Cytostatics and immunosuppressive drugs

K. Wierzba, Y. Yamada and M. Hanano

47

Cytostatics and immunosuppressive drugs

CARDIOTOXICITY (SED-IO, 832, 834; SEDA-8, 395; SEDA-9, 367; SEDA-IO, 390; SEDA-11, 384)

Early toxicity Amsacrine (m-AMSA) Administration of mAMSA is often associated with arrhythmias and ventricular dysfunction. Lindpaintner (1 r et al have reported a case of acute myocardial necrosis in previously healthy female patients. m-AMSA was administered at a dose of 120 mg/m2/d. While receiving the third dose the patient developed atrial fibrillation, and over the next 24 hours serum creatinine phosphokinase rose from 35 to 160 IU/1. Within a few days the clinical course was complicated by mild congestive heart failure. Postmortem examination of the heart revealed mild cardiomegaly and a small area of fibrosis consistent with myocardial infarction. An estimation of the incidence of cardiotoxic reactions with m-AMSA has been made by Weiss et al (2R). The authors identified 5430 patients treated with m-AMSA including 65cases of cardiotoxic effects. Sixty-four patients developed cardiac events ranging from prolongation of the QT interval and non-specific ST-T wave changes to ventricular tachycardia and/or ventricular fibrillation. Thirty-one patients had serious ventricular arrhythmia that resulted in cardiopulmonary arrest. Fourteen of these patients died as a result of the arrhythmia or cardiac arrest. The arrhythmie episodes occurred within minutes to several hours aRer drug administration. The manifestation of cardiotoxicity was not related to the total cumulative dose, and hypokalemia may be a risk factor for the development oftachyarrhythmias. Cisplatin Cardiotoxicity of cisplatin has been reported in a few cases, most of them heavily pretreated with potentially cardiotoxic drugs. Side Effects of Drugs Annual 12 M.N.G. Dukes and L. Beetey, editors 9 Elsevier Science Publishers B.V., 1988

Recently, Fassio et al (3 r have observed an untreated patient who developed paroxysmal supraventricular tachycardia during administration of cisplatin (20 mg/m 2) with etoposide (75 rag/m2). The arrhythmia seemed to be clearly related to cisplatin since a normal rhythm was observed after cisplatin had been withdrawn.

Cyclophosphamide High-dose

cyclophosphamide (120-200 mg/kg) is often used in immunosuppression of patients for bone marrow transplantation. It has become obvious that this dose of cyclophosphamide could cause a lethal cardiotoxicity characterized by severe congestive heart failure occurring 1-10 days after administration of the first dose. The clinical syndrome of severe cardiac congestive failure is accompanied by ECG findings of diffuse voltage loss, cardiomegaly, pulmonary vascular congestion, and pleural and pericardia] effusion. Pathological findings include hemorrhagic myocardial necrosis, thickening of the left ventricular wall and fibrinous pericarditis. Goldberg et al (4 c) have studied 80 patients who had received cyclophosphamide 50 mg/kg/d for 4 days in preparation for marrow grafting. Seventeen per cent of patients had symptoms consistent with cyclophosphamide cardiotoxicity. Six patients died from congestive heart failure. Older patients more often developed signs of cardiotoxicity. An extremely low incidence of cyclophosphamide cardiotoxicity occurred in pediatric patients. Trigg et al (5 c) have reported 3 patients with irreversible myocardial toxicity secondary to a combination of high-dose cytarabine cyclophosphamide and total body irradiation. No fatal myocardial reactions were seen in patients who had received lower doses of cycl0phosphamide. A similar chemotherapeutic regimen, consisting of cytarabine (5 mg/kg), cyclophosphamide (90 mg/kg) and total body irradiation, was used in patients undergoing bone marrow transplantation (6r Only a few patients showed a deterioration in left ventricular function.

Vinblastine Subar and Muggia (7 c) have re-

Cytostatics and immunosuppressive drugs Chapter 47

381

ported a patient who experienced substernai chest pain and slight nausea 8 hours after the first dose of vinblastine. ECG showed an anterolateral subendocardial myocardial infarction. Similar symptoms developed al~er administration of the subsequent dose. The mechanism of this rare complication of vinblastine therapy is unclear. It was postulated that a direct effect on the platelets or blood clotting mechanism, or VBL-indueed coronary spasms may be responsible for this mechanism. However, there were no changes in several parameters of blood clotting tested in patients who had developed myocardial infarction when treated with vincristine. A coronary spasm due to vinblastine administration was unlikely since verapamil did not prevent ischemia with ECG changes.

(10 c) have studied 29 patients treated with epirubicin in cumulative doses ranging from 147 to 888mg/m 2. The ultrastructural myocardial lesions produced by epirubicin were similar to those produced by doxorubicin (partial and total myofibrillar loss in individual myocytes). In both cases severe lesions were accompanied by replacement fibrosis. Contrary to doxorubicin, no patient who received epirubicin in their study developed congestive heart failure. Analysis of these two agents revealed that approximately 180 mg/m 2 more epirubicin can be administered before a similar degree of cardiac injury will occur.

Late cardiotoxicity

NEUROTOXICITY (SED-IO, 834, 336; SEDA-9, 399 ; SEDA-9, 376 ; SEDA-IO, 392 ; SEDA-1 I, 386)

Doxorubiein (adriamycin) The clinical application of doxorubicin is dose-limited due to its cardiotoxicity. Dose limitation may deprive the patient of effective cancer chemotherapy. Due to its relatively high anticancer activity, many attempts have been made to solve the problem of early detection of cardiotoxicity. The histological investigation of myocardial tissue appears to be the most reliable method of heart function monitoring. Mortensen et al (8 c) have studied 11 cases with signs of anthracycline cardiotoxicity, using heart catheterization with endomyocardial biopsy. Myocytic changes correlated linearly with cumulative dose. Data obtained during right heart catheterization suggested a nonlinear relationship between electron-microscopic changes and the degree of hemodynamic impairment. Some degree of tissue damage may be present without equivalent hemodynamic signs of impairment. There was a pronounced fibrous thickening of the endocardium in most of the patients, especially in the left ventricle. Endocardial fibrosis may be the first morphological sign of cardiotoxicity, and can be observed in patients with low-grade myocardial damage. Recently, Hatfield et al (9c) have demonstrated an increased cardiac uptake of gallium in a patient with congestive heart failure induced by doxorubicin (total dose 458 mg/m2). Gallium uptake markedly decreased following successful treatment for congestive heart failure.

Neurological symptoms occurring in patients with cancer are common and over 20% of cancer patients develop this disability. Cytostatic therapy may, in many instances, increase the frequency of neurotoxicity in cancer patients. The acute and late neurotoxic syndromes involve many different agents (Table 1).

Epirubicin An epimer of doxorubicin, epirubicin has similar anticancer activity and lower toxicity, including cardiotoxicity. Torti et al

Ciclosporin (cyclosporin) Neurotoxicity has recently been recognized as a serious side effect of ciclosporin treatment. Labar et al (14c) re-

Aeiviein Acivicin is a potent inhibitor of Lasparagine synthetase and other L-glutamine amidotransferases, which kills the cell by blocking nucleotide biosynthesis. Beside its myelotoxicity, acivicin possesses neurologic toxicity, manifested by lethargy and auditory as well as visual hallucinations. Some patients may experience nystagmus, incontinence and severe depression

(11 c, 12c). Azidothymidine Hagler and Frame (13 c) have reported a patient with AIDS who developed a severe neurotoxicity following azidothymidine treatment. The patient received oral azidothymidine 200 mg every 4 hours. He complained of severe headache 48 hours aRer institution of the drug and later was found to be unresponsive. Focal seizures were observed on two occasions, consisting of tonic-clonic activity of his left arm and leg. Azidothymidine was reinstituted, and 72 hours later the patient became increasingly confused, with aphasia and left-sided weakness. Focal seizures continued unabated for the next 12 hours despite intravenous anticonvulsants and the patient died of respiratory arrest.

382

Chapter 47 K. Wierzba, Y. Yamada and M. Hanano

ported 3 patients who developed neurotoxicity following treatment with ciclosporin. Neurotoxicity was manifested by grand real seizures and dysarthria. T h e plasma concentration of ciclosporin in these patients increased at when the neurological signs appeared and these resolved quickly after dose reduction.

presence of abnormal liver functions at the start of therapy and the development ofneurotoxicity appear to be significantly associated. The symptoms of neurotoxicity resolved within 4-49 days. Cold (16 ~) has reported a patient who developed the cerebellar dysfunction following cytarabine administrationat a cumulative dose of 32 g/m 2 (usually symptoms are observed when dose exceeds 36 g/m2). The symptom - a slight dyscoordination - persisted for 10months. Signs ofcerebellar dysfunction following administration of a much lower dose of cytarabine (24 g/m2), complicated by aseptic meningitis, have been reported (17~).

Cytarabine ( c y t o s i n e a r a b i n o s i d e , ara-C) Cytarabine is one of the most effective agents in the treatment of acute leukemia. It is often used, in high doses, in the treatment of acute leukemia refractory to conventional chemotherapy. The most common complication of high-dose cytarabine therapy is the cerebellar syndrome. Nand et al (15 ~) observed this syndrome in 7 out of 30 patients (23 ~o). The clinical symptoms of CNS toxicity appeared between the 3rd and 7th day after starting chemotherapy, and manifested first by lethargy and confusion. Within the next 24 hours signs ofcerebellar dysfunction were observed. These included the presence of dysarthria, atoxic tremor, nystagmus and dysmetria. In most patients in whom neurotoxicity developed, initially abnormal liver function test results worsened during chemotherapy. The

The patient was treated with cytarabine 3 g/m2, twice daily. On the 3rd day the patient suffered headache, and stiffness of the neck; the temperature rose to 39.4 ~ Examination of the CSF showed 126 polymorphonuclear cells. Aerobic and anaerobic culture of the CSF and blood were negative. Aseptic meningitis, which has been seen in this patient, can be observed in some patients given intrathecal cytarabine. This may represent

Table 1. Cytostatic agents that may be toxic to the nervous system Drug

Neurotoxic effects

Alkylating agents Mechlorethamine Chlorambucil Ifosfamide Nitrosoureas Carmustine

Rare encephalopathy following high doses Hallucinations Disorientation, cognitive dysfunction, mild memory disturbances

Antimetabolites Methotrexate Fluorouracil Vidarabine Cytarabine Vinca alkaloids Vincristine Vinblastine Vindesine Vinzolidine Cisplatin Ciclosporin L-Asparaginase Sparfosic acid (PALA) 2' -Deoxycoformycin Nitroimidazole radiosensitizers Spirogermanium CNS prophylaxis

In conventional doses when combined with radiation may cause brain damage Intrathecal: acute meningitis; chronic leukoencephalopathy, acute fatal cerebral dysfunction CerebeUar ataxia at high doses Generalized rigidity, gibberish, myoclonic jerks CerebeUar ataxia at high doses Peripheral neuropathy, abdominal pain, constipation Jaw pain, myopathy, inappropriate ADH secretion Overdosage or accidental intrathecal injection usually fatal as a consequence Peripheral neuropathy, deafness, cortical blindness, epileptic seizures Loss of visual acuity, visual hallucinations, seizures, tremor and depression Acute encephalopathy Encephalopathy, seizures Lethargy, somnolence, coma Peripheral neuropathy, encephalopathy (dose-limiting) Dizziness, somnolence, altered mental status, seizures in overdose Growth retardation

Cytostatics and immunosuppressive drugs Chapter 47

383

the first case of aseptic meningitis following intravenous administration of cytarabine. An acute neurologic and life-threatening toxicity after intrathecal administration of 80 mg of cytarabine has been reported (18c). At 48 hours following cytarabine administration, the patient developed pronounced muscle weakness, retention of urine, and seizures. Over the next few days his condition deteriorated with profound anesthesia, dysarthria, progressive weakness deteriorating respiratory function. A delayed neurotoxicity following intrathecal cytarabine was observed in 2 pediatric patients (19 c) who had received total cytarabine doses of 180 and 120 mg, respectively. The symptoms occurred at 4 and 6 months after the final doses and manifested by progressive ascending paralysis leading to respiratory insufficiency and death in one patient. At autopsy, a spinal cord demyelination characteristic of cytarabine neurotoxicity was found.

Fiudarabine phosphate Fludarabine phosphate is a new purine nucleoside antitumor agent, with ability to inhibit DNA synthesis. Dose-limiting myelotoxicity, nausea and vomiting, and elevation of liver enzymes were observed during early clinical studies. Recently, ttudarabine phosphate has been reported to have severe CNS toxicity (22c). A total of 70 patients with acute leukemia received 95 courses of the drug at dally doses ranging from 20 to 220 mg/m 2 for 5-7 days. Neurotoxicity was observed in 36% of patients who received high doses (>96mg/m2/d), but only in 0.2% of patients treated with lower doses. The onset of neurologic symptoms was delayed, usually appearing 21-60 days after the last course of fludarabine phosphate. Visual symptoms were the most frequent. Progressive deterioration of mental status or encephalopathy leading to a vegetative state developed in 11 patients. Clinicopathologic findings showed that a progressive demyelination in the CNS appears to be a main factor precipitating neurotoxic symptoms.

Doxifluridine (5'-deoxy-5-fluorouridine) Doxifluridine is a new compound of 5-fiuorouracil. Heier and Fossa (20 c) performed a neurological evaluation of 17 patients treated the drug. Ten patients developed symptoms of CNS toxicity while receiving the drug (5 or 3 g/m2/h/d for 5 days every 4 weeks for 3 months). The CNS symptoms, cerebellopathy and encephalopathy developed simultaneously and were generally first noted by the patients during the 2nd week of the 1st cycle. The neurotoxicity was dose-related and worsened during subsequent treatment. The symptoms of cerebellopathy ranged from a subjective feeling of unsteady gait to a disability, while encephalopathy was manifested by moderate difficulties of concentration and memory. Patients with marked loss of weight loss and with a pathological ECG (generalized dysrhythmia) are at increased risk to develop neurotoxicity following doxifluridine administration. Floxuridine (5-fiuoro-2'-deoxyuridine) A 66year-old patient with metastatic adenocarcinoma of the liver was treated with hepatic arterial infusion of floxuridine (35 mg/24 h) (21c). One day later the patient appeared lethargic and poorly responsive to verbal commands. Neurologic examination demonstrated severe bilateral ptosis. Motor examination showed marked dysmetria of the right upper extremity. The symptoms reappeared after reinstitution of the drug. New findings included ataxia of all limbs and marked myoclonus. An EEG showed generalized slow-wave activity consistent with a diffuse encephalopathy.

lfosfamide

Ifosfamidc is an oxazaphosphorine derivative which is usually administered intravenously together with sodium 2-mercaptoethane sulfonate, the agent protecting the urinary tract against hemorrhagic cystitis induced by acrolein, a main metabolite of ifosfamide. Usually, ifosfamide-induced neurotoxicity is manifested in transient states of confusion. However, it can be associated with moderate ototoxicity and peripheral neuropathy when administered in combination with cisplatin (24c). These symptoms improved within a few days after treatment with haloperidol. Pratt et ai (25 c) have evaluated the effectiveness of ifosfamide in 57 pediatric patients with malignant solid tumors. In their study, all patients received 1.6 g/m2/d for 5 days followed by mesna at a dose of 400 mg/m 2 at 0.25, 4, and 6 hours after ifosfamide. Neurologic toxicity occurred in 13 patients. The usual symptoms were somnolence and weakness followed by confusion, tremors, ataxia, aphasia, urinary incontinence and cranial nerve paralysis. The symptoms of neurotoxicity disappeared spontaneously within 72 hours after completion of the 5-day course. Some patients had a recurrence ofneurotoxicity upon rechallenge with ifosfamide. Recent observations indicate that characteristic, severe but reversible neurotoxicity, may be observed in some patient groups. Meanwell et al (26 C) made an analysis of the incidence and features of EEG changes associated with ifosfamide + mesna therapy. There was no significant association between EEG recorded before and during treat-

384 ment. EEG changes developed 12-24 hours before clinical toxicity. Discriminant analysis identified low serum albumin concentrations, high serum creatinine levels and the presence of pelvic disease as factors predisposing patients to the development of severe encephalopathy. An unusual neurologic disorder after high-dose methotrexate therapy has been reported in 4% of patients (27c). All patients received methotrexate approximately 8-9 g/m2 i.v. over 4 hours. The encephalopathy began abruptly, an average of 6 days after the 2nd or 3rd weekly treatment, with behavioral abnormalities. These ranged from laughter to lethargy or unresponsiveness. In some patients, there were focal sensorimotor or reflex signs and generalized seizures. The disorder usually lasted from 15 min to 72 hours and disappeared as abruptly as it began, without specific treatment. These features, plus the neurologic findings, suggest a vascular etiology, either emboli or an alteration of the cerebral vasculature with resultant ischemia. Other possible causes are transient vasospasm or small vessel occlusion. Methotrexate

Neurotoxicity is a dose-limiting factor in the clinical application of Vinca alkaloids. Rhomberg (28 c) has reported on a single agent study with vindesine, administered at a dose of 2 mg/m 2 on 2 subsequent days per week. Peripheral neuropathy with paresthesias was seen in 14 out of 22 patients while muscular weakness with loss of deep tendon reflexes was seen in 5 patients. Neuropathies were sometime oronounced at sites of pre-existing nerve damage. For instance, if a tumor had damaged peripheral nerves or a chordotomy had been performed previously, the subsequent paresthesias at that site were quite painful. Neurotoxicity was reversible, and the longest interval to full recovery was 3 months. The Vinca alkaloids may exert a synergistic activity in terms of neurotoxicity induction. Stewart et al (29c) treated 17 patients with metastatic breast cancer using the 4-drug combination of vincristine + vinblastine + doxorubiein + cyclophosphamide. The high incidence of acute neurotoxicity was observed at only half the usual dose of vincristine and vinblastine. At the usual maximum doses of these drugs, one would expect only a small proportion of patients to develop severe neurotoxicity. Vinea alkaloids

Chapter 47 K. Wierzba, Y. Yamada and M. Hanano NEPHROTOXICITY AND OTHER URINARY COMPLICATIONS (SED-IO, 838; SEDA-8, 403; SEDA-9, 374; SEDA-IO, 397; SEDA-I I, 391) Cielosporin (eyclosporin) As use ofciclosporin as an immunosuppressive agent in human renal transplantation has increased, the major side effect - nephrotoxicity - has gained more attention and importance. Ciclosporin-induced nephrotoxicity is suspected clinically when there is an abrupt rise in serum ereatinine concentration in the absence of typical symptoms of acute rejection. However, differentiation of this in patients after kidney transplantation is not only difficult but often impossible. The diagnosis of ciclosporin nephrotoxicity is based upon the clinical findings, laboratory data, and frequently the microscopic examination of biopsy specimens. The clinical symptoms are well known and include a fine tremor of the hands, a feeling of anxiety, a flushing sensation on the face and chest, gingivaI hyperplasia and occasionally generalized seizures. The ciclosporin-related injuries, including delayed allograft function, acute vasculopathy and chronic nephrotoxicity, have been previously reported (SEDA-11, 391). Ciclosporin-induced nephrotoxicity has been reported mainly in patients who had undergone major organ transplantation. Recently, some reports have appeared on nephrotoxicity of ciclosporin in patients treated for other immunological disorders. Nahman et al (30c) reported on 2 patients given ciclosporin for recurrent cataracts and ehronic inflammatory demyelinating polyradieuloneuropathy, respectively. Both patients developed irreversible renal failure. Important clinical features in these patients included the early occurrence of hypertension, which in one patient preceded by several months an elevation in serum creatinine (31c). Palestine et al (32 c) evaluated renal morphology in 17 patients who had received ciclosporin therapy for sight-threatening uveitis. Most of these patients did not require other potentially nephrotoxic drugs which might complicate the estimation of ciclospodn-induced nephrotoxicity. A variable amount of interstitial fibrosis, which was usually associated with tubular atrophy, was present in all 17 specimens. The severity of the renal abnormalities did not correlate with either the age, treatment period or the average cumulative dose. Ciclosporin nephrotoxicity can mimic many of the histologic features of acute allograft rejection and acute tubular necrosis. Because of critical differences

Cytostatics and immunosuppressive drugs Chapter 47

385

in the treatment required for toxicity (decrease in dose) as opposed to rejection (increase in dose), the ability to identify ciclosporin toxicity is an important clinical problem. Kolbeck et al (33 c) have used antibody directed against ciclosporin to identify staining patterns of renal biopsy material potentially associated with ciclosporin nephrotoxicity. Ciclosporin nephrotoxicity-associated staining involved primarily the renal tubular epithelium and interstitium. Moderate to severe nephrotoxicity was characterized by extensive ciclosporin antibody staining and low infiltration with Leu-2-positive cells. Parvin etal (34c) have used ultrasound measurement of renal volume to monitor renal function after transplantation. It was observed that in cases of rejection there was a minimum increase in renal volume (cross-sectional area) of 10% within 2 consecutive days associated with a significant rise in serum creatinine. Similarly, in cases of ciclosporin toxicity, a significant rise in serum creatinine but no significant change in cross-sectional area was observed. This technique for differentiation of rejection from toxicity has been assessed only in cellular rejection and may not apply to vascular rejection. Holt et al (35 r have based their differentiation of acute rejection from ciclosporin ncphrotoxicity on the trends in the predose blood concentration in the week before the episode of renal dysfunction. The mean ciclosporin concentration in the 7-day period before biopsy in patients suffering graft rejection (histopathologic examination) was 471 ng/ml compared with 891 ng/ml in the nephrotoxic group. This study confirmed once again the role of ciclosporin concentration in the triggering of nephrotoxicity. The incidence of ciclosporin-induced nephrotoxicity may be increased in patients receiving this drug in combination with other potentially nephrotoxic agents. Recently, Termeer et al (36 r have reported 3 cases of severe nephrotoxicity induced by the combination of ciclosporin and gentamicin in renal transplant patients. Similar toxicity was observed in patients receiving both drugs before surgical procedures, even though high or toxic serum levels of either drug were not achieved.

or tubular damage. The authors examined 9 patients using '2SI-orthoiodohippurate clearance and an estimation of glomerular filtration rate (GFR) from the rapid changes in extracellular volume and the mean transit time of 99mTc-DTPA in this volume. Early cisplatin treatment decreased the clearrance without acute changes in GFR, indicating that cisplatin inhibits the active transport of ~zSI-orthoiodohippurate in the tubules. However, in the longterm follow-up period, there was a progressive decrease in GFR. An important aspect of their study is the confirmed decrease in GFR after termination of treatment. Since cisplatin accumulates in the kidney, it may continue to exert a cytotoxic effect. Fjeldborg et al (38 c) have studied the longterm effect of cisplatin on renal function in patients who received total cumulated doses of 275-650 mg/m 2. A significant increase in serum creatinine was found during chemotherapy until 3 months. No further increase was found. Values of GFR from the time of diagnosis until the last investigations fell by 13-48~o. Serum magnesium and urinary excretion of ~-microglobulin were normal, indicating a moderate and permanent reduction of G F R without signs of persisting tubular damage. However, a number of case-reports have described hypomagnesemia and renal magnesium wasting following administration of cisplatin. Lam et al (39 c) have prospectively studied 28 patients who received a total of 82 doses of cisplatin. Hypomagnesemia occurred in all patients and was associated with significant prolonged dose-related magnesium wasting. Serum magnesium was 1.8 _ 0.1 rag/100 ml before cisplatin treatment and decreased to 0.9 _+0.1 mg/100 ml after the 4th dose. Examination of the urine sediment 2-4 days after each dose of cisplatin revealed the presence of renal tubular epithelial cells, which suggests that the drug may directly injure the tubules, thus leading to decreased reabsorption of filtered magnesium, with resultant renal magnesium wasting and hypomagnesemia. It has been suggested that routine magnesium supplementation become part of cisplatin regimens. Willox et al (40 r have also shown a cisplatin dose-related decrease in magnesium. Some of their patients were receiving magnesium supplements. The magnesium-supplemented patients showed significantly less renal tubular damage as assessed by urine N-acetyl-$-D-glucosaminidase. No patient developed clinical signs of hypomagnesemia since intravenous or oral supplements were given when the serum magnesium fell to

Cisplatin (eis-diehlorodiammine platinum; CDDP) Cisplatin, a heavy metal derivative, is predominantly a tubular toxin. Groth et al (37 c) have performed a study to explain whether acute nephrotoxicity in man is due to glomernlar

386 0.45 mmol/1. Markman et al (41 c) have shown a lower incidence of hypomagnesemia in patients receiving high-dose intracavitary cisplatin (100-200 mg/m 2) with intravenous thiosulfate. Probably thiosulfate inactivated cisplatin, reaching the systemic circulation before it reached the kidney, due to a complex formation.

Mitomyein The potential nephrotoxicity of mitomycin is frequently mentioned, but it is not well-documented. Vervey et al (42c) have initiated a prospective study to monitor patients during treatment with mitomycin. This study suggests that mitomycin may induce the hemolytic uremic syndrome, as observed in one patient after a cumulative dose of 40 mg/m 2. The incidence is likely to be less than 10%. Laboratory tests were unable to predict this side effect. Sheldon et al (43 cr) have reported 2 cases of mitomycin-associated hemolytic anemia and have considered 54 cases from 20 reports. Thirty-nine cases were taken for evaluation. Thirtysix of these 39 patients developed renal insufficiency or thrombocytopenia. Other frequent manifestations were pulmonary edema (49%), hypertension (23 %) and neurologic dysfunction (18%). The case fatality rate was 72% ; pulmonary edema was a grave prognostic factor (95 % of patients died). HEPATOTOXICITY (SED-IO, 835; SEDA-8, 406; SEDA-9,378; SEDA-IO, 400; SEDA - I I, 392)

Azathioprine The

hepatotoxic effect of azathioprine has been previously reported (SEDA-11,392) in patients with kidney transplants. Recently, Read et al (44 cr) have reported on 4 patients with renal transplants who developed hepatic veno-occlusive disease after immunosuppression with azathioprine. The diagnosis of veno-oeclusive disease was based on typical histopathologic findings: perivenular fibrosis and centrilobular sinusoidal dilatation and congestion with perisinusoidal fibrosis. Clinically the symptoms presented as a severe progressive portal hypertension followed by fulminant liver failure and death. The disease was associated with cytomegalovirus infection but not with the dose of the drug. Ciclosporin (cyclosporin) Although attention has been paid principally to the nephrotoxicity of cielosporin, its hepatotoxicity has not been prominently addressed. Lorber et al (45 c) have noted at least one episode of hepatotoxicity in

Chapter 47 K. Wierzba, Y. Yamada and M. Hanano

228 of 466 patients (49%) with renal transplants, treated with ciclosporin. The laboratory analysis of patients experiencing hepatotoxicity indicated that 110 patients had hyperalbuminemia (48%), 108 elevated SGOT (47%), 167 elevated SGPT (73%), 191 elevated LDH (84%) and 135 elevated AP (59%). Ciclosporin dose reduction resulted in resolution of hepatotoxicity in 185 patients (81%), while 32 patients (14 %) experienced recurrent or persistent liver function abnormalities. Eleven (2.4%)patients developed biliary calculous disease. The concentration of ciclosporin in the serum was relatively high among hepatotoxic patients. Pharmacokinetic analysis revealed increased AUC (area under curve), probably due to decreased drug clearance in hepatotoxic patients.

Daearbazine Over the past few years a number of reports have appeared of fatal hepatotoxicity associated with dacarbazine. McClay et al (46 c) have reported another case following dacarbazinc (500 mg/d for 5 days). The first treatment was tolerated well, but on the 3rd day of the 2nd cycle the patient developed systemic symptoms of fever, chills and profound thirst. On the next day the patient manifested symptoms of cardiovascular collapse. In addition, marked hepatomegaly and elevated liver enzymes were noted. At autopsy, the liver weighed 2230 g; microscopic examination revealed hemorrhagic necrosis of hepatocytes, the sinusoids were dilated and distended with red blood ceils, and some veins were occluded by fibrin thrombus which occasionally extended into the larger hepatic veins. The exact cause of this reaction is unclear; however, an allergic hepatic vasculitis with resultant thrombosis should be considered. A case of fatal liver necrosis due to veno-occlusire disease during chemotherapy with a regimen containing dacarbazine has been reported (47 c). A patient suffering from Hodgkin's disease was treated with ABVD regimen (doxorubicin 25 mg/m2, bleomycin 10 mg/m2 and vinblastine given on days 1 and 14 of the cycle and daearbazine 150 mg/m2 on days 1-5). After administration in the first part of 4th cycle, the patient's general condition deteriorated rapidly. Microscopic examination of autopsy material revealed the liver to be largely necrotic. Only about 20% of hepatocytes seemed to be viable. The viable cells were located in the portal area and necrosis was centrilobularily distributed. Thrombi were seen in about a third of the small central veins, whereas in larger central veins or in portal veins no thrombi could be found. These histologic findings are similar to those in patients with dacarbazine-induced liver cell necrosis.

Cytostatics and immunosuppressive drugs Chapter47

387

Floxuridine (5'-fluoro-5'-deoxyuridine; FUDR)

were identified. Changes in the gallbladder would be expected to occur with chemotherapy infusion since the gallbladder is usually in the area being infused. The authors therefore suggest prophylactic removal of the gallbladder at the time of pump placement.

Floxuridine is often used in regional arterial chemotherapy for primary and metastatic malignancies, and delivered using a wholly implantable pump (Infusaid). The principle of hepatic arterial infusion is based on the fact that hepatic tumors derive most of their blood supply from the hepatic artery, whereas the liver parenchyma receives it from the portal circulation. This method of treatment improved an objective response rate; however, it has not been free from side effects such as liver and gastrointestinal toxicity. Doria et al (48 r have treated 8 patients with liver metastases from colorectal cancer using hepatic arterial infusion of floxuridine (0.3 mg/kg/d for 14 days) and dichloromethotrexate (2 mg/m2/d for 14 days). The original liver metastases in all patients responded to the above treatment (dose range of floxuridine 1110-4792mg). During chemotherapy all 8 patients developed clinical evidence of liver toxicity, including nausea, vomiting and abdominal pain. Their alkaline phosphatase increased to 264-980IU, SGOT to 90-269 IU, SGPT to 112-212 IU, and total bilirubin was elevated to 2.9-25.2 mg/100 ml. Dosage reduction resulted in clinical improvement in some of them. Histopathological examination revealed hepatocyte necrosis, steatosis, cholestasis, central vein sclerosis and alterations in the portal triad. Some of these toxic effects appeared to be related to the dose and duration of the treatment. Haq et al (49 c) have reported a case of severe fibrosis of the extrahepatic biliary system after hepatic artery infusion of floxuridine (0.3 mg/kg/d for 14 days). Two months later the patient developed a severe and progressive jaundice and had an enlarged gallbladder. Abdominal exploration revealed dense fibrosis and scarring of the biliary tree. The common bile duct was small and could not be cannulated. A biopsy specimen, taken from the region of the porta hepatis, revealed fibrocollagenous connective tissue. After surgery and short course of steroid treatment, the patient's condition gradually improved.

Methotrexate

Methotrexate has been used for the treatment of neoplastic and other diseases such as psoriasis and rheumatoid arthritis. The latter disorder requires long-term administration of low-dose methotrexate but involves the risk of hepatotoxicity. Tolman e t a l (51 c) have reported 22 of 29 patients (76%) who were treated with lowpulse doses of methotrexate for rheumatoid arthritis. Liver biopsy specimens showed abnormal histologic findings, consisting of variabilityin nuclear size, glycogenated nuclei (in some cases) and fatty change. A mild portal infiltration with lymphocytes was found occasionally. However, there were no statistically significant differences in age, duration of treatment or cumulative dose. Serial elevations of aminotransferase and/or alkaline phosphatase enzyme levels and the development of hypoalbuminemia during treatment were specific indicators of the development of liver disease. Recently, Fairris et al (52 r have demonstrated the possibility of measurement of the serum concentration of aminoterminal procollagen type III peptide to predict the risk of developing hepatic fibrosis in patients receiving long-term methotrexate therapy. The aminoterminal procollagen type III peptide is a cleavage product of procollagen III into collagen and is released into the extracellular fluid during the conversion of procollagen type III into collagen. Patients with elevated serum concentrations of aminoterminal procollagen type III peptide received a larger total dose of methotrexate. OTOTOXICITY (SEDA-8, 408; SEDA-9, 380;

SEDA-I 1,393)

Cisplatin Pietrafitta et al (50 c) have described the development of acute and chronic cholecystitis secondary to floxuridine hepatic artery infusion. Chemotherapy in this patient was associated with persisting epigastric pain with radiation to the back which was not accompanied by any fever or white blood cell count elevation. Cholecystectomy revealed a shrunken, thickened fibrotic gallbladder that was filled with a thick, pasty, hemorrhagic material. No gallstones

(cis-dichlorodiammine platinum;

CDDP) The clinical usefulness of cisplatin is often limited by its nephrotoxic and ototoxic effects. Earlier reports have demonstrated a strong correlation between these effects. It was previously reported (SEDA-11,394) that hearing loss depended on total cumulative dose, and usually the first changes were observed at frequencies exceeding 8000 Hz. However, the nature of the ototoxic effect of cisplatin has remained unclear.

388

Chapter 47

K. Wierzba, Y. Yamada and M. Hanano

",0

o > g

o

o

~o

E

o

d

r.~

~ m

N ~.~

=

"~ V,

_r

~g

'r~ o

oo

"~ "~

~.~

~

t~

.~ .~ .-~ ~

o

0e~ 0 9-~

0

~:~,.

og

~

~~

~ . ~= ~o

g~

= ,. o . =

.~'~ ==~o

~

~

..c~ ,.,

~,~oo

"0

~.~

O2 t~

*~

.~_='~

o~ ~ . o [~

~'~

~o.~

~.~.~ ~

<~o

.~z

o o

'~

.

u.,'~

oca

.~ ~,.=

e4 ,

~

Cytostatics and immunosuppressive drugs Chapter 47

o ~

o

o

389

0

"~ "~

~

z

z

"d'R ~o

"0

.~ ~ "~,

"~ 0

.~,..~ ~.-~ o

9~.~

~

o~

~

~~

~o

"~ .~

~ ~o~.

~ ~ .l~

~

~

~

0

o~

~

.8 0 0

~

~

9~.~ o=

O .~

-.~.~ ~

0 0

o

"~ ~

~

o ~

o

~

9 .~ ~0

c~

,, ~.,~

~

~

~.~

~,

~

.~.

"o . ~

~

m ~

;,,~ 8

~.~ i.

~

0

9= ~ - ~

9- ~ "~'~

.; ~, ~

~ .~ .~

de,

~

.<

<

O

0

<

r~

o~

"~

mr~

~

~z

390

Chapter 47

~

.~~" .~-~

._ ~.~

Z

~

~u

~=

Z

Z

~

~

~ 0

K. Wierzba, Y. Yamada and M. Hanano

,,

0 o~ 0

o'~

~o

~o ~1

r

0

~'r

~

Z

"~ ~o

"~ ~'~

~m

"~.~.

ge

~ ~.~

~o~

~.~ 9r o

.~ ~

~ ~

~o ,~ ~

<

<

.~~ ~'~ .~

~

~~ . ~.~ .~

~ O o o <

<

oo

~q r

.

Cytostatics and immunosuppressive drugs Chapter 47

391

Recently, Annilo et al (53 r) performed an invitro study of the toxicity of cisplatin on hair cells and other inner ear structures to determine whether selective damage occurs in inner ear hair cells and whether morpbogenesis and cytodifferentiation are influenced by the presence of low cisplatin concentrations. The study showed that at very low cisplatin concentrations (0;1/ag/ml) selective damage to hair cells does occur. Incubation at 1/~g/ml caused morpbologic damage in the supporting cells in both cochlear and vestibular parts of the labyrinth, and 10/tg/ml caused total collapse of the membranous labyrinth. Drug exposure seemed to arrest morphogenesis as well as cytodifferentiation.

(SEDA-11,394). Recently, Meyskens et al (55 c) observed hearing loss in 48 ~o of patients treated with D F M O (3 x 2 g/d). In some patients the hearing loss was characterized audiographically as bilateral, sensorineural, primarily high frequency, with a median decibel loss of 25-30. All patients experienced hearing recovery within 1-3 months following cessation of therapy. However, there was no apparent association between total D F M O dose and degree of hearing loss.

Chlormethine (mechlorethamine; nitrogen mustard) Chlormethine administered in a massive dose of 0.6-1.5 mg/kg caused severe irreversible hearing loss. Segal and Duckert (54 c) have reported hearing loss in a patient treated with 0.4 mg/kg. The patient developed sensorineural hearing loss during the first cycle of MOPP therapy. Substitution ofchlormethine by cyclophosphamide (5 cycles) caused continued improvement in hearing. Difluoromethylornithine (DFMO) Hearing loss appeared to be the dose-limiting toxic effect for D F M O in patients receiving 4 x 2 g / d

N-Methylformamide N-Methylformamide is an antitumor polar solvent which induces differentiation in human tumor cell lines. Sternberg et al (56 c) have found hepatotoxicity to be the dose-limiting toxic effect of the drug. Hepatotoxicity ranged from asymptomatic biochemical changes to liver pain.

TOXIC EFFECTS O F SOME NEW OR INVESTIGATIONAL SUBSTANCES Table 2 provides a summary of side effects which have been reported for a number of lessknown or experimental agents during the period under review. Some of these drugs have been listed in earlier volumes but are included once again since additional information has become available.

REFERENCES 1. Lindpaintner K, Lindpaintner LS, Wentworth M et al (1986) Acute myocardial necrosis during administration of amsacrine. Cancer, 57, 1284. 2. Weiss RB, Grillo-Lope~ AJ, Marsoni S et al (1986) Amsacrine-associated cardiotoxicity:an analysis of 82 cases. J. Clin. Oncoi., 4, 918. 3. Fassio T, Canobbio L, Gasparini G e t al (1986) Paroxysmal supraventricular tachycardia during treatment with cisplatin and etoposide combination. Oncology, 43, 219. 4. Goldberg MA, Antin JH, Guinan EC et al (1986) Cyclophosphamide cardiotoxicity: an analysis of dosing and a risk factors. Blood, 68, 1114. 5. Trigg ME, Finlay JL, Bozdech M e t al (1987) Fatal cardiac toxicity in bone marrow transplant patients receiving cytosine arabinoside, cyclophosphamide, and total body irradiation. Cancer, 59, 38. 6. Baello EB, Ensberg ME, Ferguson DW et al (1986) Effect of high-dose cyclophosphamide and total-body irradiation on lef~-ventricular function in adult patients with leukemia undergoing allogenic bone marrow transplantation. Cancer Treat. Pep.. 70, 1187. 7. Subar M, Muggia FM (1986) Apparent myocar-

dial ischemia associated with vinblastine administration. Cancer Treat. Pep., 70, 690. 8. Mortensen SA, Olsen HS, Baandrup U (1986) Chronic anthracycline cardiotoxicity: haemodynamic and histopathological manifestations suggesting a restrictive endomyocardial disease. Br. Heart J., 55, 274. 9. Hatfield MK, Martin WB, Ryan JW et al (1986) Cardiac gallium uptake in doxorubicin-induced cardiotoxicity. Clin. Nucl. Med., 11, 756. 10. Torli FM, Bristow MM, Lure BL (1986) Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy. Cancer Res., 46, 3722. 11. Willson JKV, Knulman MW, Skeel RT et al (1986) Phase II clinical trial of acivicin in advanced breast cancer: an Eastern Cooperative Oncology Group Study. Cancer Treat. Pep., 70, 1237. 12. Booth BW, Korzun AH, Weiss RB et al (1986) Phase II trial of acivicin in advanced breast carcinoma: a Cancer and Leukemia Group B Study. Cancer Treat. Pep., 70, 1247. 13. Hagler DN, Frame PT (1986) Azidothymidine neurotoxicity. Lancet, 2, 1392. 14. Labar B, Bogdanic V, Plasvic F et al (1986)

392

Chapter 47 K. Wierzba, Y. Yamada and M. Hanano

Cyclosporin neurotoxicity in patients treated with allogenic bone marrow transplantation. Biomed. Pharmacother., 40, 148. 15. Nand S, Messmore HL, Patel R et al (1986) Neurotoxicity associated with systemic high-dose cytosine arabinoside. J. Clin. Oncol., 4, 571. 16. Cold S (1986) Cerebellar dysfunction during high dose cytosine arabinoside therapy in a case of acute myelogenous leukaemia. Scand. ol. Haematol.. 36, 165. 17. Thordarson H, Talstad I (1986) Acute meninghis and cerebellar dysfunction complicating high-dose cytosine arabinoside therapy. Acta Med. Scand., 220, 493. 18. Crawford SM, Rustin GJS, Bagshawe KD (1986) Acute neurological toxicity of intrathecal cytosine arabinoside. Cancer Chemother. Pharmacol., 16, 306. 19. Dunton SF, Nitsche R, Spruce WE et al (1986) Progressive ascending paralysis following administration ofintrathecal and intravenous cytosine arabinoside. Cancer, 57, 1083. 20. Heier MS, Fossa SD (1986) Wernicke-Korsakoff-like syndrome in patients with colorectal carcinoma treated with high-dose doxifluridine. Acta Neurol. Scand., 73, 449. 21. Taylor HG, Wolf CR, Maitland CG (1986) Neurologic toxicity associated with hepatic artery infusion HAl of FUdR. Cancer Chemother. Pharmacol., 17, 292. 22. Chun HG, Leyland-Jones BR, Caryk S e t al (1986) Central nervous system toxicity offludarabine phosphate. Cancer Treat. Pep., 70, 1225. 23. Amichetti M, Pfiffer S, Valdagni R et al (1987) Peripheral DTIC neurotoxicity: a case report. Cancer Chemother. Pharmacol., 19, 87. 24. Drings P, Abel U, Bulzebruck H et al (1986) Experience with ifosfamide combinations (etoposide or DDP) in non-small cell lung carcinoma. Cancer Chemother. PharmacoL, 18, Suppl 2, $34. 25. Pratt CB, Horowitz ME, Meyer WHet al (1987) Phase II trial of ifosfamide in children with malignant solid tumors. Cancer Treat. Rep., 71, 131. 26. Meanwell CA, Blake AE, Kelly KA et al (1986) Prediction of ifosfamide/mesna associated encephalopathy. Eur. J. Cancer Clin. Oncol., 22, 815. 27. Walker RW, Allen JC, Rosen G et al (1986) Transient cerebral dysfunction secondary to highdose methotrexate. J. Clin. OncoL, 4, 1845. 28. Rhomberg WU (1986) Vindesine for recurrent and metastatic cancer of the uterine cervix: a phase II study. Cancer Treat. Rep., 70, 1455. 29. Stewart DJ, Maroun JA, Lefebre B e t al (1986) Neurotoxicity and efficacy of combined Vinca alkaloids in breast cancer. Cancer Treat. Rep., 70, 571. 30. Nahman NS, Cosio FG, Kolkin S e t al (1987) Cyclosporine nephrotoxicity without major organ transplantation. Ann. Intern. Med., 106, 400. 31. Kolkin S, Nahman NS, Mendell JR (1987) Chronic nephrotoxicity complicating cyclosporine treatment of chronic inflammatory demyelinating polyradiculoneuropathy. Neurology, 37, 146. 32. Palestine AG, Austin HA, Balow JE et al (1986)

Renal histopathologic alterations in patients treated with cyclosporine for uveitis. N. Engl. Med. J., 314, 1293. 33. Kolbeck PC, Wolfe JA, Burchette J et al (1987) Immunopathologic patterns of cyclosporine deposition associated with nephrotoxicity in renal allograft biopsies. Transplantation, 43, 218. 34. Parvin SD, Rees Y, Veitch PS et al (1986) Objective measurement by ultrasound to distinguish cyclosporin A toxicity from rejection. Br. J. Surg., 73, 1009. 35. Holt DW, Marsden JT, Johnston Aet al (1986) Blood cyclosporin concentrations and renal allograft dysfunction. Br. Med. J., 293, 1057. 36. Termeer A, Hoistma AJ, Koene RAP (1986) Severe nephrotoxicitycaused by the combined use of gentamicin and cyclosporine in renal allograft recipients. Transplantation,42, 220. 37. Groth S, Nielsen H, Sorensen JB et al (1986) Acute and long-term nephrotoxicity of cis-platinum in man. Cancer Chemother. Pharmacol., 17, 191. 38. Fjeldborg P, Sorensen J, Helkjaer PE (1986) The long-term effect of cisplatin on renal function. Cancer, 58, 2214. 39. Lain M, Adelstein DJ (1986) Hypomagnesemia and renal magnesium wasting in patients treated with cisplatin. Am. J. Kidney Dis., 8, 164. 40. Willox JC, McAllister EJ, Sangster G e t al (1986) Effects of magnesium in testicular cancer patients receiving cis-platin. Br. J. Cancer, 54, 19. 41. Markman M, Cleary S, Howell SB (1986) Hypomagnesemia following high-dose intracavitary cisplatin with systemically administered sodium thiosulfate. Am. J. Clin. Oncol. Cancer Clin. Trials, 9, 440. 42. Vervcy J, De Vries J, Pinedo HM (1987) Mitomycin C-induced renal toxicity a dose-dependent side effect? Eur. J. Cancer Clin. Oncol., 23, 195. 43. Sheldon R, Slaughter D (1986) A syndrome of microangiopathic hemolytic anemia, renal impairment, and pulmonary edema in chemotherapytreated patients with adenocarcinoma. Cancer, 58, 1428. 44. Read AE, Wiesner RH, LaBrecque DR et al (1986) Hepatic veno-occlusive disease associated with renal transplantation and azathioprine therapy. Ann. Intern. Med., 104, 651. 45. Lorber MI, Van Buren CT, Flechner SM et al (1987) Hepatobiliary and pancreatic complications of cyclosporine therapy in 466 renal transplant recipients. Transplantation, 43, 35. 46. McClay E, Lusch MJ, Manstrangelo MJ (1987) Allergy-induced hepatic toxicity associated with dacarbazine. Cancer Treat. Rep., 71,219. 47. Joensuu H, Soderstrom KO, Nikkanen V (1986) Fatal necrosis of the liver during ABVD chemotherapy for Hodgkin's disease. Cancer, 58, 1437. 48. Doria MI, Shepard KV, Levin B et al (1986) Liver pathology following arterial infusion chemotherapy: hepatic toxicity with FUDR. Cancer, 58, 855. 49. Haq MM, Valdes LG, Peterson DF et al (1986) Fibrosis of extrahepatic biliary system after contin-

Cytostatics and immunosuppressive drugs Chapter 47

393

uous hepatic artery infusion of floxuridine through an implantahlc pump (Infusaid Pump). Cancer, 57, 1281. 50. Pietrafitta JJ, Anderson BG, O'Brien MJ et al (1986) Cholecystitis secondary to infusion chemotherapy. J. Surg. Oncol., 31,287. 51. Tolman KG, Clegg DO, Lee DG et al (1985) Mcthotrexate and the liver. J. Rheumatol., 12, Suppl, 29. 52. Fairris GM, Brooks B, Tanner A (1986) Elevated serum aminoterminal procollagen type III peptide in methotrexate-indueed hepatic fibrosis. Br. J. Dermatol., 114, 520. 53. Annilo M, Sobin A (1986) Cisplatin: evaluation of its ototoxic potential. Am. J. Otolaryngol., 7, 276. 54. Segal GM, Duckert LG (1986) Reversible mechlorethamine-associated hearing loss in a patient with Hodgkin's disease. Cancer, 57, 1089. 55. Meyskens FL, Kingsley EM, Glattke T et al (1986) A phase lI study of difiuoromethylornithinc (DFMO) for the treatment of metastatic melanoma. Invest. New Drugs, 4, 257. 56. Sternberg CN, Yagoda A, Scher HI et al (1986) Phase II trial of N-methylformamide for advanced renal cell carcinoma. Cancer Treat. Rep., 70, 681. 57. O'Dwyer PJ, Wagner BH, Stewart JA et al (1986) Aminothiadiazole: an antineoplastic thiadiazole. Cancer Treat. Rep., 70, 885. 58. Stewart JA, Ackerly CC, Myers CF et al (1986) Clinical and clinical pharmacologic studies of 2amino-l,3,4-thiadiazole (A-TDA; NSC 4728). Cancer Chemother. Pharmacol., 16, 287. 59. Burzynski SR, Kubove E, Burzynski B (1987) Phase I clinical studies of antincoplaston A5 injections. Drugs Exp. Clin. Res., 13, Suppl, 37. 60. Burzynski SR, Kubove E (1987) Phase I clinical studies of antincoplaston A3 injections. Drugs Exp. Clin. Res., 13, Suppl, 17. 61. Burzynski SR, Kubove E (1987) Initial clinical study with antineoplaston A2 injections in cancer patients with five years' follow-up. Drugs Exp. Clin Res., 13, Suppl, 1. 62. Momparler RL, Rivard GE, Gyger M (1985) Clinical trial on 5-aza-2'-deoxycytidine in patients with acute leukemia. Pharmacol. Ther.o 30, 277. 63. Mudier NH, Meijers WH, Van der Meulen JD et al (1987) Phase I and pharmacokinetic study of trans-N3P3Az2(NHMe)4. Cancer Treat. Rep., 71, 155. 64. Eisenhaure EA, Swenerton KD, Sturgeon JFG et al (1986) Phase II study of carboplatin in patients with ovarian carcinoma: a National Cancer Institute of Canada Clinical Trial Group Study. Cancer Treat. Pep., 70, 1195. 65. Hort-Bagyi GN, Hersh EM, Papadopoulos NEJ, Frye D et al (1986) Initial clinical studies with copovithane. J. Biol. Response Modif., 5, 319. 66. Kerpel-Fronius S, Erdelyi-Toth V, Gyergyay F et al (1986) Relation between dose, plasma concentration and toxicity in a phase I trial using high dose intermittent administration of an alkylating agent, diacetyldianhydrogalactitol (DADAG). Cancer Chemother. Pharmacol., 16, 264. 67. Erdelyi-Toth V, Kerpel-Fronius S, Kanyar B

et al (1986) Pharmacokinetic study in a phase I trim with an alkylating agent, diacetyldianhydrogalactitol (DADAG). Cancer Chemother. PharmacoL, 16, 257. 68. Ahmed T, Yagoda A, Scher HL et al (1986) Phase II trial of 10-deaza-aminopterin in patients with bladder cancer. Invest. New Drugs, 4, 171. 69. Thongprasert S, Currie VE, Budman D (1987) Phase II trial of 10-deaza-aminopterin in advanced breast cancer. Cancer Treat. Rep., 71, 95. 70. Tsukagoshi S (1986) Enoeitahine (Sunrahin): an antitumor agent. Drugs Today, 4, 169. 71. Kerr DJ, Kaye SB, Graham J etal (1986) Phase I and pharmacokinetic study of LM 985 (flavone acetic acid ester). Cancer Res., 46, 3142. 72. Carpenter JT, Vogel CL, Wang G e t al (1986) Phase II evaluation of fludarabine in patients with metastatic breast cancer: a Southeastern Cancer Study Group Trial. Cancer Treat. Rep., 70, 1235. 73. Merkel DE, Griffin NL, Hagan-Hallet K et al (1986) Central nervous system toxicity with fludarabine. Cancer Treat. Rep., 70, 1449. 74. Keller J, Bartolucci A, Carpenter JT et al (1986) Phase II evaluation of bolus gallium nitrate in lymphoproliferative disorders: a Southeastern Cancer Group Study Group Trial. Cancer Treat. Rep., 70, 1221. 75. Rowinsky EK, Ettinger DS, Grochow LB et al (1986) Phase I and pharmacologic study ofhexamethylene bisacetamide in patients with advanced cancer. J. Clin. Oncol., 4, 1835. 76. Vugrin D, Hood L, Laszlo J (1986) A phase II trial of high-dose human lymphoblastoid alpha interferon in patients with advanced renal carcinoma. J. Biol. Response Modif., 5,309. 77. Kurzrock R, Quesada JR, Talpaz Met al (1986) Phase I study of multiple dose intramuscularly administered recombinant gamma interferon. J. Clin. Oncol., 4, 1101. 78. Brown TD, Donehower RC, Grochow LB et al (1987) A phase I study ofmenogarii in patients with advanced cancer. J. Clin. OncoL, 5, 92. 79. Hainsworth JD, Forbes JT, Grosh WW et al (1986) Phase I study of MVE-2 evaluating toxicity and biologic response modification capability. Cancer Immun. Immunother., 22, 68. 80. Gouyette A, Ducret JP, Caille P e t al (1986) Preliminary phase I clinical study and pharmacokinetics of (I,2-diaminocyclohexane)(isocitro) platinum (II) or PHIC. Anticancer Res., 6, 1127. 81. Roberts JT, Bleehen NM, Walton MI etal (1986) A clinical phase II toxicity study of Ro 03-8799: plasma, urine, turnout and normal brain pharmacokinetics. Br. J. Radiol., 59, 107. 82. Kris MG, O'Conneil JP, Gralla RJ et al (1986) Phase I trial oftaxol given as a 3-hour infusion every 21 days. Cancer Treat. Rep., 70, 605. 83. Cunningham D, Soukop M, Stuart JFB et al (1986) A clinical and pharmacokinetic phase | study of 1,2,4-triglycidylurazol (TGU, NSC-332488). Eur. J. Cancer Clin. OncoL, 22, 1325. 84. Roberts JD, Stewart JA, McCormack JJ et al (1987) Phase I trial of tiazofurin administered by iv bolus daily for 5 days, with pharmacokinetic evaluation. Cancer Treat. Rep., 71,141.