of human lymphoblastoid interferon. J. Biol. Res. Modifiers 3: 19-25, 1984. Il. Mahaley, M.S., Urso, M., Whaley, R., Williams, T.E., Guaspari, A.: Interferon as adjuvant therapy with initial radiotherapy of patients with anaplastic gliomas. J. Neurosurg. 61: 1069-71, 1981.
12. Mattson, K., Holsti, L.R., Niiranen, A., Kivisaari, L., Iivanainen, M., Sovijarvi, A., Cantell, K.: Human leukocyte interferon as part of a combined treatment for previously untreated small cell lung cancer. J. Biol. Resp. Modifiers 4:
8-17, 1985. 13. Namba, M., Yamamoto, S., Tanaka, H., Kanamori, T., Nobuhara, M., Kimoto, T.: Potentiation of cytotoxic effects of anticancer drugs or Cobalt-60 gamma ray by interferon on human neoplastic cells. Cancer 54: 2262-67, 1984. 14. Nederman, T., Benediktsson, G.: Effects of interferon on growth rate and radiation sensitivity of cultured human glioma cells. Acta Radiol. Oncol. 21: 23 l-34, 1982. 15. Quesada, J.R., Swanson, D.A., Gutterman, J.U.: Phase II study of interferon alpha in metastatic renal-cell carcinoma: A progress report. J. Clin. Oncol. 3: 1086-92, 1985. 16. Real, F.X., Krown, S., Nisce, L., Oettgen, H.: Unexpected toxicity from radiation therapy in two patients with Ka&s sarcoma receiving interferon. J, Biol. Resp. Mod#iers 4: 14 l46, 1985. 17. Siegert, W., Theml, H., Fink, U., Emmerich, B., Kaudewitz, P., Huhn, D., Boning, L., Abb, J., Joester, K.E., Bard, R., Riethmuller, G., Wilmanns, W.: Treatment of non-Hodgkin’s lymphoma of low-grade malignancy with human fibroblast interferon. Anti-Cancer Res. 2: 193-98, 1982.
Copy&t0
0360-3016/86 $3.00 + .OO 1986 Pergamon Journals Ltd.
0 Session VI
PHASE I COMBINED MODALITY CLINICAL TRIAL OF ALPHA-ZINTERFERON AND RADIOTHERAPY J. TORRISI, M.D.,’ C. BERG, M.D.,’ K. HARTER, M.D.,’ E. LVOVSKY, M.D.,3 K. YEUNG, M.D.,2 P. WOOLLEY, M.D.,2 E. BONNEM, M.D.4 AND A. DRITSCHILO, M.D.’ ‘Department of Radiation Medicine, ‘Department of Medical Oncology, Georgetown University Medical Center, 3800 Reservoir Road, N.W., Washington, D.C. 20007; 3The Genesee Hospital, Rochester, NY 14607; 4Schering Corporation, Kenilworth, NJ 07033 Sixteen patients were enrolled in a Phase I study of the combined use of recombinant DNA alpha-Zinterferon (IFN) and radiation therapy, conducted at the Georgetown University Hospital (GUH) from February 1,1984 to September 20,196 Escalating IFN doses ranging from 2.0 X lo6 IU/m* to 5 X lo6 IU/m* were administered to groups of six patients per IFN dose level. Three patients at each dose level were treated on a S-day-a-week schedule and three patients were treated on a 3-day-a-week schedule. Significant toxicity including dehydration, infection, deep vein thrombosis, and myocardial infarction was noted throughout in patients receiving IFN five times per week, with eight of nine requiring hospitalization during the treatment course. There was one treatment-related death. In the five-times-per-week group, only 22% of patients tolerated the full initially planned IFN dosage and 44% tolerated the full initially planned radiation dosage, compared to 100 and 86%, respectively, in the threetimes-per-week group. A tolerance dose and schedule of 5.0 X lo6 IU/m* of alpha-a-interferon administered subcutaneously three-times-per-week in conjunction with standard radiotherapy has been identified for use in future combined modality trials. Radiotherapy, Interferon, Combined radiotherapy-chemotherapy, INTRODUmION
Radiation sensitizer.
IFN and radiation therapy conducted at the Georgetown University Hospital from Feburary 1, 1984 through September 20, 1985. Patients were declared eligible for participation, if they had histological confirmation of an advanced unresectable or metastatic carcinoma or sarcoma and a life expectancy of at least 3 months. A poor performance status, prior history of cardiac arrhythmia or failure, central nervous system malignancy, previously diagnosed clotting disorder, history of previous irradiation to the spinal axis or previous exposure to IFN were considered grounds for ineligibility. The clinical characteristics of the 16 patients are shown in Table 1.
Radiation therapy and interferon are used in the treatment of cancer. Recent laboratory studies have suggested that IFN has sensitizing properties, when used in combination with radiotherapy. 4,6,9~‘3~14 The clinical efficacy, as well as, the toxicity of the combined use of radiotherapy and IFN in humans have not been well-studied. Case reports of enhanced normal tissue toxicity in patients receiving radiation therapy, incidentally to IFN treatment, suggest that a formal evaluation of patient tolerance to the combined modality treatment is needed.‘*,16 Consequently, a Phase I clinical trial was conducted at the Georgetown University Hospital to study the combined use of radiation therapy and Schering alpha-2 recombinant DNA IFN. Factors including the optimal schedule of administration, dose, toxicity, patient tolerance, and anti-tumor efficacy were addressed.
Study design
Sixteen patients were enrolled in the Phase I study of the combined use of Schering alpha-2 recombinant DNA
Prior to enrollment, all patients were thoroughly examined and their disease clinically staged using chest X rays, computerized tomography, EKG and hematologic and blood chemistries. Clotting studies including total fibrinogen determination, PTT, PT, TT, and fibrin degradation products were screened. Thereafter, each patient was sequentially assigned to groups consisting of six subjects, then further subdivided into two subgroups of three
Presented at the Chemical Modifiers of Cancer Treatment Conference, Clearwater, Florida, 20-24 October 1985. Reprint requests to: J. Torrisi.
Acknotiledgement-We wish to thank Ms. Sandra Hawkins for her contribution in the preparation of this manuscript. Accepted for publication 25 February 1986.
METHODS
AND
MATERIALS
Patient population
1453
1454
I. J. Radiation Oncology 0 Biology??Physics Table 1. Patient characteristics Number enrolled Age (mean) Performance status (mean) Male/female Tumor sites Lung Esophagus Pancreas Cervix Renal Base of skull/orbit
:: (43-76) 0.9 (O-2) 818 9 3 1 1 1 1
patients each (Subgroup A and B). Each group of six patients received the same dose of alpha-Zinterferon, which was escalated in each succeeding group. The doses to be studied included 2.0 X IO6II-I/m*, 5.0 X lo6 III/m*, 10.0 X lo6 III/m*, 20 X lo6 IU/m*, and 30 X lo6 III/m*. Actual patient accrual was terminated at the 5.0 X lo6 III/m* level, because of toxicity. Within a given group, one subgroup (Subgroup A) received the given IFN dose subcutaneously five times per week in conjunction with the radiotherapy. The remaining subgroup (Subgroup B) received the same IFN dose subcutaneously three times per week (M, W, F). The daily dose of IFN was administered 2 hr prior to radiation therapy to allow for adequate serum levels at the time of radiation administration. The combined usage of IFN and radiation was continued unless interrupted by significant treatment toxicity or patient resignation from the protocol. The IFN dosage was adjusted in the event of granulocytopenia or thrombocytopenia. Radiation therapy was administered using standard radiation techniques and megavoltage equipment. The maximum size of the radiation portal was limited to 300 cm* with appropriate shielding of surrounding normal tissue using individually manufactured blocks. Toxicity evaluation and response criteria Each patient was vigorously monitored for early signs of toxicity and radiographic evidence of clinical effectiveness, throughout the treatment course and on a regular basis thereafter. Methods of evaluation included frequent physician examination, a regularly scheduled performance of laboratory procedures including hematologic, serum chemical, and clotting studies. Radiographic studies included chest X rays and CT scans, as appropriate. Toxicity was graded in accordance with the World Health Organization’s recommendations for grading of acute and subacute toxicity. Performance status was graded from zero to four with complete disability defined as four. Tumor response was determined by means of serial radiographic studies using standard perpendicular diameter measurements.
* Schering Corporation,
Kenilworth, NJ.
August 1986, Volume 12, Number 8
Conduct of the study All patients enrolled in the study were informed of the investigational nature of the combined use of radiotherapy with IFN and signed an informed consent form. The study was reviewed and approved by the Georgetown Institutional Review Board. Recombinant DNA alpha-2-interferon was supplied free of charge by the manufacturer.* RESULTS The combined use of alpha-2-interferon with radiotherapy was associated with more toxicity than expected from radiation therapy alone. Ten of 16 patients required hospitalization during the course of their therapy and there was one treatment related death. Accrual to the study was terminated following completion of the group at 5 X lo6 IU/m*, the dose at which hematologic toxicity was observed. Nearly all patients experienced flu-like symptoms, anorexia, fatigue, and mild weight loss previously associated with IFN therapy. Flu-like symptoms characterized by chills, fevers, malaise, and headaches were observed in 88% of the patients, but were noted to decrease in intensity with repeated IFN administration. Acetaminophen was useful in the alleviation of these symptoms. Severe to lifethreatening toxicity attributed to the combined modality approach (Grade III to IV) included significant dehydration, infection, deep-vein thrombosis, myocardial infarction, and psychosis. The one patient who died within the first week of treatment experienced an uncontrollable gastrointestinal hemorrhage thought to be caused by the tumor erosion of a major blood vessel. A post-mortem examination was not obtained. Other milder side effects observed included hypokalemia and exacerbation of psoriasis. Common side effects associated with radiotherapy, such as, radiation dermatitis and esophagitis, appeared earlier and seemed to be enhanced over that expected from radiotherapy alone. Table 2 summarizes the systemic toxicities encountered in the study. Hematological toxicity was milder than expected with only two patients in the study requiring dose modification secondary to granulocytopenia. Both patients received daily IFN at the 5.0 X lo6 III/m* level. There were no significant thrombocytopenia nor clotting abnormalities identified. Table 3 summarizes the hematologic toxicity encountered in the study. Our results provide useful information on the optimal dose and schedule of administration of IFN used in a combined modality setting. No specific differences in patient tolerance were noted between the 2 X 10” and 5 X lo6 III/m* dose levels. The 3-day-per-week (M, W, F) administration schedule, however, was better tolerated in terms of treatment-related toxicity and the ability to complete the planned irradiation course. Treatment related
1455
Combined interferon and radiotherapy trial 0 J. TORRISI et al.
expected with radiation alone. Future Phase II and III trials will be needed.
Table 2. Systemic toxicity Subgroup A
B
8 3 1
6 1
Mild to moderate (Grade I-II) Flu-like symptoms Esophagitis Hypokalemia Radiation dermatitis Exacerbation of psoriasis
1 1
Severe to life-threatening (Grade III-IV) Dehydration Pelvic infection Pneumonia Deep-vein thrombosis Myocardial infarction (same pt with DVT) Psychosis Hospitalizations
DISCUS!SION
6 1 1 1 1 1 required
819 subgroup A 217 subgroup B Treatment-related deaths 1
side effects encountered in the May-a-week (Subgroup A) resulted in this subgroup receiving only 22% of the originally planned IFN dosage. In contrast, patients placed on a 3-day-a-week schedule (Subgroup B) were able to receive 100% of the planned IFN administration. The 3day-a-week subgroup also tolerated radiotherapy better. Delivery of 86% of the originally planned radiation treatment dose was observed versus 44% for those patients receiving IFN 5-days-per-week. These findings suggest that the maximum tolerated schedule of alpha-2-interferon administered subcutaneously in conjunction with radiotherapy is 5 X lo6 IU/m2 administered on a 3-day-perweek schedule. Tumor response was determined 1 month following completion of therapy at the first follow-up visit. Complete and partial responses were observed in six patients and stable disease was noted in eight patients. No patients were noted to have tumor progression in the treated volume. Since this was a Phase I clinical trial designed to study patient tolerance, including patients with extensive local and metastatic disease, it was impossible to determine if the short-term response was different from that
The interferons represent a group of biologically active glycoproteins with proven anti-viral and anti-neoplastic properties.2q7 Anti-tumor efficacy has been shown in human tumors including renal cell carcinoma,5T8 melanoma, indolent forms of non-Hodgkin’s lymphoma,” Kaposi’s sarcoma, l6 and hairy cell leukemiai and other tumors.‘,” Details of the clinical responses of patients to IFN and radiotherapy are lacking and served as the impetus for conducting this study. Our interest in the combined use of IFN with radiation stems from in vitro studies which demonstrate that IFN has radiosensitizing properties. Dritschilo et al. studied the effect of IFN on the radiation response of mouse 3T3 cells in tissue culture.4 A speciesspecific enhancement of radiation killing of 3T3 cells irradiated in the presence of mouse L-cell IFN was observed as a reduction in the shoulder portion of the cell survival curve. Split-dose experiments designed to test for changes in sublethal radiation injury repair failed to demonstrate an inhibitory IFN effect. The authors concluded that IFN potentiates radiation injury, possibly by inhibiting the ability of the cultured cells to accumulate sublethal radiation injury. A recently published study of the combined use of IFN and radiotherapy using HeLa cells appears to confirm the above observations.13 Gould et al6 observed in vitro radiosensitization of human broncho-genie carcinoma with beta IFN but not with alpha-interferon. Nonetheless, he concluded that the anti-neoplastic effects of the combined IFN and radiation program were supraadditive indicating radiosensitization. Enhanced growth retardation (but not radiosensitization) was observed in human glioma cell cultures following combined therapy, in comparison to IFN and radiotherapy used alone.14 Although combined radiation and IFN studies have not been reported in animal model systems, primarily because of the species-specificity of IFN, Lvovsky et al9 have observed enhanced tumor control using the IFN inducer poly ICLC and radiation in the mouse Lewis lung tumor model. A delay in tumor regrowth, as well as, a prolonged duration of survival were observed in the inducer plus radiation animals, compared to either inducer or radiation alone.
Table 3. Hematologic toxicity: Nadir counts during treatment Parameter
Normal range
Average
Range
2.0 X lo6 IU/M2
5.0 X lo6 IU/M2
Hemoglobin White blood cell count Absolute granulocyte count Platelets
12-18 g/d1 4.8-10.8 X 103/mm3 900-4307/mm3 130-400 X 103/mm3
10.2 3.4 1927 206
8.1-14.2 1.3-5.9 900-4307 60-348
10.5 3.66 2242 208
9.8 2.79 1657* 203
Note: No difference in hematologic toxicity between schedule A and B were noted and thus combined data are presented. * Two patients at this dose level required interferon dose modifications for granulocyte counts less than 1000.
1456
I. J. Radiation Oncology 0 Biology 0 Physics
Few reports of the clinical use of combined IFN and radiotherapy exist. Mahaley et al. lo have reported a Phase I study of the combined use of IFN and radiation therapy in nine patients with anaplastic glioma following subtotal resection. No dose limiting or prohibitive toxicities were encountered. Patient survival was comparable to survival for a matched group treated with combined BCNU and radiotherapy. l1 Other reports, however, have suggested an unexpected increase in toxicity using a combined therapeutic approach. Severe oral cavity mucositis was noted in two patients with Kaposi’s sarcoma, requiring cessation of radiotherapy at doses of 11 and 21 Gy, respectively.‘6 Both patients required hospitalization for supportive care. Concomitant use of IFN and radiotherapy has also been associated with an increased incidence of radiation pneumonitis in patients with small cell carcinoma.‘* The results of the present Phase I clinical trial indicate
August 1986, Volume 12, Number 8
that the combined IFN and radiotherapeutic approach is feasible in the clinical setting. The maximum tolerated dose and schedule of alpha-24nterferon given subcutaneously in conjunction with daily irradiation was threetimes-per-week at 5.0 X IO6 IU/m*. This schedule was noted to be superior to daily admininistration of IFN in terms of overall patient tolerance, need for treatmentrelated hospitalization and the ability to deliver the planned full radiation dose. Significant toxicity was identified in this study, particularly, among those individuals in the 5-day-per-week subgroup, which reinforces our contention that the combination of IFN with radiation therapy is a potent modality. The information in this report pertaining to scheduling and dosage of IFN administration will benefit future studies designed to evaluate further the effectiveness of this combined therapeutic approach.
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