Inr J Radiarmn Oncology RIO/. Phys., Vol. Printed I” the U.S.A. All nghts reserved.
t .W
19, PP. 42 l-428 Copyright
0360.3016/90 $3.00 0 1990 Pergamon Press plc
??Phase I/II Clinical Trials
INTRA-ARTERIAL
BROMODEOXYURIDINE RADIOSENSITIZATION OF MALIGNANT GLIOMAS
T. J. HEGARTY, M.D.,’ A. F. THORNTON, M.D.,’ R. F. DIAZ, M.D.,9 W. F. CHANDLER, M.D.,3 W. D. ENSMINGER, M.D., PH.D.,~ L. JUNCK, M.D.,2 M. A. PAGE, R.N., M.S.,2 S. S. GEBARSKI, M.D.,5 T. W. HOOD, M.D.,3 P. L. STETSON, M.D., PH.D.,~ I;!. M. TANKANOW, B.S., M.S.,7 P. E. MCKEEVER, M.D.,8 A. S. LICHTER, M.D.’ AND H. S. GREENBERG, M.D.2 ‘Departmentof Radiation Oncology, 2Department of Neurology, ‘Department of Surgery, “Department of Internal Medicine, ‘Department of Radiology, 6Department of Pharmacology, ‘Department of Pharmacy, ‘Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48 109; and 9Methodist Hospital, Department of Radiation Oncology, Minneapolis Radiation Oncology, P.A., St. Louis Park, MN 55246 In the 1950’s it was first observed that mammalian cells exposed to the halogenateddeoxyuridineswere more sensitive to ultravioletlight and radiationthan untreatedcells. This promptedearly clinical trials with bromodeoxyuridine(BUdR:)which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR (400-600 mg/m*/day X 8; weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6f weeks). Following initial biopsy/surgery the infusion pump system was implanted, BUdR infusion began 2 weeks prior to and continued throughout the 64 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall KaplanMeier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognastically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas. Bromodeoxyuridinle,
Radiosensitization,
Malignant
gliomas.
INTRODUCTION
gliomas, improving median survival from 14 weeks for surgery alone to 36 to 40 weeks with the addition of postoperative radiation (5 l-53). The addition of single agent and combination chemotherapy to post-operative irradiation has yielded a slight improvement in median survival to between 40 and 55 weeks (8, 15, 17). Unique characteristics distinguish malignant gliomas from malignant neoplasms of other organs. Malignant gliomas do not metastasize except in rare instances. Local tumor progression in a confined inelastic space is the cause of death in virtually all cases. Total surgical excision is
It is estimated that primary central nervous system (CNS) neoplasms accounted for almost 11,000 cancer deaths in 1988 (4 1). Malignant gliomas made up over 5 100 of these cases (4). Progress in the .treatment of malignant gliomas has been slow even in the face of aggressive combined modality therapy. Since the late 1960’s the Brain Tumor Cooperative Group (BTCG) has conducted a series of prospective randomized trials demonstrating the efficacy of radiotherapy as an adjunctive treatment for malignant
Acknowledgement-We
Presented in part at the 30th Meeting of the American Society for Therapeutic Radiology and Oncology, New Orleans, LA, 13 October 1988. Reprint requests to: T. J. Hegarty, M.D., Department of Radiation Oncology, Wayne State University, 4201 St. Antoine, Detroit, MI 4820 1.
thank Ms. Beverly Ryder and Ms. Kathryn Strand for their professional assistance in the preparation of this manuscript. Accepted for publication 22 February 1990.
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rarely feasible because of the tumor’s infiltrative nature. Additionally, malignant gliomas are heterogenous tumors. 1n vitro cloning studies have shown multiple morphological cell types within a single tumor or region of a tumor with varying karyotypic numbers and differential chemosensitivity (37). Tumor progression as correlated by CT and histological studies confirms that persistent viable tumor cells adjacent to the central area of necrosis, but within the high dose external beam irradiation volume, are usually responsible for failure (3, 14, 18). Various methods to deal with these radioresistant cells have been studied. These include irradiation under hyperbaric oxygen conditions (7) use of electron affinic drugs such as metronidazole (50) and misonidazole (2, 3 1,40), and high linear energy transfer radiation (5, 6, 27). To date, none of these approaches has improved the survival results of radiotherapy alone. The use of potentially curative, higher dose external beam radiotherapy has been limited by normal brain tissue tolerance (19, 30, 38). Attempts to alter the therapeutic ratio and overall effectiveness of radiation therapy while limiting late effects has led to several trials of hyperfractionated or multiple daily fraction radiotherapy. While hyperfractionated therapy is theoretically attractive (47, 48, 54) in practice differences in survival have not been statistically significant (13, 32, 39, 43). The limitation of brain tissue tolerance has led many investigators to explore the interaction of external beam radiation and drugs that selectively increase tumor cell kill without increasing normal tissue toxicity. In the late 1950’s it was found that mammalian cells exposed to halogenated deoxyuridines, a group of thymidine analogs, were more sensitive to X ray and ultraviolet light than untreated cells (9). Considerable in vitro and in vivo experimental work confirmed that when these analogs were incorporated into the DNA of dividing cells, the degree of radiosensitization directly reflected the extent of thymidine replacement in DNA (46). In the late 1960’s and early 1970’s several clinical trials were undertaken to investigate the efficacy of radiosensitization with halogenated pyrimidines (1, 12,20, 35, 36). The brain is an area particularly well suited to halogenated pyrimidine trials since the rapidly dividing brain tumor cells can be expected to incorporate the drug, whereas the slowly dividing glial cells will not. Recently, in several Phase I studies, investigators at the National Cancer Institute established the feasibility of continuous intravenous (IV) infusion of bromodeoxyuridine (BUdR) and found survival in treated malignant gliomas to be at least comparable to that in other combined modality trials. However, they reported significant dose-limiting skin and bone marrow toxicities, and ques-
* Infusion pump manufactured wood, MA
by Shiley-Infusaid,
Inc., Nor-
August 1990, Volume 19. Number 2
tioned the optimal method of BUdR delivery (21, 2326). Intra-arterial (IA) infusion, these investigators speculated, would be the desired route of delivery. Because of the theoretical advantage of IA BUdR (10, 34) we initiated a primate toxicity study comparing carotid IA BUdR infusion to IA buffer infusion in control animals with both groups receiving external beam radiation to the brain. The study demonstrated no increase in pathology in the BUdR infused hemisphere (16). A clinical Phase I protocol was then developed utilizing IA infusion of BUdR prior to and concurrent with external beam irradiation of malignant gliomas. This paper reports on the preliminary results in the 23 patients enrolled. METHODS
AND MATERIALS
Patient selection Adult patients with histologically confirmed unilateral hemispheric malignant gliomas (World Health Organization designated anaplastic astrocytoma and glioblastoma multiforme; grade 3 and 4) (55) with blood supply primarily from one internal carotid artery and lesions measurable on CT scan were eligible for this Phase I study. Patients were required to have a Karnofsky rating 2 40, be capable of giving informed consent, be able to tolerate infusion pump placement, and have a life expectancy of at least 3 months. Eligible patients were also required to have normal peripheral blood count (WBC 2 4000 cells/ mL; platelets > 150,00O/mL), normal renal function (BUN < 30 mg/dl, creatinine < 1.5 mg/dl), and normal liver function (bilirubin < 2; SGOT and alkaline phosphatase < 2X normal). No prior radiation therapy or chemotherapy could have been given before enrollment in the study. Of 52 patients with malignant gliomas seen at the University of Michigan Medical Center during the course of this study (7/85-12/87), 23 fit the above criteria and were enrolled. Drug administration and radiation therapy BUdR was administered via the internal carotid artery. An implantable infusion pump system* was placed using previously described techniques (33). Irradiation was begun 2 weeks after initiation of BUdR infusion. All patients were treated on a linear accelerator with either 6 or 10 MeV photon energy. Tumor was defined by the rim of contrast enhancement on CT scan. A margin of 3-4 cm beyond this volume was treated to 45.0 Gy at 1.8 Gyfday and then a boost volume of enhancing lesion plus 1.5-2 cm was treated to 59.4 Gy at 1.8 Gy/day, most often with parallel opposed lateral fields (Fig. 1). Systemic corticosteroids and anticonvulsants were used in all patients. No patients received any other treatment until the time of
423
BUdRradiosensitization of malignantgliomas??T. J. HEGARTYet al. Week
0 +-
the Mantel test (29). The p-values in this report are determined from two-sided tests.
RESULTS
III= BUdR (400-600 mg/m* /day) lmtlal (3-4 cm margin around contrast ?? ?enhancing ”?lrradlatlon ‘_ ” rirn seen on CT scan) Boost irradiation (1.52 cm margin around contrast ??= enhancing rim seen on CT scan)
Fig. I. Treatment
schema.
Patient characteristics Twenty-three patients with malignant gliomas were treated on this Phase I trial between July 1985 and December 1987. Five patients had anaplastic astrocytoma/ grade 3 and 18 patients had glioblastoma multiforme/ grade 4. There were 16 males and 7 females with a median age of 48 years (range 20-7 1; 12 5 50 years, 11 > 50 years) and median Karnofsky rating of 70 (range 50-90). Six patients had only stereotactic biopsy, 15 patients underwent subtotal resection, and 2 patients underwent gross total resection.
BUdR-bromodeoxyuridine.
objective tumor progression. Twelve patients received palliative chemotherapy. Two patients required additional irradiation for spinal suba.rachnoid spread of their tumor. Two patients underwent additional surgery to debulk progressing tumor. Statistical considerations Survival was computed from date of surgery. Protocol treatment was begun usually within 2 weeks of surgery. All patients were followed a minimum of 9 months or until death. No patient has been lost to follow-up and no patient is excluded from analysis. Survival curves were plotted using the Kaplan-Meier method (22). Differences in survival were evaluated by
I.......,.....
Analysis of prognostic variables The median survival for all 23 patients entered on study is 20 months with 24% survival at 24 months (Fig. 2). In this study performance status, sex of patient, degree of antecedent tumor removal, and BUdR dose rate did not exert a discernable influence. Two factors did influence survival significantly. Patients with anaplastic astrocytomas lived longer than patients with glioblastoma multiforme (median survival not yet reached vs 14 months, p < 0.025) (Fig. 3). Patients 50 years and younger had a significant advantage over older patients (median survival 23.3 vs 13.5 months, p < 0.025) (Fig. 4). Pharmacology Systemic venous plasma steady state levels were measured in all patients using high performance liquid chro-
_.,,_.,..............,,__ 74
I2
36
MONTHS S4JRVlVAl.
Fig. 2. Kaplan-Meier plot of the probability patients. Ticks represent censored patients.
of survival
in months
from date of histological
diagnosis
for all 23
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August 1990, Volume 19, Number 2
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Fig. 3. Kaplan-Meier plot of the probability of survival in months from date of histological diagnosis for patients with anaplastic astrocytoma (5 patients, solid line) or glioblastoma multiforme (18 patients, dashed line). Ticks
represent censored patients. The survival for patients with anaplastic astrocytoma is significantly longer than for patients with glioblastoma multiforme (p < 0.025).
matography (HPLC) with UV absorption peak detection (45). The blood levels varied from 0.18 to 1.25 PM with total body clearance of 0.99 L/min to 11.3 L/min at infused dose of 400 to 600 mg/m*/day. Increasing the daily BUdR dose produced a variable response in the venous blood drug concentration. Based on these data, minimal regional brain extraction, and internal carotid blood flow of 250 ml/min, the systemic venous blood levels obtained with intraarterial infusion gave a total body clearance that
resulted in an estimated regional concentration (Rd) of BUdR of 6 to 16 fold, similar to that calculated by Russo et al. (34). Two patients underwent additional surgery for decompression and resection of progressing tumor. A DNA assay of BUdR incorporation in the tumor tissue was undertaken using gas chromatography-mass spectrometry with selected ion monitoring (44). In the first, who had resection in the 4th week of infusion, tumor samples
PeO.025
5 50 YEARS
Fig. 4. Kaplan-Meier plot of the probability of survival in months from date of histological diagnosis for patients I 50 years of age (12 patients, solid line) or patients > 50 years of age (11 patients, dashed line). Ticks represent censored patients. The survival for patients 5 50 years is significantly longer than for patients > 50 years (p < 0.025).
BUdR radiosensitization of malignant gliomas 0 T. J. HEGARTYet a/.
showed 2.2-5.0% BUdR incorporation while systemic steady state plasma levels were 0.30 PM with an infusion rate of 500 mg/m’/day. In the second, who had resection several weeks after compl’etion of infusion at 400 mg/m2/ day, tumor samples showed 3.3-5.6% BUdR incorporation while adjacent normal brain tissue included in the margin of resection showed 0.2-0.3% BUdR incorporation. Treatment toxicity There have been no vascular complications from the presence of the intraarterial pump system. Reversible dose-related myelosuppression (particularly thrombocytopenia, and to a lesser degree, leukopenia) was observed in five patients; the one moderate case was receiving the highest dose of BUdR (600 mg/m’/day). Two patients experienced transaminase elevations and one patient developed acute hepatitis, with full recovery. Adverse systemic effects included faiigue, anorexia, and weight loss in the majority of patients. All patients developed ipsilateral facial dermatitis. By the second week of BUdR infusion, before radiation had begun, slight erythema was perceptible in the region of the face supplied by the ophthalmic artery, the first branch of the infused internal carotid artery. Two weeks after irradiation began, skin changes escalated. Erythema, swelling, and induration of the forehead extended to the upper and lower eyelids and maxillary face in the distribution of the ophthalmic artery. Epilation of the eyebrows and eyelashes occurred ipsilaterally. Some reactions were marked by dry desquam,ation with pronounced scaling, while others had moist desquamation characterized by multiple erosions and serosanguinous crusts. Three patients required dose reduction of BUdR due to the severity of this reaction. Management of the mucocutaneous reactions included dose reduction of the BUdR as well as local treatment. All patients were advised to minimize sun exposure and to wear a protective hat and sunglasses. Therapy of the facial dermatitis varied depending on its nature. Mild dry desquamative determatitis was best treated with gentle soap cleansing and hydrocortisone 1% cream. Severe moist desquamative dermatitis was managed with wet antiseptic compresses to remove debris and crusts. According to each individual case, the dermatitis was dressed with a hydrogel or petrolatum-impregnated gauze, or was left uncovered. Following therapy, patients were advised to continue sun avoidance, to use an effective sunscreen, and to keep .the skin well lubricated with a non-irritating moisturizer. Four patients developed ipsilateral oral cavity and oropharyngeal ulcers. These were located on the posterior soft palate, retromolar trigone region or lateral pharyngeal wall. They were characterized by being exquisitely painful, with a deep necrotic base and shaggy angular configuration, measuring up to 4 cm in diameter. Resolution did not occur until therapy was completed. The oral ulcers
425
were symptomatically treated with dilute salt and baking soda rinses and viscous xylocaine. All patients underwent ophthalmologic evaluation. Many complained of dryness of the eyes and had ipsilatera1 eyelid erythema, induration, and pruritus. Conjunctival hyperemia was observed in all. Patients were symptomatic 1 week after starting BUdR infusion and symptoms continued until BUdR dose was lowered or treatment was completed. Mucopurulent conjunctival discharges were cultured from eight patients and found to grow Staphylococcus in six cases, Pseudomonas in one, and Neisseria in one. Mechanical ectropion was seen in four, exposure keratitis in three, and cornea1 perforation in one. Ophthalmic artificial tears were recommended during the day and an ophthalmic ointment at night. Five patients developed a pruritic, erythematous macular and papular eruption affecting the face, neck, upper trunk, and upper extremities. Skin biopsies in two affected patients demonstrated a mild superficial perivascular lymphocytic infiltrate with hyper- and parakerotosis, mild acanthosis, and focal necrotic keratonocytes compatible with a drug hypersensitivity reaction. One patient developed severe erythema multiforme major (Stevens-Johnson syndrome) 5 1 weeks following initiation of BUdR, while also taking carbamazepine and dexamethasone. She had had a previous drug eruption secondary to phenytoin prior to starting BUdR infusion. Her plasma levels of BUdR were noted to be the highest and her plasma clearances the lowest of any patient treated. The distribution of the erythema multiforme major was unusual in that it began on the face and spread to involve primarily the trunk with relative sparing of the extremities, including hands and feet. Large sheets of skin desquamated (80-90% of skin surface), leaving vast areas of denudation. Oral, ocular, and genital mucosae were involved. BUdR, carbamazepine, and irradiation were discontinued, dexamethasone maintained, and her condition was managed in the burn unit, with excellent dermatologic recovery. Patients were observed to have nail ridging affecting all fingernails and some toenails. While an uncommon occurrence, when seen, nail shedding was preceded by the formation of a depressed horizontal white band with slight discoloration superimposed. Completely normal nails regrew within 6 months.
DISCUSSION
It has been established that halogenated pyrimidines are effective non-hypoxic cell radiosensitizers in vitro and in vivo (9, 46). However, clinically, when given intravenously, BUdR has major systemic dose limiting toxicities. Investigators using intravenous BUdR have reported that escalation of dose beyond 700 mg/m2/12 hr infusion has resulted in severe myelosuppression and have shown that
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steady state plasma levels of BUdR correlate with degree of myelosuppression (34). Myelosuppression was seen and bone marrow stem cells harvested and irradiated in vitro exhibited a radiation enhancement factor as high as 2.2 when the plasma concentration was 2.1 PM (24, 26). However, neither myelosuppression nor in vitro bone marrow radiosensitization were seen when plasma BUdR concentration was 0.7 PM. Steady state plasma levels achieved in our patients ranged from 0.18 PM to 1.25 PM, well below the levels found to cause severe myelosuppression. Only one patient experienced moderately severe myelosuppression at a BUdR dose of 600 mg/m2/ day X 8 weeks and plasma steady state concentration of 0.64 PM. Although adverse systemic effects have been minimized, severe local mucocutaneous reactions have been found to be dose limiting. Our maximum tolerated dose (MTD) appears to be 400 mg/m2/day. The most significant toxic effects have been ipsilateral dermatitis, blepharitis, conjunctivitis, and oropharyngeal mucositis. These reactions begin prior to the initiation of irradiation, are not seen on the contralateral side, and so are directly attributable to the IA BUdR. Only four patients developed ipsilateral oropharyngeal ulceration and the relative infrequency of this complication is thought to be due to the variability in the origin and caliber of the ascending pharyngeal artery. The acute mucocutaneous reactions escalated during the course of the infusion and irradiation though the affected areas were not in the primary beam. Thermoluminescent dosimetric (TLD) measurements taken at the orbits showed a 7- 10% internal scatter dose contribution bilaterally. Assuming the maximal BUdR radiosensitization factor of 3 (9, 1 l), the effective dose to the ipsilateral face did not exceed 18.0 Gy over 61 weeks. This is far below the total dose necessary to realize the equivalent acute reactions seen when treating primary head and neck fields. Hence, ambient ultraviolet light may play an important role in development of the mucocutaneous toxicity, and the direct cytotoxicity of high concentrations of BUdR alone may produce some of the observed side effects. BUdR is a potent photosensitizer as its maximum absorption spectrum falls between 270-310 nm (25). In vitro studies have shown BUdR treated cells to be 5 times as sensitive to UV radiation as IUdR treated cells and 10 times as sensitive as untreated cells with D-zero’s of 27, 140, and 280 erg/mm2, respectively (11).
August 1990, Volume 19, Number 2
To counter the mucocutaneous side effects three approaches may be considered for future studies: the use of non-paraaminobenzoic acid (PABA) sunscreens to decrease photosensitization; the use of topical N-acetylcysteine which, in animal models and human pilot studies (49), has significantly reduced radiation-induced skin reactions presumably by absorption of free radicals; and the use of topical thymidine which would compete with BUdR for incorporation into DNA of these superficial structures thereby preventing photo/radiosensitization. Also, in future studies. at the time of infusion pump placement the ipsilateral ascending pharyngeal artery will be identified and ligated to preclude direct arterial oropharyngeal exposure to BUdR. In the past, the use of intraarterial BUdR infusion, while showing promise in uncontrolled trials, had been restricted by technical limitations and infectious and vascular complications associated with prolonged percutaneous intraarterial infusion (20,35,36). In our preclinical primate study ( 16) and in this clinical Phase I trial there have been no infectious or vascular complications seen in any of the six rhesus monkeys or 23 human patients who have undergone permanent infusion pump placement. These results demonstrate that prolonged intraarterial infusion can be safely performed. We have also met the challenge to “deliver optimum levels of BUdR to tumor with minimal systemic toxicity” (34) as seen in tumor tissue samples assayed for BUdR incorporation. The 2.2-5.6% BUdR incorporation measured in tumor in two patients is well within the range reported necessary for effective radiosensitization (9, 49). A recent survey of the most effective combined modality treatment protocols for patients with high grade gliomas shows median survival of 11 months and 2-year survival < 20% (28). Though the object of a Phase I trial is not to determine efficacy of treatment compared with a standard therapy (42) it is encouraging to use that the study population has achieved a 20-month median survival. These early results compare favorably with overall, age, and histologically stratified survivals reported in several Phase III BTCG trials (15, 5 l-53), but need confirmation in larger, randomized studies. To further increase the potential advantages afforded by BUdR incorporation into malignant gliomas, we are currently investigating the coadministration of 5-fluorouracil (5-FU) with BUdR, thus blocking thymidylate synthetase and increasing tumor cell BUdR incorporation.
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2 1. Jackson, D.; Kinsella, T.; Rowland, J.; Wright, D.; Katz, D.; Main, D.; Collins, J.; Kornblith, P.; Glatstein, E. Halogenated pyrimidines as radiosensitizers in the treatment of glioblastoma multiforme. Am. J. Clin. Oncol. 10:437443; 1987. 22. Kaplan, E. L.; Meier, P. Non-parametric estimation from incomplete observations. J. Am. Stat. Assoc. 53:457-481; 1958. 23. Kinsella, T. J.; Collins, J.; Rowland, J.; Klecker, R., Jr.; Wright, D., Katz, D.; Steinberg, S. M.; Glatstein, E. Pharmacology and phase I/II study of continuous intravenous infusions of iododeoxyuridine and hyperfractionated radiotherapy in patients with glioblastoma multiforme. J. Clin. Oncol. 6:871-879; 1988. 24. Kinsella, T. J.; Mitchell, J. B.; Russo, A.; Aiken, M.; Morstyn, G.; Hsu, S. M.; Rowland, J.; Glatstein, E. Continuous intravenous infusions of bromodeoxyuridine as a clinical radiosensitizer. J. Clin. Oncol. 2: 1144-l 150; 1984. 25. Kinsella, T. J.; Mitchell, J. B.; Russo, A.; Morstyn, G.; Glatstein, E. The use of halogenated thymidine analogs as clinical radiosensitizers: rationale, current status, and future prospects. Non-hypoxic cell sensitizers. Int. J. Radiat. Oncol. Biol. Phys. 10:1399-1406; 1984. 26. Kinsella, T. J.; Russo, A.; Mitchell, J. B.; Rowland, J.; Jenkins, J.; Schwade, J.; Myers, C. E.; Collins, J. M.; Speyer, J.; Kornblith, P.; Smith, B.; Kufta, C.; Glatstein, E. A phase I study of intermittent intravenous bromodeoxyuridine (BUdR) with conventional fractionated irradiation. Int. J. Radiat. Oncol. Biol. Phys. 10:69-76; 1984. 27. Laramore, G. E.; Diener-West, M.; Griffin, T. W.; Nelson, J. S.; Griem, M. L.; Thomas, F. J.; Hendrickson, F. R.; Griffin, B. R.; Myrianthopoulos, L. C.; Saxton, J. Randomized neutron dose searching study for malignant gliomas of the brain: results of an RTOG study. Int. J. Radiat. Oncol. Biol. Phys. 14:1093-l 102; 1988. 28. Leibel, S. A.; Sheline G. E. Radiation therapy for neoplasms of the brain. J. Neurosurg. 66: l-22; 1987. 29. Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep. 50: 163- 170; 1966. 30. Marks, J. E.; Baglan, R. J.; Prassad, S. L.; Blank, W. F. Cerebral radionecrosis: incidence and risk in relation to dose, time, fractionation, and volume. Int. J. Radiat. Oncol. Biol. Phys. 71243-252; 198 1. 31. Nelson, D. F.; Diener-West, M.; Weinstein, A. S.; Schoenfeld, D.; Nelson, J. S.; Sause, W. T.; Chang, C. H.; Goodman, R. L.; Carabell, S. A randomized comparison of misonidazole sensitized radiotherapy plus BCNU and radiotherapy plus BCNU for treatment of malignant glioma after surgery: final report of an RTOG study. Int. J. Radiat. Oncol. Phys. 12:1793-1800; 1986. 32. Payne, D. G.; Simpson, W. J.; Keen, C.; Platts, M. E. Malignant astrocytoma. Hyperfractionated and standard radiotherapy with chemotherapy in a randomized prospective clinical trial. Cancer 50:2301-2306; 1982. 33. Phillips, T. W.; Chandler, W. F.; Kindt, G. W.; Ensminger, W. D.; Greenberg, H. S.; Seeger, J. F.; Doan, K. M.; Gyves, J. W. New implantable continuous administration and bolus dose intracarotid drug delivery system for the treatment of malignant gliomas. Neurosurgery 11:2 13-2 18; 1982. 34. Russo, A.; Gianni, L.; Kinsella, T. J.; Klecker, R. W., Jr.; Jenkins, J.; Rowland, J.; Glatstain, E.; Mitchell, J. B.; Collins, J.; Myers, C. Pharmacological evaluation of intravenous
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1. J. Radiation Oncology 0 Biology 0 Physics delivery of 5-bromodeoxyuridine to patients with brain tumors. Cancer Res. 44: 1702- 1705; 1984. Sano, K., Nagai, M., Hoshino T. Follow-up results of BAR therapy of malignant brain tumors. In: Fusek, I., Kunc, Z., eds. Proceedings of the Fourth European Congress of Neurosurgery. Amsterdam: Excerpta Medica; 1972:7 l-75. Sano, K.; Sato, F.; Hoshino, T.; Nagai, M. Experimental and clinical studies of radiosensitizers in brain tumors, with special reference to BUdR-antimetabolite continuous regional infusion-radiation therapy (BAR therapy). Neur. Med. Chir. 7:5 l-72; 1965. Shapiro, J. R.; Yang, W. A.; Shapiro, W. R. Heterogenous chemosensitivities of subpopulations of human malignant gliomas. Cancer 42:992-998; 1982. Sheline, G. E.; Wara, W. M.; Smith, V. Therapeutic irradiation and brain injury. Int. J. Radiat. Oncol. Biol. Phys. 6:1215-1228; 1980. Shin, K. H.; Muller, P. J.; Geggie, P. H. S. Superfractionation radiation therapy in the treatment of malignant astrocytoma. Cancer 52:2040-2043; 1983. Shin, K. H.; Urtasun, R. C.; Fulton, D.; Geggie, P. H. S.; Tanasichuk, H.; Thomas, H.; Muller, P. J.; Curry, B.; Mielke, B.; Johnson, E.; Feldstein, M. Multiple daily fractionated radiation therapy and misonidazole in the management of malignant astrocytoma. A preliminary report. Cancer 56:758-760; 1985. Silverberg, E.; Lubera, J. A. Cancer statistics, 1988. Ca J. Clin. 38:5-22; 1988. Simon, R. M. Design and conduct of clinical trials. In: DeVita, V. T., Jr., Hellman, S., Rosenberg, S. A., eds. Cancer, principles and practice of oncology, 2nd edition. Philadelphia: J. B. Lippencott, Co; 1985:329-350. Simpson, W. J.; Platts, M. E. Fractionation study in the treatment of ghoblastoma multiforme. Int. J. Radiat. Oncol. Biol. Phys. 1:639-644; 1976. Stetson, P. L.; Maybaum, J.; Shukla, U. A.; Ensminger, W. D. Simultaneous determination of thymine and 5-bromouracil in DNA hydrolysates using gas chromatographymass spectrometry and selected ion monitoring. J. Chromatogr. 375: 1-9; 1986. Stetson, P. L.; Shukla, U. A.; Amin, P. R., Ensminger, W. D. High performance liquid chromatographic method for the determination of bromodeoxyuridine and its major
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metabolite, bromouracil, in biological fluids. J. Chromatogr. 341:217-222; 1985. Szbalski, W. X-ray sensitization by halopyrimidines. Cancer Chemother. Rep. 58:539-557; 1974. Thames, H. D.; Peters, L. J.; Rodney. H.: Fletcher, G. H. Accelerated fractionation vs. hyperfractionation: rationale for several treatments per day. Int. J. Radiat. Oncol. Biol. Phys. 9:127-138; 1983. Thames, H. D., Jr.; Withers, H. R.; Peters, L. J.; Fletcher, G. H. Changes in early and late radiation responses with altered dose fractionation: implications for dose-survival relationships. Int. J. Radiat. Oncol. Biol. Phys. 8:2 19-226; 1982. Thomas, G. H.; Maloney, M. A.; Cleaver J. E. Sensitization of mouse L cells to ultraviolet light by low amounts of bromodeoxyuridine. Radiat. Res. 9 1: l45- 154; 1982. Urtasun, R. C.; Band, P.; Chapman, J. D.; Feldstein M. L.; Mielke, B.; Fryer, C. Radiation and high-dose metronidazole in supratentorial glioblastomas. N. Engl. J. Med. 294: 13641367; 1976. Walker, M. D.; Alexander, E., Jr.; Hunt, W. E.; MacCarty, C. S.; Mahaley, M. S., Jr.: Mealey, J. Jr.; Norrell, H. A.; Owens, G.; Ransohoff, J.; Wilson, C. B.; Gehan, E. A.; Strike, T. A. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial. J. Neurosurg. 49:333-343; 1978. Walker, M. D.; Green, S. B.; Byar, D. P.: Alexander, E. Jr.; Batzdorf, U.; Brooks, W. H.; Hunt, W. E.; MacCarty, C. S.; Mahaley, M. S., Jr.; Mealey, J., Jr.; Owens, G.; Ransohoff, J., III; Robertson, J. T.; Shapiro, W. R.; Smith, K. R., Jr.; Wilson, C. B.; Strike, T. A. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N. Engl. J. Med. 303: 1323- 1329; 1980. Walker, M. D.; Strike, T. A.; Sheline, G. E. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int. J. Radiat. Oncol. Biol. Phys. 5: 1725-1731; 1979. Zeman, E. M.; Bedford, J. S. Changes in early and late effects with dose-per-fraction: alpha, beta, redistribution and repair. Int. J. Radiat. Oncol. Biol. Phys. 10:1039-1047; 1984. Zulch, K. J. Histologic typing of tumors of the central nervous system. In: International histological classification of tumours, No. 21. Geneva: World Health Organization; 1979:45-50.
t .W
19, PP. 42 l-428 Copyright
0360.3016/90 $3.00 0 1990 Pergamon Press plc
??Phase I/II Clinical Trials
INTRA-ARTERIAL
BROMODEOXYURIDINE RADIOSENSITIZATION OF MALIGNANT GLIOMAS
T. J. HEGARTY, M.D.,’ A. F. THORNTON, M.D.,’ R. F. DIAZ, M.D.,9 W. F. CHANDLER, M.D.,3 W. D. ENSMINGER, M.D., PH.D.,~ L. JUNCK, M.D.,2 M. A. PAGE, R.N., M.S.,2 S. S. GEBARSKI, M.D.,5 T. W. HOOD, M.D.,3 P. L. STETSON, M.D., PH.D.,~ I;!. M. TANKANOW, B.S., M.S.,7 P. E. MCKEEVER, M.D.,8 A. S. LICHTER, M.D.’ AND H. S. GREENBERG, M.D.2 ‘Departmentof Radiation Oncology, 2Department of Neurology, ‘Department of Surgery, “Department of Internal Medicine, ‘Department of Radiology, 6Department of Pharmacology, ‘Department of Pharmacy, ‘Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48 109; and 9Methodist Hospital, Department of Radiation Oncology, Minneapolis Radiation Oncology, P.A., St. Louis Park, MN 55246 In the 1950’s it was first observed that mammalian cells exposed to the halogenateddeoxyuridineswere more sensitive to ultravioletlight and radiationthan untreatedcells. This promptedearly clinical trials with bromodeoxyuridine(BUdR:)which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR (400-600 mg/m*/day X 8; weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6f weeks). Following initial biopsy/surgery the infusion pump system was implanted, BUdR infusion began 2 weeks prior to and continued throughout the 64 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall KaplanMeier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognastically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas. Bromodeoxyuridinle,
Radiosensitization,
Malignant
gliomas.
INTRODUCTION
gliomas, improving median survival from 14 weeks for surgery alone to 36 to 40 weeks with the addition of postoperative radiation (5 l-53). The addition of single agent and combination chemotherapy to post-operative irradiation has yielded a slight improvement in median survival to between 40 and 55 weeks (8, 15, 17). Unique characteristics distinguish malignant gliomas from malignant neoplasms of other organs. Malignant gliomas do not metastasize except in rare instances. Local tumor progression in a confined inelastic space is the cause of death in virtually all cases. Total surgical excision is
It is estimated that primary central nervous system (CNS) neoplasms accounted for almost 11,000 cancer deaths in 1988 (4 1). Malignant gliomas made up over 5 100 of these cases (4). Progress in the .treatment of malignant gliomas has been slow even in the face of aggressive combined modality therapy. Since the late 1960’s the Brain Tumor Cooperative Group (BTCG) has conducted a series of prospective randomized trials demonstrating the efficacy of radiotherapy as an adjunctive treatment for malignant
Acknowledgement-We
Presented in part at the 30th Meeting of the American Society for Therapeutic Radiology and Oncology, New Orleans, LA, 13 October 1988. Reprint requests to: T. J. Hegarty, M.D., Department of Radiation Oncology, Wayne State University, 4201 St. Antoine, Detroit, MI 4820 1.
thank Ms. Beverly Ryder and Ms. Kathryn Strand for their professional assistance in the preparation of this manuscript. Accepted for publication 22 February 1990.
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rarely feasible because of the tumor’s infiltrative nature. Additionally, malignant gliomas are heterogenous tumors. 1n vitro cloning studies have shown multiple morphological cell types within a single tumor or region of a tumor with varying karyotypic numbers and differential chemosensitivity (37). Tumor progression as correlated by CT and histological studies confirms that persistent viable tumor cells adjacent to the central area of necrosis, but within the high dose external beam irradiation volume, are usually responsible for failure (3, 14, 18). Various methods to deal with these radioresistant cells have been studied. These include irradiation under hyperbaric oxygen conditions (7) use of electron affinic drugs such as metronidazole (50) and misonidazole (2, 3 1,40), and high linear energy transfer radiation (5, 6, 27). To date, none of these approaches has improved the survival results of radiotherapy alone. The use of potentially curative, higher dose external beam radiotherapy has been limited by normal brain tissue tolerance (19, 30, 38). Attempts to alter the therapeutic ratio and overall effectiveness of radiation therapy while limiting late effects has led to several trials of hyperfractionated or multiple daily fraction radiotherapy. While hyperfractionated therapy is theoretically attractive (47, 48, 54) in practice differences in survival have not been statistically significant (13, 32, 39, 43). The limitation of brain tissue tolerance has led many investigators to explore the interaction of external beam radiation and drugs that selectively increase tumor cell kill without increasing normal tissue toxicity. In the late 1950’s it was found that mammalian cells exposed to halogenated deoxyuridines, a group of thymidine analogs, were more sensitive to X ray and ultraviolet light than untreated cells (9). Considerable in vitro and in vivo experimental work confirmed that when these analogs were incorporated into the DNA of dividing cells, the degree of radiosensitization directly reflected the extent of thymidine replacement in DNA (46). In the late 1960’s and early 1970’s several clinical trials were undertaken to investigate the efficacy of radiosensitization with halogenated pyrimidines (1, 12,20, 35, 36). The brain is an area particularly well suited to halogenated pyrimidine trials since the rapidly dividing brain tumor cells can be expected to incorporate the drug, whereas the slowly dividing glial cells will not. Recently, in several Phase I studies, investigators at the National Cancer Institute established the feasibility of continuous intravenous (IV) infusion of bromodeoxyuridine (BUdR) and found survival in treated malignant gliomas to be at least comparable to that in other combined modality trials. However, they reported significant dose-limiting skin and bone marrow toxicities, and ques-
* Infusion pump manufactured wood, MA
by Shiley-Infusaid,
Inc., Nor-
August 1990, Volume 19. Number 2
tioned the optimal method of BUdR delivery (21, 2326). Intra-arterial (IA) infusion, these investigators speculated, would be the desired route of delivery. Because of the theoretical advantage of IA BUdR (10, 34) we initiated a primate toxicity study comparing carotid IA BUdR infusion to IA buffer infusion in control animals with both groups receiving external beam radiation to the brain. The study demonstrated no increase in pathology in the BUdR infused hemisphere (16). A clinical Phase I protocol was then developed utilizing IA infusion of BUdR prior to and concurrent with external beam irradiation of malignant gliomas. This paper reports on the preliminary results in the 23 patients enrolled. METHODS
AND MATERIALS
Patient selection Adult patients with histologically confirmed unilateral hemispheric malignant gliomas (World Health Organization designated anaplastic astrocytoma and glioblastoma multiforme; grade 3 and 4) (55) with blood supply primarily from one internal carotid artery and lesions measurable on CT scan were eligible for this Phase I study. Patients were required to have a Karnofsky rating 2 40, be capable of giving informed consent, be able to tolerate infusion pump placement, and have a life expectancy of at least 3 months. Eligible patients were also required to have normal peripheral blood count (WBC 2 4000 cells/ mL; platelets > 150,00O/mL), normal renal function (BUN < 30 mg/dl, creatinine < 1.5 mg/dl), and normal liver function (bilirubin < 2; SGOT and alkaline phosphatase < 2X normal). No prior radiation therapy or chemotherapy could have been given before enrollment in the study. Of 52 patients with malignant gliomas seen at the University of Michigan Medical Center during the course of this study (7/85-12/87), 23 fit the above criteria and were enrolled. Drug administration and radiation therapy BUdR was administered via the internal carotid artery. An implantable infusion pump system* was placed using previously described techniques (33). Irradiation was begun 2 weeks after initiation of BUdR infusion. All patients were treated on a linear accelerator with either 6 or 10 MeV photon energy. Tumor was defined by the rim of contrast enhancement on CT scan. A margin of 3-4 cm beyond this volume was treated to 45.0 Gy at 1.8 Gyfday and then a boost volume of enhancing lesion plus 1.5-2 cm was treated to 59.4 Gy at 1.8 Gy/day, most often with parallel opposed lateral fields (Fig. 1). Systemic corticosteroids and anticonvulsants were used in all patients. No patients received any other treatment until the time of
423
BUdRradiosensitization of malignantgliomas??T. J. HEGARTYet al. Week
0 +-
the Mantel test (29). The p-values in this report are determined from two-sided tests.
RESULTS
III= BUdR (400-600 mg/m* /day) lmtlal (3-4 cm margin around contrast ?? ?enhancing ”?lrradlatlon ‘_ ” rirn seen on CT scan) Boost irradiation (1.52 cm margin around contrast ??= enhancing rim seen on CT scan)
Fig. I. Treatment
schema.
Patient characteristics Twenty-three patients with malignant gliomas were treated on this Phase I trial between July 1985 and December 1987. Five patients had anaplastic astrocytoma/ grade 3 and 18 patients had glioblastoma multiforme/ grade 4. There were 16 males and 7 females with a median age of 48 years (range 20-7 1; 12 5 50 years, 11 > 50 years) and median Karnofsky rating of 70 (range 50-90). Six patients had only stereotactic biopsy, 15 patients underwent subtotal resection, and 2 patients underwent gross total resection.
BUdR-bromodeoxyuridine.
objective tumor progression. Twelve patients received palliative chemotherapy. Two patients required additional irradiation for spinal suba.rachnoid spread of their tumor. Two patients underwent additional surgery to debulk progressing tumor. Statistical considerations Survival was computed from date of surgery. Protocol treatment was begun usually within 2 weeks of surgery. All patients were followed a minimum of 9 months or until death. No patient has been lost to follow-up and no patient is excluded from analysis. Survival curves were plotted using the Kaplan-Meier method (22). Differences in survival were evaluated by
I.......,.....
Analysis of prognostic variables The median survival for all 23 patients entered on study is 20 months with 24% survival at 24 months (Fig. 2). In this study performance status, sex of patient, degree of antecedent tumor removal, and BUdR dose rate did not exert a discernable influence. Two factors did influence survival significantly. Patients with anaplastic astrocytomas lived longer than patients with glioblastoma multiforme (median survival not yet reached vs 14 months, p < 0.025) (Fig. 3). Patients 50 years and younger had a significant advantage over older patients (median survival 23.3 vs 13.5 months, p < 0.025) (Fig. 4). Pharmacology Systemic venous plasma steady state levels were measured in all patients using high performance liquid chro-
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MONTHS S4JRVlVAl.
Fig. 2. Kaplan-Meier plot of the probability patients. Ticks represent censored patients.
of survival
in months
from date of histological
diagnosis
for all 23
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August 1990, Volume 19, Number 2
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Fig. 3. Kaplan-Meier plot of the probability of survival in months from date of histological diagnosis for patients with anaplastic astrocytoma (5 patients, solid line) or glioblastoma multiforme (18 patients, dashed line). Ticks
represent censored patients. The survival for patients with anaplastic astrocytoma is significantly longer than for patients with glioblastoma multiforme (p < 0.025).
matography (HPLC) with UV absorption peak detection (45). The blood levels varied from 0.18 to 1.25 PM with total body clearance of 0.99 L/min to 11.3 L/min at infused dose of 400 to 600 mg/m*/day. Increasing the daily BUdR dose produced a variable response in the venous blood drug concentration. Based on these data, minimal regional brain extraction, and internal carotid blood flow of 250 ml/min, the systemic venous blood levels obtained with intraarterial infusion gave a total body clearance that
resulted in an estimated regional concentration (Rd) of BUdR of 6 to 16 fold, similar to that calculated by Russo et al. (34). Two patients underwent additional surgery for decompression and resection of progressing tumor. A DNA assay of BUdR incorporation in the tumor tissue was undertaken using gas chromatography-mass spectrometry with selected ion monitoring (44). In the first, who had resection in the 4th week of infusion, tumor samples
PeO.025
5 50 YEARS
Fig. 4. Kaplan-Meier plot of the probability of survival in months from date of histological diagnosis for patients I 50 years of age (12 patients, solid line) or patients > 50 years of age (11 patients, dashed line). Ticks represent censored patients. The survival for patients 5 50 years is significantly longer than for patients > 50 years (p < 0.025).
BUdR radiosensitization of malignant gliomas 0 T. J. HEGARTYet a/.
showed 2.2-5.0% BUdR incorporation while systemic steady state plasma levels were 0.30 PM with an infusion rate of 500 mg/m’/day. In the second, who had resection several weeks after compl’etion of infusion at 400 mg/m2/ day, tumor samples showed 3.3-5.6% BUdR incorporation while adjacent normal brain tissue included in the margin of resection showed 0.2-0.3% BUdR incorporation. Treatment toxicity There have been no vascular complications from the presence of the intraarterial pump system. Reversible dose-related myelosuppression (particularly thrombocytopenia, and to a lesser degree, leukopenia) was observed in five patients; the one moderate case was receiving the highest dose of BUdR (600 mg/m’/day). Two patients experienced transaminase elevations and one patient developed acute hepatitis, with full recovery. Adverse systemic effects included faiigue, anorexia, and weight loss in the majority of patients. All patients developed ipsilateral facial dermatitis. By the second week of BUdR infusion, before radiation had begun, slight erythema was perceptible in the region of the face supplied by the ophthalmic artery, the first branch of the infused internal carotid artery. Two weeks after irradiation began, skin changes escalated. Erythema, swelling, and induration of the forehead extended to the upper and lower eyelids and maxillary face in the distribution of the ophthalmic artery. Epilation of the eyebrows and eyelashes occurred ipsilaterally. Some reactions were marked by dry desquam,ation with pronounced scaling, while others had moist desquamation characterized by multiple erosions and serosanguinous crusts. Three patients required dose reduction of BUdR due to the severity of this reaction. Management of the mucocutaneous reactions included dose reduction of the BUdR as well as local treatment. All patients were advised to minimize sun exposure and to wear a protective hat and sunglasses. Therapy of the facial dermatitis varied depending on its nature. Mild dry desquamative determatitis was best treated with gentle soap cleansing and hydrocortisone 1% cream. Severe moist desquamative dermatitis was managed with wet antiseptic compresses to remove debris and crusts. According to each individual case, the dermatitis was dressed with a hydrogel or petrolatum-impregnated gauze, or was left uncovered. Following therapy, patients were advised to continue sun avoidance, to use an effective sunscreen, and to keep .the skin well lubricated with a non-irritating moisturizer. Four patients developed ipsilateral oral cavity and oropharyngeal ulcers. These were located on the posterior soft palate, retromolar trigone region or lateral pharyngeal wall. They were characterized by being exquisitely painful, with a deep necrotic base and shaggy angular configuration, measuring up to 4 cm in diameter. Resolution did not occur until therapy was completed. The oral ulcers
425
were symptomatically treated with dilute salt and baking soda rinses and viscous xylocaine. All patients underwent ophthalmologic evaluation. Many complained of dryness of the eyes and had ipsilatera1 eyelid erythema, induration, and pruritus. Conjunctival hyperemia was observed in all. Patients were symptomatic 1 week after starting BUdR infusion and symptoms continued until BUdR dose was lowered or treatment was completed. Mucopurulent conjunctival discharges were cultured from eight patients and found to grow Staphylococcus in six cases, Pseudomonas in one, and Neisseria in one. Mechanical ectropion was seen in four, exposure keratitis in three, and cornea1 perforation in one. Ophthalmic artificial tears were recommended during the day and an ophthalmic ointment at night. Five patients developed a pruritic, erythematous macular and papular eruption affecting the face, neck, upper trunk, and upper extremities. Skin biopsies in two affected patients demonstrated a mild superficial perivascular lymphocytic infiltrate with hyper- and parakerotosis, mild acanthosis, and focal necrotic keratonocytes compatible with a drug hypersensitivity reaction. One patient developed severe erythema multiforme major (Stevens-Johnson syndrome) 5 1 weeks following initiation of BUdR, while also taking carbamazepine and dexamethasone. She had had a previous drug eruption secondary to phenytoin prior to starting BUdR infusion. Her plasma levels of BUdR were noted to be the highest and her plasma clearances the lowest of any patient treated. The distribution of the erythema multiforme major was unusual in that it began on the face and spread to involve primarily the trunk with relative sparing of the extremities, including hands and feet. Large sheets of skin desquamated (80-90% of skin surface), leaving vast areas of denudation. Oral, ocular, and genital mucosae were involved. BUdR, carbamazepine, and irradiation were discontinued, dexamethasone maintained, and her condition was managed in the burn unit, with excellent dermatologic recovery. Patients were observed to have nail ridging affecting all fingernails and some toenails. While an uncommon occurrence, when seen, nail shedding was preceded by the formation of a depressed horizontal white band with slight discoloration superimposed. Completely normal nails regrew within 6 months.
DISCUSSION
It has been established that halogenated pyrimidines are effective non-hypoxic cell radiosensitizers in vitro and in vivo (9, 46). However, clinically, when given intravenously, BUdR has major systemic dose limiting toxicities. Investigators using intravenous BUdR have reported that escalation of dose beyond 700 mg/m2/12 hr infusion has resulted in severe myelosuppression and have shown that
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1. J. Radiation Oncology 0 Biology 0 Physics
steady state plasma levels of BUdR correlate with degree of myelosuppression (34). Myelosuppression was seen and bone marrow stem cells harvested and irradiated in vitro exhibited a radiation enhancement factor as high as 2.2 when the plasma concentration was 2.1 PM (24, 26). However, neither myelosuppression nor in vitro bone marrow radiosensitization were seen when plasma BUdR concentration was 0.7 PM. Steady state plasma levels achieved in our patients ranged from 0.18 PM to 1.25 PM, well below the levels found to cause severe myelosuppression. Only one patient experienced moderately severe myelosuppression at a BUdR dose of 600 mg/m2/ day X 8 weeks and plasma steady state concentration of 0.64 PM. Although adverse systemic effects have been minimized, severe local mucocutaneous reactions have been found to be dose limiting. Our maximum tolerated dose (MTD) appears to be 400 mg/m2/day. The most significant toxic effects have been ipsilateral dermatitis, blepharitis, conjunctivitis, and oropharyngeal mucositis. These reactions begin prior to the initiation of irradiation, are not seen on the contralateral side, and so are directly attributable to the IA BUdR. Only four patients developed ipsilateral oropharyngeal ulceration and the relative infrequency of this complication is thought to be due to the variability in the origin and caliber of the ascending pharyngeal artery. The acute mucocutaneous reactions escalated during the course of the infusion and irradiation though the affected areas were not in the primary beam. Thermoluminescent dosimetric (TLD) measurements taken at the orbits showed a 7- 10% internal scatter dose contribution bilaterally. Assuming the maximal BUdR radiosensitization factor of 3 (9, 1 l), the effective dose to the ipsilateral face did not exceed 18.0 Gy over 61 weeks. This is far below the total dose necessary to realize the equivalent acute reactions seen when treating primary head and neck fields. Hence, ambient ultraviolet light may play an important role in development of the mucocutaneous toxicity, and the direct cytotoxicity of high concentrations of BUdR alone may produce some of the observed side effects. BUdR is a potent photosensitizer as its maximum absorption spectrum falls between 270-310 nm (25). In vitro studies have shown BUdR treated cells to be 5 times as sensitive to UV radiation as IUdR treated cells and 10 times as sensitive as untreated cells with D-zero’s of 27, 140, and 280 erg/mm2, respectively (11).
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To counter the mucocutaneous side effects three approaches may be considered for future studies: the use of non-paraaminobenzoic acid (PABA) sunscreens to decrease photosensitization; the use of topical N-acetylcysteine which, in animal models and human pilot studies (49), has significantly reduced radiation-induced skin reactions presumably by absorption of free radicals; and the use of topical thymidine which would compete with BUdR for incorporation into DNA of these superficial structures thereby preventing photo/radiosensitization. Also, in future studies. at the time of infusion pump placement the ipsilateral ascending pharyngeal artery will be identified and ligated to preclude direct arterial oropharyngeal exposure to BUdR. In the past, the use of intraarterial BUdR infusion, while showing promise in uncontrolled trials, had been restricted by technical limitations and infectious and vascular complications associated with prolonged percutaneous intraarterial infusion (20,35,36). In our preclinical primate study ( 16) and in this clinical Phase I trial there have been no infectious or vascular complications seen in any of the six rhesus monkeys or 23 human patients who have undergone permanent infusion pump placement. These results demonstrate that prolonged intraarterial infusion can be safely performed. We have also met the challenge to “deliver optimum levels of BUdR to tumor with minimal systemic toxicity” (34) as seen in tumor tissue samples assayed for BUdR incorporation. The 2.2-5.6% BUdR incorporation measured in tumor in two patients is well within the range reported necessary for effective radiosensitization (9, 49). A recent survey of the most effective combined modality treatment protocols for patients with high grade gliomas shows median survival of 11 months and 2-year survival < 20% (28). Though the object of a Phase I trial is not to determine efficacy of treatment compared with a standard therapy (42) it is encouraging to use that the study population has achieved a 20-month median survival. These early results compare favorably with overall, age, and histologically stratified survivals reported in several Phase III BTCG trials (15, 5 l-53), but need confirmation in larger, randomized studies. To further increase the potential advantages afforded by BUdR incorporation into malignant gliomas, we are currently investigating the coadministration of 5-fluorouracil (5-FU) with BUdR, thus blocking thymidylate synthetase and increasing tumor cell BUdR incorporation.
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