Bisphosphonates are frequently used worldwide mostly in osteoporosis and skeletal bone metastases. However, a serious side-effect is bisphosphonate related osteonecrosis of the jaws (BRONJ). The mechanism behind BRONJ remains unclear. In literature several origins are suggested. Presence of the teeth in the jaws may play an important role. Therefore in this study 45 patients were analyzed retrospectively.Files of 45 patients with a diagnosis of BRONJ were analyzed, meaning clinical features, bisphosphonate use, dental history including luxating moment and (previous) treatment.In 97.5% (n = 44) a certain or presumable dental focus, such as extractions, a previous dental treatment or prosthesis complaints were found as initiating factor of BRONJ.In contrast to findings in literature, in our group of patients a dental focus was found in 44 of 45 cases. This implies a dentoalveolar start of BRONJ with subsequent spreading into the jaws in nearly all cases.

Background: Bortezomib (Bz, VELCADE®) is a novel proteasome inhibitor that has demonstrated efficacy and safety in patients (pts) with relapsed and/or refractory multiple myeloma (MM) in clinical trials. In a large randomized phase 3 trial, Bz achieved superior response rates (RR), TTP, and survival compared with high-dose dexamethasone in relapsed MM pts after 1–3 prior therapies. Peripheral neuropathy (PN) has been dose limiting, especially in pts with pre-existing PN. The objective of this multicenter phase 2 trial was to evaluate the activity and safety of Bz as monotherapy in previously untreated MM pts and prospectively examine PN at baseline (BL) and across treatment.

Introduction: Histone deacetylases (HDACs) affect cell growth at the transcriptional level by regulating the acetylation status of nucleosomal histones, and HDAC inhibition induces differentiation and/or apoptosis in transformed cells. We have recently shown that HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), induce apoptosis of human multiple myeloma (MM) cells via a constellation of antiproliferative and/or proapoptotic molecular events, including decreased expression of multiple signaling molecules and oncogenes implicated in MM pathophysiology. Based on these promising pre-clinical data, we embarked on a phase I clinical trial of oral SAHA in patients with advanced MM. Methods : An open-label phase I dose-escalation of oral SAHA (200, 250 and 300 mg po bid for 5 consecutive days followed by 2 days of rest) was administered in 4-week cycles in pts with relapsed/refractory MM. The primary objective was to determine the maximum tolerated dose (MTD), and secondary objectives included evaluation of tumor response, as well as assessment of markers of biologic activity in peripheral blood mononuclear cells and bone marrow plasma cells. Dose limiting toxicity (DLT) was defined as grade 4 or greater hematologic toxicity and/or grade 3 or greater non-hematologic toxicity within the first 28 days of treatment. Results : To date, 8 pts with advanced MM (5 relapsed and 3 with relapsed, refractory MM) have been enrolled at the first 2 dose levels, receiving a median of 3 cycles (range 2–9) of therapy. In 7 evaluable pts, one pt at the 2nd dose level (250 mg po bid) developed DLT with grade 3 fatigue, prompting dose reduction with the next cycle. Other side effects have included grade 2 fatigue (3 pts), grade 2 diarrhea (2 pts), grade 2 indigestion (2 pts) and grade 2 dehydration (2 pts), which have been manageable with appropriate supportive care. In one patient, during cycle 4 at dose level 2, grade 3 dehydration occurred with associated metabolic abnormalities that readily resolved with electrolyte supplementation and rehydration. The patient has continued on therapy at reduced dose (250 mg po bid, 4 days on, 3 days off) without recurrence of this toxicity. Importantly, no significant myelosuppression, neuropathy or sedation, which are associated with other anti-MM agents, has been seen. In 7 evaluable pts: minor responses (MR) were documented in 2 patients (25–50% reduction in serum paraprotein levels); stable disease (SD: less than 25% reduction in paraprotein levels) was observed in 2 pts; and progressive disease (PD) was documented in 3 pts. Conclusion: SAHA is an orally administered HDAC inhibitor with manageable toxicity and preliminary evidence of antitumor activity in advanced MM. Clinical evaluation of this agent continues, with enrolment at 250 mg b.i.d. ongoing, to further define the safety and tolerability at this dose level and provide insight into the future uses of SAHA, either alone or in combination with other agents, to treat pts with advanced MM.

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 docetaxel was determined for 30 hours following docetaxel infusion in both periods. Results: The pharmacokinetic parameters of docetaxel are summarized in the table below. Docetaxel pharmacokinetics were not affected by coadministration of aprepitant. No difference in toxicity was noted in the two chemotherapy cycles: mean absolute neutrophil count nadirs were 0.96 x 109/L with aprepitant and 0.85 x 109/L without aprepitant. Conclusions: Aprepitant has no effect on docetaxel pharmacokinetics or toxicity. Moderate inhibitors of CYP3A4 metabolism such as aprepitant are unlikely to have significant clinical effects on chemotherapeutic agents metabolized by CYP3A4. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck & Co., Inc. Merck & Co., Inc. Merck & Co., Inc. Merck & Co., Inc. Merck & Co., Inc.

Abstract Introduction: Bortezomib, a first in class proteasome inhibitor, has become a standard of care in the treatment of relapsed and refractory MM. A recent randomized Phase 3 trial showed an improvement in time to progression (TTP) and overall survival relative to dexamethasone (dex) in patients with relapsed MM and 1–3 prior lines of therapy. In relapsed MM, the rate of treatment -emergent significant peripheral neuropathy (PN) with bortezomib was higher in patients with baseline neuropathy. The incidence and severity of PN in front-line treatment will be important to define. This multi-center, Phase 2 study was planned to evaluate the activity and toxicity (in particular PN) of single agent bortezomib in previously untreated pts. Methods: Response rate, TTP, tolerability, incidence and severity of PN, and the effect of dose modification, symptomatic treatment and nutritional supplements on PN were evaluated in previously untreated, symptomatic MM pts. Pts received bortezomib 1.3 mg/m2 on D 1, 4, 8, and 11 of a 21-d cycle and response to treatment was assessed every 2 cycles. Dex was not permitted. Neurologic evaluation was required before and after treatment, and if significant PN developed during therapy. Results: 28 pts with symptomatic MM have been treated with a median age of 60 yrs, IgG isotype in 68% and Stage III disease in 52%. Analysis of best paraprotein response after ≥ 2 cycles revealed CR in 1 (5%) pt and PR in 8 (36%), for an ORR of 41% in 22 evaluable pts. An additional 5 pts (23%) achieved MR, with stable disease in 6 pts (27%); 2 pts progressed (9%). The most commonly reported adverse events included PN, fatigue, GI symptoms and rash. Neurological evaluation has been performed in all pts, including nerve conduction studies (NCS), assessment of autonomic function and skin biopsy for EM imaging of small fibers in a subset (n=19). Six of 28 pts (21%) so far have developed PN with most being G2: 1 pt experienced G3 PN and drug was discontinued. Dose modification was required in 4 pts and supplements have been used in all pts with PN. Preliminary results of neurological testing and NCS have indicated subclinical PN at baseline prior to therapy in 6/19 (30%) of pts evaluated by NCS, with small fiber, axonal PN documented in 1 pt with treatment-emergent PN. Bortezomib-related toxicity has otherwise been manageable. Conclusion: Single agent bortezomib is a promising approach for newly diagnosed pts and is without the complications of high-dose dex. The incidence of subclinical PN by NCS at baseline prior to therapy is currently 30%; G2 or greater treatment-emergent PN has occurred in 21% of pts and was G3 in only 1 pt (4%) to date. Further assessment of PN including analysis of skin biopsies is ongoing.

The objective of this study was to accurately determine the within- and between-patient variability in etoposide pharmacokinetics for i.v. and p.o. administered drug. Inter-and intrapatient variability in systemic etoposide exposure was measured following i.v. and p.o. drug administration using stable isotope dilution methodology. Seven patients received 50 mg of etoposide by both p.o. and i.v. routes of administration on three separate occasions 1 month apart. Etoposide plasma concentrations following p.o. and i.v. drug administration were quantitated by liquid chromatography-mass spectrometry for each route of administration. The area under the plasma etoposide concentration versus time curve, plasma etoposide clearance, and etoposide plasma half-life were calculated for each dose of drug. Kinetic measurements following i.v. and p.o. drug administration were compared. The within-patient variation in the areas under the plasma etoposide concentration versus time curves following i.v. drug administration was minimal [coefficient of variation (CV) = 9.3%]. Within-patient variability was increased 2.4-fold with oral drug administration (intrapatient CV = 22.2%). Between-patient variability was roughly three times as great as within-patient variability (interpatient i.v. CV = 28.4%; interpatient p.o. CV = 58.3%). Mean etoposide bioavailability at a dose of 50 mg was 64.6%, again with greater interpatient than intrapatient variability (34.8 versus 22.6%). Greater variation in drug toxicity is expected with p.o. compared with i.v. etoposide use. Administration of repeated doses of etoposide to the same patient should produce less variation in toxicity than between-patient dosing.

Purpose: A Phase II study to evaluate the response rate and toxicity of daily protracted cisplatin and etoposide with concurrent chest irradiation in patients with locally advanced, unresectable nonsmall cell lung cancer (NSCLC).Methods and Materials: Twenty-one patients with histologically confirmed Locally advanced inoperable NSCLC (Stage IIIA or IIIB) were entered on study, Radiotherapy consisted of 50.4 Gy in 1.8 Gy fractions followed by a 10 Gy boost in 2 GS fractions, Chemotherapy included the following: Cisplatin was given at 5 mg/m(2) i.v. Monday-Friday before RT weeks 1-6, Etoposide was given at 25 mg/m(2) i.v. M-F weeks 1, 2, 5, and 6, with 50 mg/m(2) p.o. daily on the same weekends, Because of severe myelosuppression in the first two patients, etoposide only was subsequently changed to 20 mg/m(2) i.v. M-F weeks 1, 2, 5, and 6,Results: Twenty patients were eligible and evaluable, The overall response rate was 65% (95 % confidence interval 41-85%), The median progression-free survival was 43 weeks, The median overall survival was 50.2 weeks with a I-year survival rate of 45%, Five patients (25%) developed severe radiation pneumonitis, leading to early closure of the study.Conclusions: Combining daily protracted cisplatin and etoposide with concurrent thoracic irradiation in patients with locally advanced unresectable NSCLC yields a high overall response rate and a median survival that is at least comparable to other combined modality trials, However, future studies using protracted radiosensitizing chemotherapy should be approached cautiously in light of the high incidence of severe radiation pneumonitis encountered in this trial. Copyright (C) 1997 Elsevier Science Inc.

Clinical Pharmacology & Therapeutics (1996) 59, 199–199; doi: 10.1038/sj.clpt.1996.294

To further investigate the antineoplastic efficacy and safety of somatostatin analogues, 2 trials were performed. Octreotide, SMS 201-995 (Sandostatin), was escalated in doses ranging from 1,500 micrograms to 6,000 micrograms daily in 14 patients with carcinoid. Somatuline, (BIM 23014C, Angiopeptin, Lanreotide) was given in doses ranging from 2,250 micrograms to 9,000 micrograms daily to 13 neuroendocrine patients (6 carcinoid, 2 atypical carcinoid, 3 pancreatic islet cell and 2 small cell lung cancer patients). All patients successfully completed dose escalations without significant adverse effects and were evaluable for toxicity. The dose limiting side-effect of octreotide was the injection volume. No dose limiting adverse effects have been observed with somatuline. Carcinoid syndrome symptoms were better controlled with higher octreotide doses. Thirteen patients were evaluable for octreotide's antitumor efficacy with a partial response observed in 4 (31%), stable disease in 2 and progressive disease in 7 patients. Radiographic changes of increased tumor necrosis occurred in 5 patients and was independent of response. Somatuline resulted in a partial response in 4 patients (2 carcinoids, 1 gastrinoma and 1 small cell lung cancer) (31%), stable disease in 1 atypical carcinoid, and progressive disease in 8 (4 carcinoid, 1 atypical carcinoid, 2 islet cell and 1 multi-drug resistant small cell lung cancer). Six of the 8 carcinoid patients had radiographic changes of increased necrosis. Dose escalation of somatostatin analogues is well tolerated and may be associated with antitumor activity in some neuroendocrine neoplasms.

Etoposide is used commonly to treat both small cell lung cancer and non-small cell lung cancer. It is usually administered intravenously over 3 to 5 consecutive days, and usually given in combination with cisplatin. Preclinical cellular and clinical pharmacokinetic studies have demonstrated that etoposide is schedule-dependent and is optimally administered at low doses over prolonged periods of time. Recent early phase clinical trials have demonstrated that oral etoposide can be administered safely for 14 to 21 consecutive days. This schedule has demonstrated outstanding activity in patients with both recurrent and previously untreated small cell lung cancer. Activity against non-small cell lung cancer has also been reported; response rates are similar to those seen with the most active single agents used in the treatment of the disease. Chronic oral etoposide also has the advantages of outpatient convenience and tolerable side effects. This overview discusses the role of chronic oral etoposide in the management of small cell lung cancer and non-small cell lung cancer. The scientific rationale, results of early phase clinical trials, ongoing research, and future directions regarding the chronic administration of this important antineoplastic drug are also reviewed.

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 < 0.05). However, median survival was not improved with the three-drug regimen, and myelosup- pression 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 vin- desine did not make a significant impact in response rate or overall survival in this study.

The clearance of etoposide and formation of etoposide glucuronide have been measured in an isolated, perfused rat liver model to evaluate the effect of impaired hepatic function on etoposide kinetics. Hepatocellular injury was produced by pretreatment of rats with allyl alcohol or carbon tetrachloride; ligation of the bile duct simulated obstructive biliary disease. Etoposide clearance (3.59 +/- 1.06 ml/min) was reduced by both carbon tetrachloride (2.07 +/- 0.64 ml/min; P = 0.05) and allyl alcohol treatment (2.14 +/- 0.62 ml/min; P = 0.05). Biliary obstruction also impaired etoposide clearance but to a lesser extent than hepatocellular injury (2.47 +/- 0.69 ml/min; P = 0.20 versus control). In both hepatocellular and obstructive models, direct biliary etoposide excretion decreased. The metabolic clearance of etoposide to its glucuronide declined by 36% in the hepatotoxin models but was not decreased by biliary obstruction. Following hepatic injury, there is a reduction in the metabolism and excretion of etoposide by the liver. This effect is most marked on biliary drug excretion. Obstructive biliary disease does not significantly alter etoposide glucuronidation. Since most cancer patients have increased bilirubin on the basis of obstructive disease, little or no etoposide dose alteration will be needed. However, in the patient with significant hepatocellular injury, impaired etoposide clearance will be more pronounced, and etoposide dose alterations may be needed.

Isolated livers from male Sprague-Dawley rats were perfused at 20 ml/min for 3 h at 37 degrees C with 100 ml of an oxygenated, recirculating solution of 20% rat blood in Krebs bicarbonate buffer containing 20 micrograms/ml [3H]etoposide. Ninety % of administered radioactivity was eliminated in bile over a 3-h collection period. The clearance of etoposide was 3.56 ml/min indicating that, in the rat, it is not highly extracted. Its clearance is, therefore, independent of hepatic blood flow. Etoposide was both excreted into the bile and metabolized by the liver. Perfusate and bile samples analyzed by reverse-phase high-performance liquid chromatography techniques were found to contain three peaks of radioactivity. Positive and negative ion fast atom bombardment mass spectrometry identified the first two peaks as etoposide glucuronides and the third peak as parent drug. Following the i.v. administration of etoposide to rabbits, etoposide glucuronide was also identified in rabbit urine. The recovery of etoposide both from rabbit urine and rat bile was increased by preincubation with glucuronidase. However, the glucuronides were relatively resistant to the action of glucuronidase and showed varying sensitivity to the type of glucuronidase and the reaction conditions used. These studies document the presence of etoposide glucuronide as an etoposide metabolite in two mammalian species and suggest that previous clinical studies using beta-glucuronidase to quantitate glucuronide formation may have underestimated this metabolite due to its relative resistance to some glucuronidase preparations.

This study had two objectives. The first was to determine if hypercalcemia presents as an isolated finding in patients with lung cancer prior to the development of abnormalities on chest radiography. The second was to correlate the presence of hypercalcemia with survival after surgical therapy. A review of clinical material over a seven-year period yielded 67 patients with diagnoses of hypercalcemia and lung cancer. No patient presented with surgically curable lung cancer associated with hypercalcemia. A review of the literature disclosed only four cases in which a putative cure occurred in the presence of hypercalcemia. Review of the clinical material and the literature revealed no instance in which hypercalcemia per se led to the diagnosis of clinically occult lung cancer. Hypercalcemia was almost always associated with large tumor masses. Median survival after the discovery of hypercalcemia complicating carcinoma of the lung was one month.