Faculty Bibliography

Pegylated liposomal doxorubicin (PLD, Doxil, Caelyx) is widely used for the treatment of ovarian cancer. It is a stable formulation encapsulating doxorubicin in a 'Stealth' (i.e., pegylated) liposome with a half-life of about 72 hours. This drastically altered pharmacology confers on it a considerably lower risk of cardiotoxicity, no acute emesis, and near absence of alopecia or problems with extravasation necrosis. On the other hand, PLD's dose-limiting toxicity is cutaneous. Since the original phase I report, cutaneous toxicities reported with PLD fall into four common categories: the well known hand-foot syndrome (also called palmoplantar erythrodysesthesia, or PPE), a diffuse follicular rash, intertrigo-like eruption, and hyperpigmentation including melanotic macules

PURPOSE: Conflicting results on prognostic factors for advanced epithelial ovarian cancer (EOC) have been reported because of small sample size and heterogeneity of study population. The purpose of this study was to identify factors predictive of poor prognosis in a similarly treated population of women with advanced EOC. PATIENTS AND METHODS: A retrospective review of demographic, pathologic, treatment, and outcome data from 1,895 patients with International Federation of Gynecology and Obstetrics stage III EOC who had undergone primary surgery followed by six cycles of intravenous platinum/paclitaxel was conducted. A proportional hazards model was used to assess the association of prognostic factors with progression-free survival (PFS) and overall survival (OS). RESULTS: Increasing age was associated with increased risks for disease progression (HR = 1.06; 95% CI, 1.02 to 1.11 for an increase every 10 years) and death (HR = 1.12; 95% CI, 1.06 to 1.18). Mucinous or clear-cell histology was associated with a worse PFS and OS compared with serous carcinomas. Patients with performance status (PS) 1 or 2 were at an increased risk for recurrence compared with PS 0 (HR = 1.12; 95% CI, 1.01 to 1.24). Compared with patients with microscopic residual disease, patients with 0.1 to 1.0 cm and > 1.0 cm residual disease had an increased risk of recurrence (HR = 1.96; 95% CI, 1.70 to 2.26; and HR = 2.36; 95% CI, 2.04 to 2.73, respectively) and death (HR = 2.11; 95% CI, 1.78 to 2.49; P < .001; and HR = 2.47; 95% CI, 2.09 to 2.92, respectively). CONCLUSION: Age, PS, tumor histology, and residual tumor volume were independent predictors of prognosis in patients with stage III EOC. These data can be used to identify patients with poor prognosis and to design future tailored randomized clinical trials.

BACKGROUND: Few studies have evaluated concomitant pegylated liposomal doxorubicin (PLD) plus trastuzumab as therapy for HER2-overexpressing metastatic breast cancer (MBC). This open-label, prospective, phase II trial assessed the safety and efficacy of this regimen, with cardiac tolerance as the principal focus. PATIENTS AND METHODS: Women with HER2-overexpressing recurrent MBC, baseline left ventricular ejection fraction >or= 55%, and no history of serious cardiac illness were eligible; preexisting cardiac risk factors, including previous anthracyclines and previous trastuzumab for MBC, were allowed. Patients received weekly trastuzumab and every-3-week PLD until progression, prohibitive toxicity, or patient refusal. Left ventricular ejection fraction was assessed during and after therapy. Grade 3/4 congestive heart failure (CHF) was monitored for premature closure. RESULTS: The trial closed after 2.5 years for slow accrual. Twelve patients were enrolled: 7 had received adjuvant anthracyclines; 9 had received previous MBC treatment, of whom 7 had received trastuzumab in combination with chemotherapy. Patients received a mean of 4.8 cycles of PLD; 8 patients experienced stable disease; 4 patients experienced progression. Mean left ventricular ejection fraction levels did not change substantially: 60.4%, 57%, 60.3%, and 56.8% at baseline, after cycle 2, after cycle 4, and after completion of treatment, respectively. No patients experienced grade 4 CHF. One patient discontinued treatment after grade 3 CHF. Three patients experienced grade 2 left ventricular dysfunction, of whom 2 discontinued treatment. Cardiac function improved in all 4 patients after going off study. Other adverse events were generally mild (grade 1/2) and infrequent. CONCLUSION: Pegylated liposomal doxorubicin plus trastuzumab might be an option for heavily pretreated patients with recurrent HER2-overexpressing MBC

The authors report and discuss a case of a mucinous carcinoma of the appendix, a rare entity with a distinct natural history that poses diagnostic and therapeutic challenges. Mucinous peritoneal carcinomatosis is most commonly associated with primary tumors of the appendix and colon. Typically, spread remains confined to the abdominal cavity. Imaging assessment of these mucinous lesions is difficult, while tumor markers (CEA and CA19.9) may be surrogates for extent of disease. Treatment consists of surgical debulking, sometimes coupled with intraperitoneal drug delivery, but recurrence is universal. New treatment approaches are needed. Mucin genes are regulated in part by epidermal growth factor receptor signaling. Therefore, we initiated a phase II study of cetuximab for mucinous peritoneal carcinomatosis, that was part of this patient's treatment

BACKGROUND: We hypothesized that a response to pegylated liposomal doxorubicin (PLD, Caelyx/Doxil) followed by maintenance is beneficial and safe in recurrent ovarian cancer. PATIENTS AND METHODS: Sixteen patients have received PLD for more than 1 year for recurrent ovarian (14) or fallopian tube (2) cancer. All had stable disease or better responses to PLD + carboplatin (5) or topotecan (9) doublets or to PLD alone (2). PLD maintenance therapy 30-40 mg/m(2) was given every 4-8 weeks. This analysis focuses on cardiac status, overall tolerance, and time to recurrence. RESULTS: Termination of PLD was due to progression in all patients. Noteworthy was the lack of cumulative myelosuppression and, with one exception, clinical cardiac toxicity. This patient was hospitalized with cardiogenic shock and fever complicating grade 4 pancytopenia from topotecan ten months after discontinuation of PLD. Seven patients continue to receive PLD after a median of 1680 mg/m(2) (1180-2460 mg/m(2)). Four of these had documented relapses after 3-6 years on maintenance occurring in the setting of lengthening of the treatment interval. Maintenance PLD was reinstituted after 'reinduction' with a platinum. CONCLUSIONS: PLD appears to be safe as long-term maintenance in ovarian cancer and may be important for a continued response.

OBJECTIVE: The primary objective of this study was to determine the rate of response to matuzumab in patients with recurrent, EGFR-positive ovarian, or primary peritoneal cancer. Secondary end points included safety and tolerability, time to tumor progression, duration of response, and overall survival. METHODS: A multi-institutional single arm phase II trial. RESULTS: Of 75 women screened for the study, 37 were enrolled and treated. Median age of the treated patient population was 58 years, and most patients had more than four prior lines of chemotherapy. Therapy was well tolerated, the most common toxicities being a constellation of skin toxicities, including rash, acne, dry skin, and paronychia, as well as headache, fatigue, and diarrhea. Serious adverse events were very rare but included a single episode of pancreatitis that may have been drug related. All patients completed therapy, receiving 1 to 30 infusions of matuzumab. There were no formal responses (RR=0%, 95% CI: 0-9.5%), although 7 patients (21%) were on therapy for more than 3 months with stable disease. CONCLUSIONS: Matuzumab at the dose and schedule selected is well tolerated. In this population of very heavily pretreated patients with epithelial ovarian and primary peritoneal malignancies, there was no evidence of significant clinical activity when matuzumab was administered as monotherapy.

The purpose of this study was to estimate the response rate of 26-h continuous infusion cyclosporine A (CSA) combined with carboplatin (CBDCA) and subcutaneous alpha-interferon (IFN), in recurrent ovarian cancer (OC), and to measure their effects on CBDCA pharmacokinetics. OC patients relapsing following platinum-based chemotherapy received CBDCA area under the curve (AUC 3) with CSA and IFN, every 3 weeks. The pharmacokinetics of CSA and CBDCA were determined in a subset of patients. Thirty patients received 84 courses of therapy. Three partial responses were observed. Nine patients were stable for >4 months. Toxicity was similar to that observed in our previously reported phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean end of infusion CSA level (high-performance liquid chromatographic assay [HPLC]) was 1109 +/- 291 microg/mL (mean +/- SD). CBDCA pharmacokinetics revealed a measured AUC of 3.61 versus a targeted AUC of 3, suggesting a possible effect of IFN on CBDCA levels versus errors in the estimation of CBDCA clearance using measured creatinine clearance. Steady-state levels of >1 microg/mL CSA (HPLC assay) are achievable in vivo. Insufficient clinical resistance reversal was observed in this study to warrant further investigation of this combination.

BACKGROUND: We previously demonstrated that peak microtubule bundle formation (MBF) in peripheral blood mononuclear cells (PBMCs) occurs at the end of drug infusion and correlates with drug pharmacokinetics (PK). In the current study, a new expanded evaluation of drug target effect was undertaken. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with ixabepilone 40 mg/m2 administered as a 1-h i.v. infusion every 3 weeks. Blood, plasma, and tumor tissue sampling was carried out to characterize pharmacodynamics and PK. RESULTS: Forty-seven patients were treated with 141 cycles of ixabepilone. In both PBMCs (n=27) and tumor cells (n=9), peak MBF occurred at the end of infusion; however, at 24-72 h after drug infusion, the number of cells with MBF was significantly greater in tumor cells, relative to PBMCs. A Hill model (EC50=109.65 ng/ml; r2=0.94) was fitted, which demonstrated a relationship between percentage of PBMCs with MBF and plasma ixabepilone concentration. The percentage of PBMCs with MBF at the end of infusion also correlated with severity of neutropenia (P=0.050). CONCLUSIONS: Plasma ixabepilone concentration and severity of neutropenia correlate with the level of MBF in PBMCs. Therefore, this technically straightforward assay should be considered as a complement to the clinical development of novel microtubule-binding agents.

Background: ChemoRT after surgery for locally advanced gastric cancer improves overall and relapse-free survival (OS and RFS) compared to observation (NEJM 2000,345:72530). However, loco-regional recurrences (>50%) remain high and we hypothesized that adding IP FUDR would further improve outcome. Methods: Patients (pts) ECOG performance status (PS) 02, gastric/gastroesphogeal(GEJ) adenocarcinoma stage Ib-IV (M0) undergoing R0 resection were eligible, and had insertion of IP catheters at surgery. IP FUDR(3gm/dose/day) was given on protocol days 1, 2, 3 and 15, 16, 17 prior to 5-FU/LV and external beam RT (45Gy) as in cited study. Simon 2-stage optimum design was used to demonstrate safety. Endpoints also included were loco-regional recurrence and survival. Results: 28 pts with gastric/GEJ adenocarcinoma (25/3) were enrolled from 2002 to 2006 at 2 institutions: median age 59.5 years (range 3981), M /F (21/7). R0 gastric resection was performed with dissection of median 22 (range 8102) lymph nodes(LN's). 22/28 pts were lymph node positive. Full dose IP FUDR was completed in 20/28 pts. 4 pts required dose reduction (1 for grade(gr) 2 hepatic enzyme elevation, 2 gr 2 neutropenia, 1 gr 4 neutropenia), 3 discontinued therapy (1 gr 3 abdominal pain, 1 GI abscess, and 1 bleeding arterial pseudoaneurysm). One pt received no IP treatment due to catheter failure. 24/28 pts completed chemoRT and had toxicity comparable to that previously reported in the Intergroup 0116 trial. At 26 month median follow up (range 2.843.4), of the 26 pts evaluable for response, 16 pts are NED, 6 alive with disease, 3 dead of disease, and 1 dead from other cause. 5 recurrences were intra-abdominal, 1 local, 2 distant, and 1 at multiple sites. At present analysis, the median RFS is 32.5 months. Conclusions: IP FUDR prior to chemoRT after R0 gastric cancer resection is well tolerated. A randomized study to test its role in reducing regional recurrence and improving outcome is warranted. (FDA Orphan Products grant# FD-R-215004)