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Matrix metalloproteinases (MMPs) are a family of enzymes involved in a number of normal cellular processes, such as regulation of endometrial growth and menstruation, and abnormal processes, such as tumor growth, invasion, and metastasis. There are now 18 distinct enzymes that fall into three functional classifications based on their substrate target: collagenases which degrade fibrillar collagen; gelatinases which degrade denatured and basement membrane collagens, and stromelysins which degrade proteoglycans and glycoproteins. The MMPs can also be separated into five categories based on structural and functional similarities.

Agents which 'poison' the enzyme topoisomerase II, have proven to be useful drugs for cancer treatment. Six antineoplastic drugs, which target topoisomerase II (doxorubicin, daunorubicin, idarubicin, mitoxantrone, etoposide and teniposide) are currently approved for clinical use in the United States. In this paper, the strategies and goals of cancer chemotherapy are summarized for the non-clinician. The use, pharmacology and toxicity of each of the six currently approved topoisomerase II inhibiting agents are reviewed.

679 Background: 5-fluorouracil (5-FU), a synthetic fluoropyrimidine, is a critical component of chemotherapy in many cancers. Its metabolites inhibit Thymidylate Synthetase (TS) causing cessation of DNA synthesis and are misincorporated into DNA and RNA causing ineffective DNA repair and faulty mRNA splicing. The rate limiting step in the catabolism of 5-FU is by the Dihydropyrimidine Dehydrogenase enzyme (DPD) which catabolizes over 80% of 5-FU. Patients with near total DPD enzymatic deficiency develop life threatening toxicity after a single administration and those with less severe deficiency will have delayed elimination of 5-FU and slowly accumulate active metabolites leading to toxicities. Methods: We conducted a pilot retrospective cohort study of African American (AA) and Caucasian patients treated for colorectal cancer over a 9 year period, 2000 – 2008, in this IRB approved study. The primary outcome of interest was the rate of development of grade 3 or 4 neutropenia (Absolute Neutrophil Count Results: There were 66 evaluable patients (40 men, 26 women), 40 AA, 24 Caucasians and 2 of other races. Thirty-eight patients (15 Caucasians and 23 AA) received 5-FU containing chemotherapy. The two groups were comparable in baseline characteristics. AA were more likely to develop grade 3-4 hematological toxicity. Nine of 23 AA (39.1%) and one of 15 Caucasians (6.7%) developed grade 3-4 hematological toxicity. RR 8.56, 95% confidence interval 0.95 – 421.06 (p-value of 0.0561) Conclusions: These results suggest that AA were more likely than Caucasians to have severe hematologic toxicity with the use of 5-FU containing chemotherapy. This difference did not meet statistical significance due to small sample size and few numbers of events in the Caucasian arm. A larger prospective study is needed to further evaluate the observed difference.

PURPOSE This trial evaluated the activity and toxicity of a prolonged schedule of low-dose, daily infusional etoposide in patients with etoposide-sensitive neoplasms. PATIENTS AND METHODS Fifteen patients (non-Hodgkin's lymphoma, n = 10; small-cell lung cancer, n = 3; germ cell neoplasm, n = 2) were treated. Ten had received etoposide previously. Etoposide 18 to 25 mg/m2/d was administered by continuous intravenous infusion for at least 21 days, or until either leukocyte count decreased to less than 2,000/microL, platelets decreased to less than 75,000/microL, or tumor progressed. Plasma etoposide levels were monitored during infusion. RESULTS Duration of therapy ranged from 21 to 560 days; uninterrupted infusion ranged from 21 to 153 days. Seven patients (47%) had an objective tumor response (six partial, one complete), with a median duration of 7 months (range, 2 to 19). Myelosuppression limited the infusion; however, only four patients had grade 4 leukopenia, and most tolerated infusions with mild to moderate leukopenia. Nine patients required RBC transfusions. Only one patient developed severe thrombocytopenia. Alopecia was universal; however, other grade 3 or 4 nonhematologic toxicities were not encountered. The mean serum etoposide concentration was 0.7 +/- 0.42 microgram/mL. Only three patients had serum etoposide levels greater than 1 microgram/mL. CONCLUSION Etoposide administered as a low-dose continuous infusion is active in etoposide-sensitive neoplasms. Myelosuppression is the major toxicity, but seems reduced when compared with other schedules. Tumor cytotoxicity was demonstrated with plasma levels ranging from 0.5 to 1.0 microgram/mL. Chronic low doses of etoposide may be superior to the standard dose and schedule and further study of this issue is warranted.

Purpose: To identify patients with lymphoma at risk for tumor lysis after chemotherapy. Patients and methods: The case records of 102 patients receiving combination chemotherapy for non-Hodgkin's lymphoma (intermediate to high-grade histology) were reviewed. Patients were considered to have "laboratory tumor lysis" if two of the following metabolic changes occurred within 4 days of treatment: a 25% increase in the serum phosphate, potassium, uric acid, or urea nitrogen concentrations, or a 25% decline in the serum calcium concentration. "Clinical tumor lysis" was defined as laboratory tumor lysis plus one of the following: a serum potassium level greater than 6 mmolL, a creatinine level greater than 221 μmolL, or a calcium level less than 1.5 mmolL, the development of a life-threatening arrhythmia, or sudden death. Results: Laboratory tumor lysis occurred in 42% of patients and clinical tumor lysis in 6%. There was no statistical difference in the frequency of either tumor lysis syndrome among lymphoma subgroups. Clinical tumor lysis occurred more frequently in patients with pretreatment renal insufficiency (serum creatinine level greater than 132 μmolL) than in patients with normal renal function (36% versus 2%; p=0.01). The development of azotemia correlated with high pretreatment serum lactate dehydrogenase concentrations (p 2 = 0.11). Conclusion: Clinically significant tumor lysis is a rare occurrence in patients with lymphoma when they are receiving allopurinol. However, tumor lysis can occur in patients with all types of moderate to high-grade non-Hodgkin's lymphoma. Patients with a high serum lactate dehydrogenase level or renal insufficiency are at increased risk for metabolic complications after chemotherapy and should be closely monitored.

PURPOSE The trial was undertaken to investigate the activity and toxicity of a prolonged schedule of oral etoposide in the treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Between March 1989 and August 1990, 25 patients with advanced NSCLC were treated with oral etoposide 50 mg/m2/d for 21 consecutive days, repeated every 28 to 35 days. The median patient age was 60 years (range, 38 to 84 years); male:female ratio was 12:13. Eight patients had stage IIIB disease; 17 had stage IV. Seventy-six percent of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. No patient had received previous chemotherapy with standard agents; nine patients had received previous or concurrent radiation therapy. Plasma etoposide concentrations were measured to estimate etoposide bioavailability and kinetics. RESULTS Five of 22 patients (23%; 95% confidence interval [CI], 10% to 43%) had partial responses. Median response duration was 5 months (range, 2 to 6 months). Four of five responders were female. Besides alopecia, which occurred in all patients, myelosuppression was the most common toxicity, but was mild or moderate in most patients. Median leukocyte nadir during course 1 was 3,200/microL; only four of 69 courses produced a leukocyte nadir less than 1,000/microL. Severe thrombocythemia (less than 75,000/microL) did not occur. Gastrointestinal toxicity was uncommon. Median peak etoposide concentration was 3.4 micrograms/mL. A mean serum etoposide concentration greater than 1 microgram/L was maintained for more than 13 hours; the plasma concentration-time curve (AUC) was estimated to be 90% of that predicted after an identical dose of etoposide given intravenously. CONCLUSIONS Etoposide given by this dose and schedule has moderate activity as first-line systemic therapy for advanced NSCLC. In previously untreated patients, chronic oral etoposide is well tolerated, and incorporation into combination regimens should be feasible. Etoposide bioavailability may be increased at lower oral doses.

The kinetics and urinary excretion of etoposide and etoposide glucuronide were determined in 11 patients with obstructive jaundice (bilirubin greater than 2.0 mg/dL) and in 23 patients with normal renal and hepatic function. Mean (+/- SE) measurements of clearance (24.5 +/- 2.06 v 26.5 +/- 2.05 mL/min/m2), half-life (5.7 +/- 0.5 v 6.4 +/- 0.5 hours), and volume of distribution (12.4 +/- 1.1 v 13.7 +/- 1.6 L/m2) were not significantly different in patients with jaundice when compared with controls. Similarly, etoposide kinetics in three patients determined during a period of hyperbilirubinemia were not different from measurements made in the same patients following resolution of their obstructive jaundice. In patients with jaundice, 46% of an administered etoposide dose was excreted in the urine as etoposide compared with 35% in controls (P = .15). Urinary excretion of etoposide glucuronide accounted for 29% of an administered etoposide dose in control patients and 15% in those with hepatic obstruction (P = .03). Biliary etoposide excretion measured in four patients with T-tubes was insignificant (less than 2.0% of an administered dose). The calculated renal clearance of etoposide was 11.5 mL/min/m2 in patients with jaundice and 10.4 mL/min/m2 in controls (P = .53). Respective metabolic clearance was 4.9 and 6.9 mL/min/m2 in these two study groups (P = .13). Although hepatic metabolism of etoposide may be slightly decreased in patients with obstructive jaundice, a modest increase in renal etoposide excretion appears to compensate for this change, so that total clearance is similar in the patients with jaundice when compared with controls. No etoposide dose reductions appear to be needed in treating patients with obstructive jaundice who have normal renal function.

Six female rabbits were given 20 mg/kg cyclophosphamide (containing 100 microCi [3H-chloroethyl]-cyclophosphamide) alone or 1 h following 100 mg/kg cimetidine. Serial plasma and urine specimens were collected and levels of cyclophosphamide and its metabolites (4-hydroxycyclophosphamide, 4-ketocyclophosphamide, phosphoramide mustard, and carboxyphosphamide) were measured. 4-Ketocyclophosphamide was the major metabolite present in rabbit plasma and urine, with lesser amounts of 4-hydroxycyclophosphamide, carboxyphosphamide, and phosphoramide mustard also being identified. Cimetidine pretreatment resulted in prolongation of cyclophosphamide's half-life from 24.3 +/- 7.3 to 33.5 +/- 9.5 min (mean +/- SD; P = 0.036) but did not significantly alter the AUC0-8 h for the latter drug. Cimetidine pretreatment resulted in a significantly greater AUC0-8 h for 4-hydroxycyclophosphamide (189.4 +/- 77 vs 364.6 +/- 126.7 mumol min/l-1; P = 0.016) as compared with control values. A higher AUC0-8 h value for phosphoramide mustard (53.7 +/- 69.2 vs 95.7 +/- 34.7 mumol min/l-1) was also observed after cimetidine dosing but the difference was not significant (P = 0.21). Kinetics of 4-ketocyclophosphamide and carboxyphosphamide were not significantly affected by cimetidine treatment. Cimetidine was added to hepatic microsomes isolated from phenobarbital-treated rabbits; it did not inhibit cyclophosphamide's metabolism in vitro, suggesting that its in vivo effect may be mediated through mechanisms other than cytochrome P-450 inhibition. Cimetidine pretreatment increases exposure to cyclophosphamide and its major activated metabolite, 4-hydroxycyclophosphamide. Potentiation rather than inhibition of cyclophosphamide's pharmacodynamic effect is to be predicted when cimetidine is given concomitantly with the former. Alterations in hepatic blood flow or mechanisms other than microsomal inhibition by cimetidine may explain this potentiation.

2094 Background: Several cancer chemotherapeutic agents are metabolized by CYP3A4. Co-administration of compounds that inhibit CYP3A4 may lead to decreased metabolic clearance, increased exposure, and increased toxicity of these antineoplastic agents. Aprepitant (EMEND), a recently approved antiemetic agent, moderately inhibits human CYP3A4 in vivo and in vitro (Ki of ∼10 uM). To determine if aprepitant affects the pharmacokinetics of chemotherapeutic agents metabolized by CYP3A4, this study examined the effect of aprepitant on docetaxel, which is cleared largely by CYP3A4 metabolism. Methods: Ten patients at 3 investigative sites were given the same dose of docetaxel (DOC) monotherapy (60 to 100 mg/m2) on two separate occasions (∼3 weeks apart). In one of the cycles, patients received aprepitant (APR) 125 mg PO 1 hour prior to docetaxel infusion, followed on Days 2 and 3 with a single oral aprepitant dose of 80 mg. On the alternate treatment, they received docetaxel alone. The pharmacokinetic profile of ...

2079 Background: ABT-751 is an oral anti-mitotic agent that binds to the colchicine site of β-tubulin. ABT-751 has antitumor activity in various human xenograft models and additive effects in combi...

2074 Background: PKA RIa is a primary mediator of cAMP activity and is upregulated in many cancers. GEM231 (G) is a 2nd generation RNA/DNA oligonucleotide targeting the PKA regulatory subunit (RIa). Preclinically, G has synergistic antitumor effects when combined with irinotecan (IRI). Methods: This study evaluated the safety, PK, and biological profile of IRI combined with. Initially IRI was administered at 85 mg/m2 q wk X 4 along with G (40, 80 or 120 mg/m2/d for 5d X 4 wks) followed by a 2 wk rest. Due to DLTs (see table) in initial cohorts, the protocol was amended to administer full dose IRI (125 mg/m2) with a lower dose of G (20 mg/m2/day x 5) by a 2 wk on 1 wk off schedule. Additional PK sampling (@ 48 hrs) was added to evaluate the potential for altered SN-38 clearance by G, as found in preclinical models. Extracellular PKA (ECPKA) is measured in plasma at baseline and weekly thereafter. Results: 19 patients were enrolled on the original protocol, and 3 patients have received treatment on the amen...

To exploit possible dose-response and combination drug synergism, 20 previously untreated patients with extensive-stage small-cell lung cancer (SCLC) received one or two courses of high-dose induction chemotherapy consisting of cyclophosphamide (100 mg/kg), etoposide (1,200 mg/m2), and cisplatin (120 mg/m2) (HDCEP). HDCEP was followed by four cycles of standard-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1.4 mg/m2) (CAV). Response was determined after HDCEP and following CAV. Reevaluation included repeat bronchoscopy and chest computerized tomography (CT), as well as repetition of all initially abnormal studies. All patients were evaluable for response and toxicity. Overall response to HDCEP was 90%, with a complete response (CR) rate of 65% (95% confidence limits, 44% to 86%) and a partial response (PR) rate of 25% (95% confidence limits, 6% to 44%). All patients either maintained or improved their initial response while receiving CAV. Median duration of response was 6 months (range, 2 to 12 months) and median survival was 9.5 + months (range, 2 to 21 + months). All 37 courses of HDCEP were associated with leukopenia (less than 1,000/microL), 92% with thrombocytopenia (less than 20,000/microL), and 84% with fever of greater than 38.5 degrees C. Additional toxicities included bacteremia (24%), nausea and emesis (59%), mucositis (57%), diarrhea (38%), and hemorrhagic cystitis (5%). There were two treatment-related deaths due to infection. A third patient died 4 months after completing HDCEP with pulmonary fibrosis. Although response duration and median survival were not improved, HDCEP produced a high CR rate in ambulatory patients with extensive-stage SCLC.

Seventeen ambulatory patients with extensive-stage small-cell lung cancer received one or two courses of high-dose induction chemotherapy consisting of cyclophosphamide (100 mg/kg) plus etopside (1,200 mg/m2) followed by four or five cycles of conventional-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1.4 mg/m2) (CAV) given every 21 days. No additional chemotherapy was given until relapse or progression was documented. Response was assessed initially after high-dose induction therapy and again after completion of all chemotherapy. After induction therapy, 16/17 (94%) patients had achieved an objective response, including five (29%) complete responses and 11 (65%) partial responses. Two partially responding patients improved to a complete response after CAV, while one partial responder progressed and one patient died of an intercurrent illness while receiving CAV. Thus, the overall response after completing all chemotherapy was 15/16 (94%), including seven (44%) complete responses and eight (50%) partial responses. Median response duration was six months (range, 3 to 11 months), and overall median survival was ten months (range, 2 to 17 months). All 31 courses of induction therapy were associated with leukopenia (less than 1,000/microL), 81% with thrombocytopenia (less than 20,000/microL), and 77% with fever (greater than 38.5 degrees C). Seven episodes of bacteremia and one axillary abscess were documented, and there was one treatment-related death (6%). These toxicities are similar to that produced by high-dose etoposide alone. High-dose cyclophosphamide combined with high-dose etoposide can be administered to ambulatory patients with extensive-stage small-cell lung cancer without requiring bone marrow transplantation to reestablish hematopoiesis. Complete response and median survival rates, however, are similar to those obtained with less intensive therapy.

Clinical and histopathologic data from 87 patients with primary non-Hodgkin's lymphoma of the gastrointestinal (GI) tract diagnosed between 1974 and 1984 were reviewed. B-cell lymphomas of intermediate- or high-grade histology constituted 78% of lesions. Stage of disease varied with histologic grade, with a preponderance of advanced disease (stages IIIE and IV) in patients with low-grade lymphoma (15 of 21) (71%), compared with higher grade lesions (38%, P = .01). Among patients with nonlocalized (stages IIE through IV) lymphoma of intermediate- or high-grade histology, surgical resection of the primary focus afforded a higher rate of complete remission (CR) (70% v 50%) and sustained CR (61% v 21%, P = .04) after cytotoxic therapy compared with the nonresected cohort. The median survival in the resected group was 51 months + compared with 13 months in the nonresected patients (P = .012). Differences in outcome were attributable to a high risk of treatment-related complications (perforation and/or hemorrhage) (43% v 0%, P = .001) and local relapse (29% v 4%, P = .05) in nonresected individuals. Life-threatening local complications were not observed in patients with low-grade lymphoma managed solely with medical therapy. Histologic findings from surgically staged patients identified presence of extravisceral disease and intermediate- or high-grade tumor histology as features predictive of transmural invasion, enabling potential identification of patients who might be optimally managed by resection of the primary GI focus before initiation of cytotoxic therapy.

Cytidine deaminase, an enzyme found in the supernatant fluid of hepatocytes, granulocytes and tumor cells, and in plasma, degrades the antitumor agents cytosine arabinoside and 5-azacytidine. Uridine and its analogs, 3-deazauridine, 5-bromodeoxyuridine, 5-fluorodeoxyuridine and 6-azauridine, were found to competitively inhibit cytidine deaminase; the most potent inhibitor was 3-deazauridine ( K i = 1.9 × 10 −5 M). In addition, deoxycytidylate deaminase, which degrades cytosine arabinoside monophosphate to the inactive uracil arabinoside monophosphate ( K m = 9 × 10 −4 M), was competitively inhibited by 3-deazauridine monophosphate, as well as by the nucleotides of other uridine analogs. These results suggest that uridine analogs such as 3-deazauridine may have value in protecting cytosine arabinoside, 5-azacytidine and their monophosphate nucleotides from degration by neucleoside and nucleotide deaminases.

The results of staging and treatment of 18 patients with diffuse histiocytic lymphoma involving the gastrointestinal tract are summarized. Widespread disease (Stage IV) was found in the majority (72%) of patients after rigorous staging, indicating the relative rarity of localized gastrointestinal lymphoma and the resulting need for systemic therapy in most of these patients. Chemotherapy combined with surgical resection and/or radiation therapy produced complete remissions in only 5 of 18 patients (28%). Patients failed to achieve complete remission due to 1) tumor resistance to drug therapy (46% of treatment failures), and 2) massive intestinal hemorrhage or bowel perforation secondary to tumor necrosis (38% of treatment failures). These findings indicate the need for more active chemotherapeutic regimens and for measures aimed at preventing complications such as bowel perforation or hemorrhage, possibly by combining surgical resection of bowel lesions with systemic chemotherapy.

A competitive protein binding assay for allopurinol or oxipurinol has been developed based on the tight binding of these drugs to reduced xanthine oxidase. Free drug is separated from that bound to xanthine oxidase by absorption with dextran-albumin coated charcoal. This assay can detect as little as 0.1 μ m allopurinol or oxipurinol in water, serum, plasma, or urine. Competitive analogs such as hypoxanthine, xanthine, and uric acid require concentrations 100- to 1000-fold greater than those of allopurinol or oxipurinol to cause significant interference with the assay. This assay is simple and rapid with the ability to assay 20–30 samples within 2 h. Measurement of oxipurinol levels in clinical samples shows good correlation with published results using more complex analytical techniques.

One hundred fifty-two patients with locally advanced or metastatic non-small-cell lung cancer were randomized to receive treatment with one of three cis-platin-containing chemotherapy regimens: vindesine/cis-platin, etoposide/cis-platin, or vindesine/etoposide/cis-platin. Following an 8-week induction course of treatment, patients were evaluated for response; responders continued to receive monthly chemotherapy. All patients were followed until death. Response rates for the three regimens were 10%, 6%, and 24%, respectively; the cis-platin/vindesine/etoposide regimen produced more responses than did either cis-platin/etoposide or cis-platin/vindesine (p less than 0.05). However, median survival was not improved with the three-drug regimen, and myelosuppression produced by this regimen was worse. The 20-week median survival for the entire group suggests that these treatments had no impact on survival. None of these regimens can be recommended for routine treatment of patients with advanced non-small-cell lung cancer. The addition of vindesine did not make a significant impact in response rate or overall survival in this study.

We compared doxorubicin and metabolite pharmacokinetic data obtained from thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) assay of plasma samples from six patients who had been treated with doxorubicin. Duplicate 1-ml samples were extracted with chloroform: isopropanol (1:1) and assayed using a sensitive HPLC system incorporating a dual pump gradient with tetrahydrofuran as the mobile phase and fluorescence detection. Duplicate 1-ml samples from the same specimens were assayed using a modification of a previously described TLC assay. Areas under the curve for doxorubicin by HPLC (3.36 +/- 2.30 microM X h) and TLC (4.16 +/- 2.50 microM X h) were not significantly different (P = 0.5). Terminal half-life of doxorubicin by HPLC (28.0 +/- 6.98 h) and TLC (23.2 +/- 7.8) (P = 0.29) and the calculated total-body clearances by HPLC (0.55 +/- 0.29 l/min) and TLC (0.45 +/- 0.23) (P = 0.55) were not significantly different. Areas under the curve for doxorubicinol by HPLC (2.75 +/- 1.4 microM X h) and TLC (2.53 +/- 7.1 microM X h) (P = 0.73) showed no significant differences. HPLC detected a mixed 7-deoxydoxorubicinol aglycone-doxorubicin aglycone peak, 7-deoxydoxorubicin aglycone, and two nonpolar, unidentified metabolites. TLC detected the following aglycone metabolites: doxorubicin aglycone, doxorubicinol aglycone, 7-deoxydoxorubicinol aglycone, an unidentified polar metabolite, and several unidentified nonpolar metabolites. From these data we conclude that HPLC and TLC detect concentrations of doxorubicin and doxorubicinol from human plasma equally well to concentrations of 7.0 nM (4 pmol injected doxorubicin). Aglycones do circulate in human plasma at concentrations above the detection limits of both assays. Doxorubicinol aglycone, which is detected by TLC but not by HPLC, may be formed from artifactual breakdown of doxorubicinol during TLC development. Unidentified nonpolar compounds seen on HPLC and TLC may represent further doxorubicin metabolism than previously described.

A life-threatening toxicity syndrome consisting of an erythematous, desquamative skin rash, fever, hepatitis, eosinophilia, and worsening renal function in 78 patients receiving allopurinol is described. In a majority of cases, the development of this syndrome was associated with the use of standard (200 to 400 mg per day) doses of allopurinol in patients with renal insufficiency. In pharmacologic studies, it was demonstrated that the renal clearance of the major metabolite of allopurinol, oxipurinol, is directly proportional to the renal clearance of creatinine (oxipurinol clearance = 0.22 X creatinine clearance -2.87). An inverse linear relation was noted between the serum oxipurinol half-life and the renal creatinine clearance [( serum oxipurinol half-life in hours]-1 = 0.00034 X creatinine clearance in milliliters per minute + 0.0045). Long-term use of 300 mg per day of allopurinol was found to result in elevated steady-state serum oxipurinol concentrations in patients with renal insufficiency (serum oxipurinol concentration in micromoles per liter = -2.5 X creatinine clearance in milliliters per minute + 326). Avoidance of allopurinol or use of reduced doses in patients with renal insufficiency according to proposed guidelines should be adequate to inhibit uric acid production in most patients and may reduce the incidence of life-threatening allopurinol toxicity.

In a study of the antiemetic effectiveness of high-dose oral metoclopramide, 66 previously untreated patients receiving 60 mg/m2 cisplatin were entered into a double-blind randomized trial. Patients were stratified according to age and tumor type, then randomized to receive either oral or intravenous (IV) high-dose metoclopramide. Patients were evaluated for antiemetic protection, toxicity, affect (anxiety, hostility, and depression), and autonomic arousal (pulse rate and blood pressure) at three-hour intervals on the day of their chemotherapy. Metoclopramide serum levels were measured by high-performance liquid chromatography. Results indicated no significant differences between the oral and IV groups on any measurement of antiemetic protection, affect, or autonomic arousal. There were also no significant differences in side effects except for frequency of stools; patients who received oral metoclopramide had significantly more stools than patients who received IV metoclopramide. The mean (+/- SD) serum metoclopramide level at four hours achieved orally was 1,171 +/- 660 ng/mL; the mean (+/- SD) level achieved IV was 1,030 +/- 392 ng/mL (P = .498). We conclude that high-dose oral and IV regimens of metoclopramide as administered in this study have equivalent antiemetic efficacy in previously untreated patients receiving 60 mg/m2 cisplatin.

Various renal complications occur during the course of neoplastic disease. The therapeutic and prognostic implications differ according to the reversibility of both the underlying malignancy and the superimposed complications in the kidney. Since the mechanisms of renal failure vary significantly in patients with different types of malignancy, it is essential to avoid generalizations about etiologic factors or likely outcomes of the disease processes. The pathophysiologic abnormalities should be determined in each patient, and the reversibility of both the neoplastic and problems assessed before therapeutic decisions are made. This often requires a team effort by the internist, oncologist, nephrologist, urologist and, most importantly, the patient.

33 patients with locally and regionally advanced squamous cell carcinoma of the head and neck were treated with a single course of a combination of chemotherapy. Twenty-two of these patients were previously untreated, while the other eleven were previously treated with radiation therapy and/or surgery. Seventeen of the previously untreated patients had stage IV (M0) and the other 5 had stage III disease. Of the 33 patients; 26 received a three drug combination that consisted of: Cis-diamminedichloro-platinum II (DDP), Bleomycin (Bleo) and high dose Methotrexate (MTX) and leucovorin rescue. DDP was given on day 1; 100 mg/m2 with hydration and Lasix and Mannitol diuresis over 6 hours intravenously (iv). Bleo was administered as 15 units/m2 iv push on day 5 followed by 15 units/m2 a day for 5 days by continuous iv infusion. On day 10, the patient was evaluated and if there was no evidence of any toxicity, the patient was hydrated and alkalinated and MTX was given as 50 mg/m2 by rapid iv infusion followed by 1500 mg/m2 over 36 hours while maintaining the hydration and alkalinization. This was followed immediately by leucovorin; 25 mg/m2 iv over 15 minutes, then 200 mg/m2 over 12 hours iv. The patient then received leucovorin 25 mg/m2 intramuscularly (im) every 6 hours for 6 doses. The other 7 patients tolerated the first two drugs only, i.e., DDP and Bleo, and received no MTX because of decreased creatinine clearance. All patients were evaluated for response 2 weeks after the chemotherapy course, and prior to the local-regional therapy that consisted of surgery or radiotherapy. The response rates were 72.7% in previously untreated patients (16/22); with 4 complete responses (CR) and 12 partial responses (PR), and 54.5% in the previously treated group (6/11) all of them were PR. However, if we excluded three unevaluable patients that were considered failures from the study, the response rate in previously untreated patients would be 16/19 or 84.2%. The duration of response to such single course of chemotherapy was estimated to be 8–12 weeks. The toxicity in the 33 patients included vomiting in 18, alopecia, in 33, WBC below 2000 in 6, platelet count less than 50,000 in 6, mucositis in 7, and peak serum creatinine above 2 in 4 patients with two deaths. This combination chemotherapy seemed to be very effective in squamous cell carcinoma of the head and neck and could be applied prior to local-regional therapy. However, such program is still in experimental stages and should be carried out only in centers that have adequate facilities for close monitoring of the patients. Cancer 43:1025-1031, 1979.

Ocular lymphoma is an uncommon clinical entity with a propensity for intracranial extension. Palliation has been reported following radiotherapy, but the ultimate prognosis is poor, and significant treatment-related morbidity is common. Recent pharmacokinetic studies have suggested that sustained therapeutic drug concentrations are achievable in cerebrospinal fluid after systemic administration of high-dose cytosine arabinoside (Ara-C). These data led the authors to attempt treatment of a case of recurrent ocular lymphoma with high-dose Ara-C. Therapeutic drug levels were documented in intraocular fluids, and prolonged objective regression of tumor was seen. Systemic high-dose Ara-C deserves consideration for the treatment of ocular lymphoma.

Lymphomatous involvement of the gastrointestinal tract occurs with greater frequency than is generally appreciated, demonstrable in 30–50% of patients with non-Hodgkins lymphoma at post-mortem examination [1–4]. Although primary gastrointestinal involvement is less prevalent (3–11% overall frequency), the gastrointestinal tract is the most common primary site of extranodal lymphoma [1–3, 5–10]. Non-Hodgkin’s lymphoma accounts for less than 20% of primary bowel malignancies [2] and fewer than 5% of neoplasms of the stomach and colon [11–15]. Roughly 1,300 new cases of primary gastrointestinal lymphoma are seen in the United States each year.

Forty patients with limited-stage small cell carcinoma of the lung were prospectively evaluated for adjuvant surgery after intensive chemotherapy to determine resectability. All patients giving informed consent and having a Karnofsky performance status greater than or equal to 50% were included in the study, which ran from May, 1980, to September, 1982. Ages ranged from 40 to 70 years (median, 59 years). One patient was lost to follow-up. Thirty-nine patients were evaluated for operation 9 to 15 weeks after diagnosis and after having received two to four cycles of chemotherapy intravenously every 3 weeks (cyclophosphamide, 1,000 mg/m 2 ; doxorubicin, 50 mg/m 2 ; vincristine, 1 mg/m 2 ; VP-16, 300 mg/m 2 ). Two patients had clinical Stage I tumors; 12 patients, Stage II; and 25 patients, Stage III. At the time of reevaluation there were 13 (33%) complete responders, 21 (54%) partial responders, and 5 (13%) with stable disease. Eleven (28%) of the 39 patients underwent thoracotomy using standard resection criteria for non–small cell carcinoma. Eight of these 11 had resectable lesions (2, Stage I; 3, Stage II; 3, Stage III); five pneumonectomies and three lobectomies were performed. Tumor was present in six of eight specimens. Twenty-eight patients were not candidates for operation for various reasons: poor pulmonary function, 5; unresectable tumors, 10; refusal, 6; very poor medical condition, 6; and primary site not identified, 1. Median survival for complete responders was 17 months and for partial responders, 11 months. We have prospectively identified suitable candidates for adjuvant surgery among the total group (denominator population) of patients with limited-stage small cell carcinoma. Operation was performed in only 11 of 39 patients and resection, in 8. For 28 patients with this disease, adjuvant surgery was not appropriate. Also, it appears that resection is applicable in only a selected subset of patients with this tumor.

Plasma, urine, cerebrospinal fluid, and tear concentrations of cytarabine (ara-C) were measured in 15 patients receiving 3 gm/m2 IV ara-C given as a 1 hr infusion every 12 hr for 6 days. The two assay methods used for measuring ara-C concentrations (high-pressure liquid chromatography and radioimmunoassay) gave much the same results. Peak plasma ara-C concentrations (2.0 microM) after high-dose therapy were 50 times those achieved with more conventional (100 to 300 mg/m2) doses. High doses of ara-C were not sufficient to saturate cytidine deaminase; plasma ara-C half-lifes (t1/2) after high-dose therapy (distribution t1/2 = 6.2 min; elimination t1/2 = 154 min) were much the same as those after conventional ara-C doses. Kinetics of ara-C were not altered by repeated dosing over a 6-day period. Cerebrospinal fluid ara-C concentrations after high-doses (mean = 7.8 microM) were 10 times those after conventional intravenous dosing, bot were 0.5% to 1.0% those achieved by intrathecal ara-C doses. Tear concentrations of 22 and 38 micro M were measured in two patients who developed conjunctivitis after high-dose therapy so that the presence of ara-C in tears may be a cause of the conjunctivitis seen in some patients.

Sepsis with a previously undescribed species of Corynebacterium was documented in four patients. All patients had predisposing illness at the time of infection, three patients having leukemia in relapse and one having a porencephalic cyst and a ventriculoatrial shunt. The isolates from blood cultures had a characteristic metallic sheen when grown on blood agar. They were resistant to most antibiotics tested, including the penicillins, but were uniformly sensitive to vancomycin. Common biochemical characteristics, the metallic sheen, and the unusual antibiotic sensitivity pattern suggest that these isolates comprise a new species or group of closely related species of Corynebacterium that is capable of infection in man.

Four patients with disseminated Merkel cell tumors were treated with cyclophosphamide (C), doxorubicin (A), and vincristine (V). Two partial responses (PR) were noted and in one case disease remained stable. One of the patients who achieved a PR achieved a second PR when treated with VP-16 (E) and cis-platin (P) after progressive disease developed. Systemic chemotherapy appears capable of inducing objective responses in some patients with disseminated Merkel cell tumors.

Allopurinol toxicity has been associated with the use of this drug in patients with renal insufficiency, a situation where the half-life of oxipurinol, the major metabolite of allopurinol, is prolonged. Allopurinol toxicity has also been associated with the concomitant use of allopurinol and thiazide diuretics. In the present study, the effect of hydrochlorothiazide administration on the renal clearance and serum half-life of oxipurinol has been studied in eight normal volunteers to determine if thiazides delay the clearance of oxipurinol. Oxipurinol's renal clearance and serum half-life were measured in each volunteer during a control period and again while the volunteer was receiving 50 mg/day hydrochlorothiazide for 1 week. No change in renal oxipurinol clearance (21.1 +/- 5.9 vs. 20.4 +/- 8.7 ml/min) or serum oxipurinol half-life (23.7 +/- 4.2 vs. 23.4 +/- 4.4 hours) was noted with the addition of thiazides. The association previously noted between the use of thiazide diuretics and the development of allopurinol toxicity cannot be explained by alterations in oxipurinol pharmacokinetics.

Review of clinical data from 350 patients with small-cell lung cancer (SCLC) revealed hyponatremia (sodium less than 130 mEq/L) attributable to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in 40 patients (11%). Although hyponatremia was severe in most instances (median, sodium 117 mEq/L), symptoms attributable to water intoxication were identified in only 27% of hyponatremic episodes. Development of SIADH showed no correlation with clinical stage, distribution of metastatic sites, sex, or histologic subtype of small-cell carcinoma. SIADH occurred most often with initial presentation (33 of 40), and resolved promptly (less than 3 weeks) with initiation of combination chemotherapy in 80% of evaluable patients. The presence of SIADH did not influence response to chemotherapy or overall survival as an independent variable. However, in five patients profound hyponatremia developed immediately following primary cytotoxic therapy (range, one to five days). Despite initial control of SIADH, dilutional hyponatremia recurred in 70% of patients with tumor progression. Our findings suggest that development of clinically demonstrable SIADH in patients with SCLC is dependent on functional properties of the neoplastic cells, rather than tumor burden or metastatic site. The potential for development of clinically significant hyponatremia early in the course of cytotoxic therapy emphasizes the need to closely monitor patients, particularly those receiving chemotherapy regimens requiring substantial intravenous hydration.

Forty patients with extensive small cell lung cancer randomly received either high-dose or low-dose methotrexate with leucovorin rescue in combination with cycles of cyclophosphamide, doxorubicin, and vincristine alternating with cycles of VP-16, vincristine, and hexamethylmelamine. Nineteen patients were treated with the high-dose methotrexate regimen, and 21 received the low-dose methotrexate treatment protocol; both treatment groups were similar in median age, performance status and spread of disease. Response rates (74 percent for high-dose therapy; 67 percent for low-dose therapy), median survival (nine months versus nine months), and overall survival were similar for the two treatment groups. Myelosuppression was equivalent in both treatment groups but moderate to severe mucositis developed more often when patients were treated with the high-dose methotrexate regimen as compared with low-dose methotrexate therapy (p less than 0.001). Central nervous system recurrences developed after three patients received high-dose methotrexate therapy. This study indicates that when used with other antineoplastic agents, high-dose methotrexate therapy does not improve the remission rate or survival nor does it decrease central nervous system metastasis in patients with small cell lung cancer when compared with standard doses of methotrexate; high-dose methotrexate is associated with greater cost and toxicity.

Assay of plasma methotrexate has been established as important to its safe use. We have investigated the specificity of 2 assay procedures for methotrexate: the competitive dihydrofolate reductase binding assay (CRBA) and the radioimmunoassay (RIA). The RIA of plasma methotrexate resulted in consistently higher values than the CRBA, with greater differences at later measurement times. A compound that strongly cross-reacts in the RIA, but not the CRBA, has been identified in plasma and urine of patients on high-dose methotrexate therapy, and appears to be the carboxypeptidase cleavage product (2,4-diamino-N10-methylpteroic acid) on the basis of chromatographic and ultraviolet spectral properties. Although this compound is present as a minor contaminant in commercial methotrexate preparations, quantitative assessment of urinary excretion suggests that in man a major portion of the compound is derived from methotrexate metabolism.

To correlate the pharmacokinetics and toxicity of methotrexate, we measured the drug's clearance from plasma after 395 high-dose, six-hour infusions given to 78 patients. After 375 infusions, 48 hour methotrexate levels fell within 2 standard deviations of the mean for nontoxic infusions, and myelosuppression did not occur. Methotrexate concentrations exceeded the range for nontoxic patients (mean +/- 2 standard deviations) after 20 infusions. Serious myelosuppression occurred after six of these 20 infusions, including five of 12 infusions associated with 48-hour drug concentrations above 9 X 10(-7) M. In seven patients with 48-hour concentrations above 9 X 10(-7) M, the absence of toxicity could be attributed to subsequent rapid clearance of the drug; four of these patients also received large doses of supplemental leucovorin (50 to 100 mg per square meter every six hours). Determination of methotrexate concentration in plasma thus identified patients at high risk of toxicity, a group that may benefit from supplemental leucovorin rescue.

Nine (2%) of 429 small-cell lung cancer (SCLC) patients seen at Vanderbilt University between 1977 and 1983 had a combined subtype SCLC at diagnosis (ie, small-cell carcinoma plus squamous cell or adenocarcinoma). Staging procedures and chemotherapy treatment were uniform for all 429 patients. The diagnosis of combined histology was established via bronchoscopy (six patients), needle aspiration biopsy (one), lymph node biopsy (one), and thoracotomy (one). The clinical characteristics of the combined subtype patients were similar to patients with other subtypes of SCLC (ie, there were no differences in median age, sex, performance status, and stage of disease). However, patients with a combined subtype histology had a higher incidence of peripheral lesions on chest x-ray (56% v 14%, P less than .001) and a lower median lactate dehydrogenase (LDH) (301 IU/L v 341 IU/L, P = .0002) at diagnosis. The overall response to chemotherapy (57% v 78; P = .5) and the median survival (8 months v 10 months; P = .4) of the combined subtype patients were similar to patients with other subtypes of SCLC. Two (22%) combined histology patients survived greater than or equal to 5 years. Both had had surgical resection in addition to chemotherapy. These data suggest that the combined subtype of SCLC is clinically similar to pure SCLCs and that surgery may play a prominent role in the management of these tumors. The possibility of a combined histology tumor should be considered in patients thought to have SCLC on the basis of limited biopsy material, such as a needle aspiration or bronchial biopsy, and when the primary lesion is peripherally located on chest x-ray.

Carcinoma of the lung remains the leading cause of death due to malignant disease in the United States, and is rapidly becoming the leading cause of cancer death in women [1]. Although surgical therapy of non-small cell lung cancers has improved during the past two decades, the overall results remain discouraging. The limited efficacy of surgical therapy has led to exploration of other treatment modalities such as radiation or chemotherapy either alone or in combination with surgery, particularly for the two thirds of the patients who present with advanced disease and for those in whom the presence of associated disease renders resection too hazardous. This chapter will attempt to review the present limitations and usefulness of radiation therapy and chemotherapy in the treatment of non-small cell lung cancer.

Nineteen patients with non-small-cell carcinoma of the lung were treated with high-dose methotrexate and leucovorin rescue. Two partial responses (10.5%) were observed, lasting 13 and 17 weeks. Toxicity was acceptable. It is concluded that the occasional benefit of high-dose methotrexate with leucovorin rescue at this dose and according to the schedule described for these patients does not warrant further study.

VP-16-213, a congener of epipodophyllotoxin, is a useful chemotherapeutic agent especially against small-cell carcinoma of the lung, germ cell carcinoma, and lymphoma. The standard dose of this drug is limited by myelosuppression. Autologous transplantation of cryopreserved bone marrow assures the restoration of hematopoiesis after marrow ablative cytotoxic therapy. By using this technique, VP-16-213 was dose-escalated using a Fibonacci scheme from the previous highest dose administered to humans (1,500 mg/m2) to 2,700 mg/m2 (900 mg/m2 per day for three consecutive days). At 2,700 mg/m2, severe extramedullary toxicity of the mucous membranes was observed in three of three courses. At the next highest dose (2,400 mg/m2), two of 18 courses (11%, p less than 0.01) resulted in severe mucositis, thus defining this dose as the maximally tolerated dose based on extramedullary toxicities. As anticipated, myelotoxicity was severe but based on the kinetics of marrow recovery, VP-16-213 in these doses appeared not to be marrow ablative. Based on responses observed in this study, high-dose VP-16-213 should be explored in phase II studies or used in combination chemotherapy.

The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin was studied in six female New Zealand white rabbits. Plasma pharmacokinetic data were first obtained from rabbits given 3 mg/kg doxorubicin. After 1 month, the same rabbits were treated with ranitidine, 2.5 mg/kg or 25 mg/kg, before and during doxorubicin administration. The plasma doxorubicin assays to determine pharmacokinetic parameters were repeated. Drug toxicity was evaluated using complete blood counts, and hepatic function was measured using a 14C-aminopyrine breath test. High-dose ranitidine increased the total exposure to doxorubicin (area under the curve of doxorubicin alone = 1.44 +/- 0.88 microM.h/ml vs 4.49 +/- 2.35 microM.hr/ml for doxorubicin given with high-dose ranitidine; P = 0.06). Low-dose ranitidine did not alter doxorubicin pharmacokinetics. Exposure to doxorubicinol was altered by either high-dose or low-dose ranitidine. 14C-Aminopyrine half-life was altered by a ranitidine dose of 25 mg/kg (aminopyrine half-life after placebo control = 97 +/- 6 min as against aminopyrine half-life after ranitidine = 121 +/- 7 min; mean +/- SEM; P less than 0.02). Low-dose ranitidine did not exacerbate doxorubicin-induced myelosuppression. High-dose ranitidine enhanced doxorubicin-induced erythroid suppression while sparing the myeloid series. At cytochrome P-450-inhibitory doses, ranitidine's effects upon doxorubicin plasma pharmacokinetics are similar to those previously seen with cimetidine. These changes did not appear to alter drug detoxification and are not related to microsomal inhibition of doxorubicin detoxification. Low doses of ranitidine do not alter doxorubicin plasma pharmacokinetics or toxicity in rabbits.

High-dose methotrexate and Leucovorin (calcium folinate) rescue was evaluated as induction chemotherapy in combination with cyclophosphamide, doxorubicin, and vincristine in 21 patients with extensive-stage small cell lung cancer. Nine (42%) of 21 had a complete remission. The median duration of remission has been short (5 months), and attempts are now under way to improve consolidation chemotherapy. In general, the degree of myelotoxicity was not increased by the high-dose methotrexate, although the antitumor activity of the combination appears enhanced. Attempts at further increasing the intensity of this regimen or comparative trials with other therapy appears warranted.

Twenty 36-hour infusions of high-dose methotrexate were given preoperatively to 10 patients with head and neck cancer. Plasma methotrexate levels of greater than 1 X 10(-5) M were maintained for 36 hours and declined with primary and secondary plasma half-lives of 1.7 and 9.2 hours following the end of the infusion. Toxicity of this infusion regimen was minimal (10% incidence of significant (WBC less than 2000/mm3) myelosuppression; no renal toxicity) and all patients underwent surgical resection within 3 weeks of therapy without obvious increase in operative complications. Four of ten patients responded to chemotherapy. Further comparison of the therapeutic efficacy of this prolonged preoperative infusion regimen with surgery alone or schedules employing conventional doses or 6-hour infusions of high-dose methotrexate appears warranted.

Production of interferon was studied in fibroblasts cultured from human fetal, neonatal, and maternal tissue. Human fetal and maternal cells were paired to diminish genetic variability. Fetal cells displayed an increased response to two inducers of interferon, virus and synthetic double-stranded ribopolynucleotide. Fetal cells released 300-fold more interferon than maternal cells on exposure to poly rI:rC. This enhanced capacity for interferon production was consistent in cultures developed from fetal skin obtained between the 10th and 20th gestational week. The response was relatively stable, persisting in cells cultured for 18 generations (about 14 weeks). On infection with Newcastle disease virus, fetal cells produced, on the average, 4 to 6.5 times more interferon than maternal or neonatal cells. The virus was adsorbed with equal efficiency by each type of cell. Increased production is apparently independent of the rates of overall protein synthesis, since fetal and maternal cells have very similar rates of total protein synthesis.

10003 Background: Preclinical studies demonstrate synergistic anti-tumor activity by inhibiting mTOR and IGF-1R. This study evaluated the safety and efficacy of A12 and TEM in 3 chemo-refractory cohorts: IGF-1R (+) STS (Arm A), IGF-1R (+) bone (Arm B), and IGF-1R (-) bone and STS (Arm C). Methods: An optimal Simon 2 stage design was used for each arm. The primary end-point was progression free survival (PFS) at 12 weeks. Based on historical data, a 40% PFS rate was considered promising and a 20% PFS non-promising (type I/ II error, 0.05/0.10). ≥5 PFSs at 12 weeks were required in the first 19 and ≥16 PFSs were required in a total of 54 pts to consider each arm positive. Key eligibility: measurable disease (RECIST 1.1), age ≥18, 1- 4 priors, ECOG status 0-1. A12 (6 mg/kg) and TEM (25 mg) were administered IV weekly. Pre and post treatment tumor biopsies and plasma for IGF-1 and IGFBP3 were obtained. 20 Sarcoma Centers participated. Results: Starting in 02/2010, 383 pts were tested for IGF-1R by immunohistochemistry (IHC; 54% +) and 171 were treated: mean age 47 (range: 18-80), mean # priors 2.2 (range: 1-4). Grade 3/4 toxicities ≥10%: lymphopenia (12%), mucositis (10%). By intent to treat (ITT) analysis, each arm of the study achieved its primary 12 week PFS end-point (≥16 PFSs): Arm A: 18/56 (32%), Arm B: 19/50 (38%) (4 too early), Arm C: 27/63 (43%). The one-sided 95% CI for 12-week PFS is (0.22, 1), (0.27, 1), and (0.32, 1), respectively. By ITT the median PFS (95% CI) in weeks for each arm is 6.3 (5.9, 12.0), 11.0 (8.0, 18.0) and 11.6 (9.0, 17.9), respectively, and for chondro (n=18), Ewing’s (n=24), and osteo (n=23) only it is 22.6 (5.7, 40.9), 10.4 (5.7, 17.9) and 6.0 (6.0, 18.0), respectively. Westerns on 32 matched pair tumor biopsies indicate inhibition of IGF-1R, pAKT and pS6. Of biopsies on 7 IGF-1R (-) IHC pts (Arm C), 5 were IGF-1R (+) by western. Plasma biomarkers did not correlate with PFS. Conclusions: A12 and TEM met its primary end-point of improved PFS in pts with metastatic sarcoma. This effect was independent of IGF-1R status by IHC. These results support further clinical development of this combination in bone and STS.