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Disparities occur in the incidence and mortality of cervical cancer among minority women in the US. Screening lowers cervical cancer incidence. Screening rates are lower for minority women than for White women in the US. This study sought to identify demographic, risk factor, and perception of the role of Pap smears between Latinas and non-Latinas.A written survey was administered to 150 Latinas and 150 non-Latinas attending a colposcopy unit. Data on demographics, risk factors, screening rates, knowledge about cervical cancer screening, and perceived barriers to participation in screening programs were collected.A total of 140 Latinas and 146 non-Latinas completed the survey. Marital status and health insurance status were similar in the two groups. 30% of Latinas and 73.3% of non-Latinas reported completing college (p0.0001). Only 55.7% of Latinas were employed, compared to 82.2% of non-Latinas (p0.0001). 21% of Latinas and 53.4% of non-Latinas reported an annual income greater than 35,000 dollars (p0.0001). Among Latinas, women with 1-5 lifetime Pap smears were less likely to have completed college than those with more than 5 lifetime Pap smears (OR=2.11; 95% CI 1.05-4.22) and to have an annual income of less than 35,000 dollars (OR=3.81; 95% CI 1.64-8.87). Latinas were less likely to haveor =6 lifetime sexual partners, use tobacco, and have a history of sexually transmitted infections. Latinas more commonly reported fear of test results (OR, 0.04; 95% CI 0.02-0.09) and inability to communicate with their provider in Spanish (p0.0001) as barriers to screening than the non-Latina respondents.Several of the barriers limiting access to cervical cancer screening programs are also present among screened Latinas undergoing further evaluation for abnormal Pap smears.

Previously, we reported the use of three sequential doublets (Triple Doublets) in the treatment of women with newly diagnosed and advanced stage müllerian malignancies. The surgically defined negative second look operation (SLO) rate to Triple Doublets was 38%. Modifications were made to this treatment regimen that were predicted to reduce toxicity and possibly increase efficacy.Open label two-cohort study. Patients with a new diagnosis of Stages II-IV müllerian malignancy were eligible. After cytoreductive surgery, patients were treated with three sequential doublets including 3 cycles of carboplatin and gemcitabine, and 3 cycles of carboplatin and paclitaxel, and 3 cycles of doxorubicin and topotecan. After therapy, all women were clinically staged and evaluated at SLO if clinical staging was negative for residual disease. Primary endpoints were toxicity and negative SLO rate with rates of 60% and 40% defined a priori in optimally cytoreduced (cohort 1) and suboptimally cytoreduced or Stage IV (cohort 2), respectively.Eighty-five eligible patients were enrolled with a median age of 52 years. Forty-seven and thirty-eight women were in cohorts 1 and 2, respectively. 723 cycles of chemotherapy were delivered with no toxic deaths. Grades 3 and 4 toxicities included neutropenia in 75% of patients and thrombocytopenia in 65% of patients during at least one cycle of therapy. Fever and neutropenia were seen in 3.5% of patients. All Grades 3 and 4 non-hematologic toxicities were seen at a frequency of10%. Seventy women underwent SLO with a negative SLO rate of 53% with an additional 9% having microscopically positive procedures. Negative SLO rate was 74% in cohort 1 and 36% in cohort 2.Treatment with the modified triple doublet regimen is tolerable with an encouraging pathologic CR rate.

The manuscript by Armstrong et al. in this issue of The Oncologist, reviewing the toxicity and efficacy of full-dose topotecan delivered as second-line therapy in individuals with small cell lung cancer or ovarian cancer, will likely serve as both the most comprehensive and the final review of this active agent delivered at the U.S. Food and Drug Administration–approved dosage and schedule. The review represents large, relative lyhomogeneous patient populations with prior platinum exposure and convincingly describes topotecan as an agent with activity that is comparable with those of all other approved drugs in this setting and a well-defined and relatively circumscribed set of toxicities. While the activity of topotecan in small cell carcinoma provides individuals with the hope for further palliation at the time of tumor recurrence, as discussed by Dr. Markman in this issue, the best use of this agent in the management of recurrent ovarian cancer is far from clear because, in part, of a growing list of approved active agents, most notably liposomal doxorubicin, gemcitabine, and weekly paclitaxel; a return to platinum; or a host of other agents such as vinorelbine, altretamine, irinotecan, docetaxel, etoposide, and others. The most pressing need is to accept that palliative therapies are designed to palliate and improve symptoms, and to move away from end points of radiologic and marker response to a focus on “clinical benefit” and clinically more meaningful end points.

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH) founded The Kenneth B. Schwartz Center at MGH. The Schwartz Center is a nonprofit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient and support to caregivers and encourages the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. The diagnosis of cancer is incredibly stressful, and treatments are arduous. Humor may help to ease the pain, show the human side of the health care team, and help everyone cope. Whether the patient uses humor to lighten the mood of a difficult consultation with their physician, or health care workers use it to help cheer each other through the day, humor and laughter can be valuable tools. Humor can soften the isolation experienced by both patients and staff. When used sensitively, respecting the gravity of the situation, humor can build the connection among the caregiver, patient, and family. However, insensitive joking is offensive and distressing, and experience suggests a variable acceptance of humor by patients with life-threatening illnesses, making humor a high-risk strategy, and it can be a pejorative maker of an adversive power differential. The medical literature contains little on humor, and very little research has been conducted on this common aspect of human communication. Through an examination of physician and nurse experiences, the role of humor in medicine is reviewed.

Purpose To evaluate the response rate, toxicity profile, and pharmacokinetics of ecteinascidin-743 (ET-743) as first-line therapy in patients with unresectable advanced soft tissue sarcoma (STS). Patients and Methods Thirty-six patients with STS were enrolled onto the study between September 1999 and August 2000. Patients were treated with 1.5 mg/m2 of ET-743 given as a 24-hour continuous intravenous (IV) infusion every 21 days. Pharmacokinetic sampling was performed in 23 patients. Results One complete and five partial responses were achieved in 35 assessable patients for an overall response rate of 17.1% (95% CI, 6.6% to 33.6%). In addition, one patient had a minor response, leading to an overall clinical benefit of 20%. Neutropenia and transaminitis were the main grade 3 to 4 toxicities, which occurred in 33% and 36% of the patients. The estimated 1-year progression-free and overall survival rates were 21% (95% CI, 11% to 41%) and 72% (95% CI, 59% to 88%), respectively. Total body clearance (L/h) was not significantly correlated with body-surface area (r = −0.28; P = .21). Mild hepatic impairment or the extent of prior cytotoxic therapy does not seem to contribute significantly to the high interpatient variability (49%) in the clearance of this drug. Severity of treatment-related toxicity was not correlated with pharmacokinetic variables. Conclusion ET-743 demonstrates clinical activity as first-line therapy against STS with acceptable toxicity. Additional studies to establish empirical dosing guidelines may be necessary to improve the safety of the drug in patients with varying degrees of hepatic dysfunction and definitively establish the role of ET-743 for patients with these malignancies.

This Award funded the initiation of a mentored research experience in ovarian cancer biology at the Dana Farber/Harvard Cancer Center. The primary aims, articulated in the Statement of Work, included creating a mechanism to identify and select outstanding postdoctoral fellows who had a commitment to serious multi-year experience in research that was directly related to a topic in or immediately applicable to ovarian cancer. The second aim was to provide a mentored experience for selected fellows. The third aim specified the delivery of feedback to the trainees by mentors and the program PI. The final aim described a rigorous review process for the program. These aims are all being addressed. Of the four senior post doctoral fellows selected to work with Faculty at Harvard Medical School in the fields of oncogenesis, signal transduction, pathology and mouse models and cell biology, one fellow graduated from the program and is successfully transitioning towards an independent academic research career. The vacancy was competed for and filled successfully. A new faculty member with extensive training in biologic models was added to the program to mentor the fellows, who continue to pursue their research productively at 3 different institutions within the Dana Farber/Harvard Cancer Center.

BACKGROUND Tezacitabine [(E)-2'-deoxy-2'-(fluoromethylene) cytidine; FMdC] is a novel nucleoside analog with potent antiproliferative and antitumor activity in preclinical studies. A tolerable safety profile and clinical activity have been shown in Phase I and Phase II clinical studies. The purpose of the current open-label, Phase I dose-escalation trial was to evaluate the combination of tezacitabine and 5-fluorouracil (5-FU) in the treatment of patients with advanced solid tumors. METHODS Twenty-four patients with a variety of advanced solid tumors for which there was no curative therapy were enrolled. Bolus infusion tezacitabine was administered on Day 1 of a 14-day cycle at escalating doses of 150–350 mg/m2, with continuous infusion 5-FU (CI 5-FU) given on Days 1–7 at a fixed dose of 200 mg/m2 per day. Patients underwent objective tumor evaluation by radiologic methods or clinical examination at baseline and after every fourth treatment cycle. RESULTS The maximum tolerated dose of the combination therapy was determined to be tezacitabine, 200 mg/m2, with CI 5-FU, 200 mg/m2 per day. The toxicities were manageable, the most notable being transient severe (National Cancer Institute Common Toxicity Criteria Grade 3 or 4) neutropenia in 23 patients (96%). Eleven (55%) of the 20 assessable patients had partial responses or stabilization of disease. The highest response rate was in patients with primary tumors of esophageal origin. CONCLUSIONS Tezacitabine at a dose of 200 mg/m2 in combination with CI 5-FU at a dose of 200 mg/m2 per day was relatively well tolerated and had clinical activity in patients with advanced solid tumors, particularly in patients with esophageal and other gastrointestinal carcinomas. Cancer 2005. © 2005 American Cancer Society. Cancer 2005. © 2005 American Cancer Society.

Objectives: To describe the clinical, perimetric, and electroretinographic (ERG) results of 4 patients with cone dysfunction following irofulven treatment including the histopathologic and immunocytochemical features of one patient’s retinas. Design: Observational case series. Methods: The patients were examined clinically, including perimetric and ERG evaluations. Eyes from patient 1 and healthy postmortem eyes were processed for histopathologic and immunocytochemistry studies with antibodies specific for cones, rods, and reactive Muller cells. Main Outcome Measures: Clinical signs and symptoms, perimetry, ERG, retinal histopathologic and immunocytochemistry study results. Results: All 4 patients had ERG changes consistent with abnormal cone responses and relatively normal rod responses. Compared with control eyes, the retina of patient 1 had approximately half the normal numbers of macular cones and fewer peripheral cones. The number of rods were normal but all rod and cone outer segments were shortened. Conclusion: High-dose irofulven treatment causes conespecific damage with relative sparing of rods. Arch Ophthalmol. 2005;123:29-34

Objectives To determine the toxicity, tolerability, and feasibility of delivering combination chemotherapy with subsequent radiation therapy to women with high-risk endometrial cancer and to evaluate the long-term bowel toxicity of this regimen. Methods The trial was approved by the Dana Farber/Partners Cancer Care (DFPCC) Institutional Review Board (IRB). Patients with stage 3 or stage 4 endometrial cancer or patients with high-risk histology and any stage disease were prospectively entered. Complete surgical staging and a normal gated blood pool scan were required prior to entry. Patients were treated with three cycles of paclitaxel (160 mg/m 2 ), doxorubicin (45 mg/m 2 ) and carboplatin (AUC 5) (TAC) all on day 1 of a 21-day schedule as an outpatient with G-CSF support. At the conclusion of chemotherapy, patients received radiation therapy (4500 cGy to the whole pelvis) commencing within 35 days of the last cycle of chemotherapy. Paraaortic radiation and/or vaginal brachytherapy were allowed at the discretion of the treating radiation oncologist. Results Twenty patients were entered onto the trial from November 2000 through February 2003. Eighteen patients successfully completed the trial, and two patients came off trial during chemotherapy (both later completed planned radiation therapy). Patients were initially stage 1 ( n = 3), stage 3 ( n = 14), and stage 4 ( n = 3). Papillary serous was the dominant histology with 13 patients. Chemotherapy was given on average within 32 days of surgery (range 11–63 days) and radiation was initiated on average within 14 weeks of surgery (range 10–18 weeks). Chemotherapy was well tolerated, with 57 total cycles delivered of a planned 60 cycles. Two patients required dose modification in two cycles (two patients in cycle 3 secondary to hematologic toxicity). No grade 3 or grade 4 neurotoxicity was reported. There were six episodes of grade 3 short-term toxicity with radiation therapy reported in a single patient. Late radiotherapy toxicity included bowel obstruction requiring laparotomy in two patients and grade 3 constipation in one patient. Late radiation toxicity data are still being collected as follow-up continues. Conclusions The TAC chemotherapy regimen is well tolerated and three cycles were delivered successfully with G-CSF support without evidence of the neurotoxicity or cardiac toxicity reported with the cisplatin containing TAP regimen. Standard radiation was deliverable following TAC therapy without excessive toxicity. Further study of this regimen with subsequent radiation therapy is warranted in patients at risk for systemic and regional recurrence of their malignancy.

Objective To determine the activity and tolerability of weekly docetaxel in patients with platinum-resistant mullerian origin tumors. Methods Patients with persistent disease, or those recurring less than 6 months after receiving platinum-containing therapy, were eligible for this phase II study. Docetaxel was initially administered at a dose of 40 mg/m 2 on days 1, 8, and 15, with a cycle length of 28 days. This starting dose was subsequently reduced to 30 mg/m 2 due to toxicity. Dexamethasone prophylaxis was administered at a dose of 4 mg PO every 12 hours for 3 doses, starting 12 hours before each dose of docetaxel. Results Thirty-two patients were enrolled, with a median age of 59 years. The majority of patients received a median of 3 prior regimens, with 45% of the study group having received 4 or more prior regimens. The overall response rate in 29 evaluable patients was 6.9%, with no complete responses. Seventeen percent of patients experienced stable disease. Dose reduction or delay was required in 10 of the first 22 patients enrolled, prompting a reduction in the starting dose to 30 mg/m 2 . Hematologic toxicity was generally tolerable, and no patient experienced febrile neutropenia. Non-hematologic toxicity was generally grade 1 in nature, although a combination of multiple low grade toxicities occurring in an individual patient oftentimes mandated dose reduction. Conclusions Weekly docetaxel demonstrated modest activity in a heavily pre-treated, platinum-resistant population. A starting docetaxel dose of 30 mg/m 2 would be reasonable for future studies exploring the utility of weekly dosing in less heavily pre-treated patients.

To identify genes involved in the paclitaxel resistance phenotype. High-density Affymetrix HG-U95Av2 microarrays were used to quantify gene expression in the resulting cell lines, SKOV-3TR, OVCAR8TR and MCF-7TR, and their drug-sensitive parental lines, SKOV-3, OVCAR8 and MCF-7. Three paclitaxel-resistant human ovarian and breast cancer cell lines were established. We identified 790 (SKOV-3TR), 689 (OVCAR8TR) and 964 (MCF-7TR) transcripts that were more than twofold overexpressed relative to their expression in the corresponding parental cell line. A comparison of these transcripts identified eight genes that were significantly overexpressed in all three drug-resistant daughter cell lines. These genes included MDR1, a gene often implicated in both in vitro and in vivo resistance to multiple chemotherapeutics, including paclitaxel. The remaining seven genes have not been previously associated with resistance to paclitaxel in human cancer. Furthermore, we identified 815 (SKOV-3TR), 430 (OVCAR8TR) and 332 (MCF-7TR) transcripts that were more than twofold decreased relative to their expression in the corresponding parental cell line. Comparison of these transcripts identified three genes that were significantly underexpressed in all three drug-resistant cell lines, none of which have been previously associated with paclitaxel resistance. Our results confirm that the paclitaxel resistance phenotype is associated with a large number of transcriptional changes. In addition, acquired paclitaxel resistance was associated with distinct transcriptional changes in each of the cell lines studied, suggesting that paclitaxel resistance is a complex phenotype that can arise through multiple mechanisms.

Topotecan and pegylated liposomal doxorubicin (Doxil) interact with topoisomerase I and II (topo I and II), respectively, with schedule dependent, and potentially synergistic cytotoxicity.Define dose-limiting toxicity (DLT) and determine the maximum tolerated dose (MTD) of topotecan delivered by 72-h infusion administered immediately after Doxil delivered at a fixed dose (30 mg/m(2)) in a cohort of women with recurrent müllerian malignancies.Topotecan dose was escalated from 0.5 mg/m(2)/day for 3 days in 0.2 mg/m(2)/day increments with treatment repeated every 21 days. Eligibility criteria required ECOGor = 2 and no more than four prior lines of chemotherapy. No dose reductions were allowed in the first two cycles to allow evaluation of cutaneous toxicity.Between November 2000 and August 2002, 18 patients were enrolled. Median age 59 (40-71) years. Patients received a median 1 (1-6) cycles of chemotherapy, with 39 cycles of treatment delivered at DL 1. All patients were evaluable for toxicity and 12 for response. At dose level 2, dose-limiting toxicity consisted of nausea and vomiting, mucositis, cutaneous toxicity, and neutropenia. There was no clinically significant cardiac toxicity. There were no radiologically confirmed partial responses.Doxil 30 mg/m(2) and topotecan 0.5 mg/m(2)/day by 72-h infusion (total dose 1.5 mg/m(2)), although a rational combination of cytotoxic therapies, have limited clinical activity.

Objective To evaluate the efficacy and toxicity of the selective aromatase inhibitor anastrozole (Arimidex), we conducted a phase II trial in 53 women with asymptomatic recurrent/persistent mullerian cancer. Methods Patients with ovarian, peritoneal, or fallopian tube carcinoma were eligible for enrollment. Eligible patients had an ECOG PS ≤ 1 and no clinical indication for immediate systemic chemotherapy. Patients were assigned to measurable (cohort 1) or evaluable disease (cohort 2) cohorts, respectively. Patients were treated with anastrozole 1 mg po daily. Monthly follow-up included interim history, physical exam, and CA-125 with radiologic evaluation every 3 months. Estrogen, progesterone, and Her-2/neu receptor status was also evaluated in archived tumor samples. Results Fifty-three women with a median age of 63 (range, 46–86) years were enrolled. Twenty-nine women enrolled in cohort 1 and 24 in cohort 2. Included were 43, 7, and 3 women with ovarian, primary peritoneal, and fallopian tube carcinoma, respectively. All 53 patients were evaluable for treatment toxicity and response. The median time to disease progression was 85 days (85 days for cohort 1 and 82 days for cohort 2). A partial response was documented in a single patient with measurable disease. Forty-two percent of patients had stable disease (measured as time to treatment termination) for >90 days, 15% for >180 days, 7% for >270 days, and 4% for >360 days. One patient remained on anastrozole at 15 months. Toxicity was modest (grade I) and infrequent, with the most common toxicities being fatigue and hot flashes. There were no thrombotic complications. Median time to progression for patients with estrogen receptor-positive tumors was 72 days as compared to 125 days for those with tumors negative for the estrogen receptor ( P = 0.95, log-rank test). The median time to progression in patients with progesterone-positive tumors was 77 days and 91 days for patients with progesterone-negative tumors. Conclusion In summary, anastrozole is a well-tolerated oral agent but with minimal tumoricidal activity in women with recurrent/persistent mullerian cancers. A minority of patients demonstrated prolonged stable disease while on this agent.

The spicamycin analogue KRN5500 is a nucleoside-like antibiotic with broad spectrum activity against human solid tumor models. It appears to possess a novel mechanism of action directed against the endoplasmic reticulum and Golgi apparatus with effects on protein processing. A Phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities, and pharmacokinetic behavior of KRN5500 given as a 1-h i.v. infusion for 5 consecutive days every 3 weeks.Adult patients with refractory solid tumors, good performance status, and normal to near normal renal, hepatic, and hematological function were eligible for the study. At least three patients were evaluated at each dose level, and a modified Fibonacci algorithm was used for dose escalation. The MTD was based on the occurrence of severe toxicity during the first cycle of therapy. The plasma pharmacokinetics of KRN5500 was characterized during the first week of dosing.Characteristics of the 26 patients entered into the study were as follows: 13 males and 13 females; median age, 54.5 years (range, 40-70 years); and Eastern Cooperative Oncology Group performance status 0-1. A majority had refractory colorectal carcinoma (17 of 26 patients) with at least two prior regimens of therapy. The dose of KRN5500 was escalated from 0.8 to 4.9 mg/m(2)/day in five dose levels, and the MTD was 2.9 mg/m(2)/day. All dose-limiting toxicities were nonhematological and included pulmonary toxicities, hyperglycemia, fatigue, hepatotoxicity, and ataxia, with one fatality due to interstitial pneumonitis. Clinically significant toxicities occurring in multiple patients that were not dose-limiting included nausea/vomiting, diarrhea, fatigue, neurological symptoms, hyperbilirubinemia, hyperglycemia, lymphopenia, and thrombocytopenia. There were no objective responses, although 3 of 17 evaluable patients exhibited disease stabilization for 5-6 cycles. The pharmacokinetics for the first dose of KRN5500 was biexponential and linear across all five dose levels. Mean values of pharmacokinetic parameters were as follows: total plasma clearance, 6.15 +/- 2.37 liters/h/m(2); apparent volume of distribution at steady state, 6.56 +/- 1.98 liters/m(2); biological half-life, 1.29 +/- 0.37 h; and mean residence time, 1.07 +/- 0.31 h. Clearance was significantly lower (P = 0.011) in the eight patients who were at least 65 years old (4.6 +/- 1.6 liters/h/m(2)) as compared with the 18 younger patients (7.1 +/- 2.3 liters/h/m(2)). Peak plasma concentrations of KRN5500 in the cohort receiving the MTD ranged from 350 to 400 ng/ml.The MTD of KRN5500, when given as a 1-h i.v. infusion for 5 consecutive days, was 2.9 mg/m(2)/day. The only suggestion of therapeutic activity observed in this study was disease stabilization in three patients with chemorefractory colorectal cancer. Administering KRN5500 as a continuous i.v. infusion with the objective of prolonging systemic exposure to potentially cytotoxic concentrations of the drug should be considered.

Previous studies directed at identifying paclitaxel resistance genes in a paclitaxel-resistant subclone of the human ovarian cancer cell line SKOV-3 identified a novel cancer testis antigen, Taxol resistance-associated gene 3 (TRAG-3). Because investigation suggested that TRAG-3, located on chromosome Xq28, does not directly participate in the paclitaxel-resistant phenotype, it was hypothesized that TRAG-3 might be linked to a neighboring gene that is directly involved in the drug-resistant phenotype, or alternatively, overexpression of TRAG-3 might be attributable to coregulation with other cancer testis antigens. To distinguish between these two hypotheses, expression of the genes that flank TRAG-3 was evaluated, namely the Centrin 2 gene and several members of the MAGE gene cluster. Northern analysis demonstrates overexpression of MAGE2 but not Centrin 2. Extension of this analysis to other neighboring and non-neighboring representative cancer testis antigens reveals overexpression of MAGE3, MAGE6, MAGE11, and MAGE12, as well as GAGE-2, GAGE-4, GAGE-5, GAGE-6, and GAGE-7 (clustered on Xp11) in SKOV-3(TR), as compared with SKOV-3. In addition, Affymetrix-based analysis of gene expression in SKOV-3 subclones with variable paclitaxel resistance demonstrates MAGE gene overexpression occurs early in the development of the paclitaxel-resistant phenotype, whereas GAGE gene overexpression occurs somewhat later. Evaluation of additional breast and ovarian cancer cell lines reveals MAGE/GAGE overexpression in both paclitaxel- and doxorubicin-resistant cell lines, whereas gemcitabine-resistant subclones of several ovarian cancer cell lines, including SKOV-3(GR), reveals no change in MAGE/GAGE expression. To determine whether MAGE gene overexpression contributes directly to the drug-resistant phenotype, MAGE2 or MAGE6, cDNA was introduced into the paclitaxel-sensitive human ovarian cancer cell line OVCAR8. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity analysis of both MAGE2 and MAGE6 transfectants demonstrates a 4-fold increase in resistance to paclitaxel and 2-fold increase in resistance to doxorubicin but not to other drugs, such as topotecan and cisplatin, through a nonmultidrug resistance-1 mechanism. MAGE2 or MAGE6 overexpression also induces a growth advantage in OVCAR8-transfected cells. These studies suggest that the in vitro acquisition of paclitaxel and doxorubicin resistance can be associated with increased expression of a variety of both neighboring and non-neighboring cancer testis antigens genes. This does not appear to be a consequence of random genetic instability or genomic amplification of the X chromosome. These antigens, because of limited expression in normal tissues, may be suitable targets for immunotherapy and novel therapeutic strategies in the treatment of chemotherapy-resistant epithelial tumors.

Objective . The role of MDR1 in clinical paclitaxel resistance remains poorly characterized. This study sought to identify the incidence and significance of P-glycoprotein (P-gp) over-expression on survival, tumor response to paclitaxel and the effect of prior cytotoxic exposure on P-gp expression in patients with paired primary and recurrent ovarian cancer samples. Methods . Retrospective survival analysis. P-gp expression was evaluated immunohistochemically with antibodies c494 and c219. Results . Thirty-two patients were identified from the tumor registry. Median interval between primary and secondary surgery was 17.9 (5.7–40.9) months. Only five primary tumors (16%) demonstrated +++ staining for P-gp. First-line treatment contained paclitaxel in 17 patients (53%) and 26 patients (81%) had been exposed to P-gp exportable chemotherapy before second surgery. Only seven of the recurrent tumors (22%) were +++. Only one of seven (14% (95% CI 0–46%)) recurrent tumors with ++ or +++ staining responded to subsequent paclitaxel, while 8 of 10 (80% (CI 46–100%)) recurrent tumors with 0/+ staining responded ( P = 0.025). In multivariate analysis of outcome following second surgery, response to paclitaxel ( P = 0.004) and P-gp over-expression ( P Conclusions . De novo strong P-gp over-expression is uncommon, appears to change little over time or with prior exposure to chemotherapy. However, P-gp over-expression is a significant prognostic factor, and at the time of disease, relapse is inversely correlated with tumor response to paclitaxel.

Ovarian cancer is currently the most lethal gynecological malignancy in the United States. Although effective therapies exist, the acquisition of multidrug resistance within persisting tumor cells renders curative therapies elusive for the majority of women with ovarian cancer. In an attempt to better define the evolution of paclitaxel resistance, three SKOV-3 sublines were selected during successive rounds of exposure to increasing paclitaxel concentrations. The sublines were selected to represent early (0.003 micro M), intermediate (0.03 micro M), and late (0.3 micro M) paclitaxel resistance. RNA from these cell lines, SKOV-3(0.003TR), SKOV-3(0.03TR), and SKOV-3(0.3TR), as well as the parent cell line SKOV-3, was analyzed by cDNA array to evaluate transcript expression profiles. Arrays were performed using Affymetrix HG-U95Av2 arrays, which contain probes for approximately 9600 known human genes. Signal intensities were calculated by Microarray Suite 5.0 (Affymetrix, Santa Clara, CA). Expression patterns were analyzed by Affymetrix Data Mining Tool 3.0 with filtering of expression patterns for fold change in expression (maximum divided by minimum expression value/gene) and for variation of expression (maximum minus minimum expression value/gene). This analysis dismissed approximately 11,000 of approximately 12,000 expression patterns. The remaining approximately 1000 expression patterns were normalized and segregated into 20 partitions of a self-organizing map (SOM). The resulting SOM discriminates between genes, which are differentially expressed in early versus intermediate versus late paclitaxel resistance. For example, multidrug resistance 1 transcript expression is not elevated in SKOV-3(0.003TR) as compared with parental SKOV-3 but demonstrates elevated expression in SKOV-3(0.03TR) and SKOV-3(0.3TR). In contrast, SOM analysis demonstrates early (SKOV-3(0.003TR)) transcriptional changes in a wide variety of genes, including gene families involved in cell growth/maintenance, cell structure, signal transduction, and inflammatory response. The use of array analysis with SOMs in sublines with progressive paclitaxel resistance can successfully define an evolution of resistance. Such an analysis may be useful at defining candidate gene families involved in the early-drug resistance phenotype.

A large number of cancer-associated gene products evoke immune recognition, but host reactions rarely impede disease progression. The weak immunogenicity of nascent tumors contributes to this failure in host defense. Therapeutic vaccines that enhance dendritic cell presentation of cancer antigens increase specific cellular and humoral responses, thereby effectuating tumor destruction in some cases. The attenuation of T cell activation by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) further limits the potency of tumor immunity. In murine systems, the administration of antibodies that block CTLA-4 function inhibits the growth of moderately immunogenic tumors and, in combination with cancer vaccines, increases the rejection of poorly immunogenic tumors, albeit with a loss of tolerance to normal differentiation antigens. To gain a preliminary assessment of the biologic activity of antagonizing CTLA-4 function in humans, we infused a CTLA-4 blocking antibody (MDX-CTLA4) into nine previously immunized advanced cancer patients. MDX-CTLA4 stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in three of three metastatic melanoma patients and the reduction or stabilization of CA-125 levels in two of two metastatic ovarian carcinoma patients previously vaccinated with irradiated, autologous granulocyte–macrophage colony-stimulating factor-secreting tumor cells. MDX-CTLA4 did not elicit tumor necrosis in four of four metastatic melanoma patients previously immunized with defined melanosomal antigens. No serious toxicities directly attributable to the antibody were observed, although five of seven melanoma patients developed T cell reactivity to normal melanocytes. These findings suggest that CTLA-4 antibody blockade increases tumor immunity in some previously vaccinated cancer patients.

The interaction between paclitaxel and its target, beta tubulin, is essential for effective cytotoxicity. Alterations or mutation of beta tubulin have the potential to alter paclitaxel binding and confer a drug resistant phenotype.Twenty-nine paired tumor samples from women with ovarian cancer were examined to evaluate the incidence of exon four mutations in tumors with evolving paclitaxel resistance. Tissue was dissected from five-micron paraffin slices and analyzed for mutations in exon four of human beta tubulin by PCR-SSCP. Nested PCR primers generated three partially overlapping or neighboring fragments corresponding to exon four of beta tubulin. 32P labeled PCR fragments were then subjected to SSCP analysis polyacrylamide gel electrophoresis.PCR-SSCP analysis demonstrated no mutations in the twenty-nine paired tumor samples studied.This result suggests that mutations within exon four of human beta tubulin are rare in newly-diagnosed and recurrent paclitaxel resistant human ovarian cancer.

It has been approximately ten years since the Food and Drug Administration (FDA) approved paclitaxel for the treatment of platinum resistant epithelial ovarian carcinoma. Since the approval, the drug has found therapeutic applications in a variety of schedules and in a wide variety of epithelial malignancies. Its novel mechanism of action provided the hope that it would demonstrate anti-neoplastic activity in multidrug resistant tumor cells. Unfortunately, as with other chemotherapeutic drugs, resistance is commonly seen. Laboratory investigation has defined a wide variety of resistance mechanisms including overexpression of multidrug resistance (MDR-1) gene, molecular changes in the target molecule (betatubulin), changes in apoptotic regulatory and mitosis checkpoint proteins, and more recently changes in lipid composition and potentially the overexpression of interleukin 6 (IL-6). This review describes the in vitro molecular data that define and support the various mechanisms of resistance and critically evaluates the evidence for the participation of these mechanisms in clinically relevant paclitaxel resistance. This review also explores pharmacologic attempts to modulate paclitaxel resistance, principally through inhibition of the MDR-1 drug efflux pump. Future avenues for drug resistance research and its pharmacologic manipulation in the clinic are discussed.

Although many dysplastic cervical lesions regress spontaneously, treatment is common due to concern for progression. Lesions persist or progress in women whose immune systems are unable to clear infection by human papillomavirus (HPV). Dehydroepiandrosterone (DHEA) is an adrenal steroid that has both immune modulatory and tumor inhibitory activity. A pilot study was conducted to examine the feasibility, safety and potential efficacy of intravaginal DHEA in women with low-grade cervical dysplasia. Twelve women with low-grade dysplasia, confirmed by colposcopic exam, were given 150 mg of intravaginal micronized DHEA daily for up to 6 months. Follow-up evaluations of the cervix were done at 3 and 6 months of use. DHEA, DHEA-S, androstenedione and testosterone levels were also measured. By the end of the study period, 10 of the 12 women (83%) had no evidence of dysplasia; the remaining 2 had normal colposcopic exams but cytology showing atypical cells of undetermined significance. There were no serious side effects. Androstenedione levels were elevated at 3 months, whereas testosterone levels were unchanged over the course of treatment. The results suggest that intravaginal DHEA is safe and well tolerated and may promote regression of low-grade cervical lesions. Further study is needed to establish efficacy.

To determine whether agents that target topoisomerase I and II could be administered sequentially.A Phase I study was conducted to evaluate sequential treatment with bolus IV doxorubicin followed 48 h later by topotecan given as a 30-min i.v. infusion on 3 consecutive days, with additional cycles of therapy repeated every 3 weeks. Characteristics of the 22 patients entered into the study were: 13 male and 9 female; median age, 49.5 (range 33-66) years; Eastern Cooperative Oncology Group performance status, 0-1; and normal cardiac, hematological, hepatic, and renal function. All patients had received prior therapy (medianor=2 prior regimens).The maximum tolerated dose of the combination was 25 mg/m(2) doxorubicin and 5.25 mg/m(2) topotecan (1.75 mg/m(2)/day x 3). Neutropenia was the dose-limiting toxicity. Attempts to further escalate the dose using 5 microg/kg granulocyte colony-stimulating factor proved unsuccessful because of thrombocytopenia. Among the 17 patients who were evaluable for response, 6 had a partial response, and 4 showed evidence of disease stabilization. The partial responses occurred in patients with small cell lung cancer (3 of 7), non-small cell lung cancer (1 of 6), esophageal adenocarcinoma (1 of 2), and ovarian carcinoma (1 of 1), and it lasted for 3-6 months. Administration of doxorubicin 2 days before topotecan did not alter topotecan pharmacokinetics. Changes in topoisomerase mRNA levels were observed during chemotherapy.The sequential combination of doxorubicin followed by topotecan is highly active in several chemotherapy refractory long, ovary, and esophageal cancers. Despite significant neutropenia, toxicity is manageable and well tolerated. Phase II trials to further evaluate the efficacy of this promising combination regimen against non-Hodgkin's lymphoma and lung cancer have been initiated.

Background. Both ovarian carcinoma and high-dose chemotherapy tend to preclude future pregnancies. Case. We report a case of a young woman with borderline ovarian carcinoma and invasive tumor implants who underwent surgical debulking with preservation of future fertility followed by carboplatinum, paclitaxel (Taxol), and subsequent high-dose chemotherapy with subsequent peripheral blood stem cell rescue as part of a phase I clinical trial. After a brief period of amenorrhea, the patient had a successful pregnancy that was complicated by a spontaneous abortion in the first trimester. Several months later she conceived and delivered a healthy baby at term. Conclusions. To our knowledge this is the first reported case of pregnancy after high-dose chemotherapy with stem cell transplant in a woman with ovarian carcinoma.

The effectiveness of systemic chemotherapy is dramatically limited by both intrinsic and acquired drug resistance. Several new technologies have been developed over the last decade to more rapidly identify underlying genetic alterations that impart a drug-resistant phenotype. Techniques such as cDNA-based subtraction technologies, SAGE analysis, and most recently cDNA array and high-density micro-array technologies have rapidly expanded our ability to detect changes in RNA transcription in drug-resistant tumors. These technologies are currently being applied to generate a large number of new hypotheses regarding the regulatory molecules underlying the drug-resistance phenotype. These techniques suggest that there is a large number of transcriptional changes which occur in the drug-resistance phenotype and future work will need to focus on dissecting which of these transcriptional changes are central to the drug resistance phenotype, both in vitro, and more importantly within clinical neoplasia. Copyright 2000 Harcourt Publishers Ltd.

Objectives. The aim of this study was to determine the efficacy and toxicity of single agent off-protocol, liposomal doxorubicin (Doxil Alza), in consecutive patients with recurrent ovarian cancer and to investigate the influence of HER-2/neu expression on response to liposomal doxorubicin. Patients and methods. Retrospective analysis of 72 consecutive patients treated, typically with liposomal doxorubicin 40 mg/m 2 q28 days between January 1997 and December 1998. Results. Twenty-nine patients (40%) had platinum- and taxane-resistant tumors. Nineteen patients (27%) responded with clinical or radiological evidence of response with reduction in CA-125 of >50%. One complete response (CR) and 7 partial responses (PRs) occurred in platinum- and taxane-resistant patients (radiological response (RR) 29%) and 8 PRs occurred in patients with visceral metastases (RR 28%). Time to progression was 5.3 (2.1–12.1) months. Only 7 dose delays (3%) and 20 dose reductions (8%) were necessary in 265 cycles of treatment. Hematological toxicity was generally mild with grade (Gr) ≥III neutropenia in 1 (2%), Gr ≥III thrombocytopenia in 1 (1%), and Gr ≥III anemia in 8 patients (11%). One patient (1%) was admitted with fever and neutropenia. Other toxicity was minimal with Gr ≥III mucositis occurring in 3 patients (4%). Gr ≥III cutaneous toxicity was seen in 6 patients (8%). Three patients (4%) had a >10% fall in ejection fraction but there was no unequivocal clinical heart failure. Conclusions. The data suggest that liposomal doxorubicin is an active drug in both taxane- and platinum-sensitive and resistant recurrent ovarian cancer. Liposomal doxorubicin is associated with tolerable toxicity and is particularly well tolerated in patients with multiple prior lines of treatment.

Objectives. The goal of this study was to determine the maximally tolerated doses (MTDs) of carboplatin, paclitaxel (Taxol), etoposide, and cyclophosphamide (CTEC) with granulocyte-colony stimulating factor (G-CSF, Filgrastim) support as first-line chemotherapy in women with advanced epithelial ovarian cancer (EOC). Methods. Newly diagnosed patients with either stage IV EOC, or stage III EOC and any amount of gross residual tumor after surgical debulking were eligible to receive six cycles of CTEC over five different dose levels in this phase I trial (planned 21-day cycle length). Paclitaxel, carboplatin, and cyclophosphamide were administered intravenously on Day 1, and oral etoposide was administered on Days 1, 2, and 3. G-CSF was administered beginning Day 4. Results. Twenty patients received a total of 98 cycles of CTEC over the five dose levels evaluated. Bone marrow suppression was the major toxic effect, with grade 4 neutropenia and thrombocytopenia being observed in 25 and 23% of cycles, respectively. The overall incidence of febrile neutropenia was 10%, and no toxic deaths occurred. No grade IV thrombocytopenia or febrile neutropenia was observed once the carboplatin dose was reduced from AUC of 7 to 5. Nonhematologic toxicity was generally mild (grade 2 or less). Dose-limiting toxicity was not observed at the highest dose level evaluated in this study, preventing assignment of the MTD. The clinical complete response rate was 92%, although 15 of 16 evaluable patients have progressed with a median progression-free interval of 4 months (range, 2–11 months). One patient remains disease-free 9 months from the completion of CTEC. Conclusions. The CTEC regimen is well tolerated and highly active. Although the MTD was not reached in this study, the short median progression-free interval suggests that this regimen is unlikely to be superior to standard treatment with paclitaxel and carboplatin. Strategies to optimize the development of future combination chemotherapy regimens in the treatment of newly diagnosed ovarian cancer are discussed.

The mechanisms responsible for the development of the taxol resistance phenotype are unclear, and are likely explained by multiple mechanisms. To understand the molecular changes associated with drug resistance more fully, a taxol-resistant subline, derived from the human ovarian cancer cell line SKOV-3, was established through selection by culture in incrementally increasing taxol concentrations. Comparison of SKOV-3 to SKOV-3TR by differential display identifies a new gene, TRAG-3 ( T axol R esistance A ssociated G ene-3). In comparison to the parental line, SKOV-3, TRAG-3 mRNA is overexpressed in the taxol-resistant cell line SKOV-3TR. The nucleotide sequence of the TRAG-3 cDNA contains an open reading frame of 333 bp that predicts for a protein product of 110 amino acids. A GenBank search identifies a cosmid clone containing a genomic sequence corresponding to that of TRAG-3. DNA and protein analysis reveals that TRAG-3 has no homology to any known cDNAs or proteins. Northern analysis demonstrates that TRAG-3 is overexpressed in the taxol-resistant breast cancer cell line MDA 435TR as well as the doxorubicin-resistant multiple myeloma cell lines 8226/DOX40 and 8226/MDR10V. A survey of normal tissue shows minimal or absent TRAG-3 mRNA expression. Screening of a wide variety of cancer cell lines demonstrates TRAG-3 expression in many cell lines derived from different tissue types. In summary, TRAG-3 is a novel gene whose expression is associated with the chemotherapy-resistant and neoplastic phenotype.

High dose chemotherapy with stem cell rescue has been used in an attempt to overcome chemotherapy resistance and increase survival in patients with poor prognosis epithelial ovarian cancer. Untreated patients with advanced stage disease and those with chemosensitive recurrent disease do better in terms of response rates as well as duration of response and overall survival. Newer strategies using multiple cycles of dose intense therapy may improve results although it will be difficult to document changes in the natural history of advanced ovarian cancer without the completion of randomized phase III trials.

Objectives To evaluate the prognostic significance of reverse transcriptase polymerase chain reaction (RT PCR) detection of prostate-specific antigen (PSA) mRNA in relation to survival in patients with metastatic androgen-independent prostatic carcinoma (AIPC). Methods Peripheral blood from 122 men (64 from Memorial Sloan-Kettering Cancer Center [MSKCC] and 58 from the Dana Farber Cancer Institute [DFCI]) with metastatic (Stage D2) AIPC was analyzed for PSA mRNA using RT PCR. Forty-one controls without prostatic carcinoma were also evaluated. Results RT PCR positivity for PSA mRNA was present in 24 of the 64 (38%) patients seen at MSKCC and in 26 of the 58 (45%) patients followed at DFCI. All control individuals were PSA PCR negative. There was a significant correlation between RT PCR positivity and decreased survival in each of the Memorial and Dana Farber populations (P = 0.028 and 0.039, respectively). Serum PSA (at time of blood collection for PCR) was not predictive of survival as a continuous variable in the MSKCC (P = 0.31) and the DFCI (P = 0.09) groups. RT PCR for PSA mRNA was found to be independent from and superior to serum PSA in predicting survival in both the MSKCC and DFCI populations (P = 0.048 and P = 0.027, respectively). Conclusions The detection of PSA mRNA in the peripheral blood by RT PCR is a predictor of survival in patients with metastatic AIPC, and PCR is superior to a single serum PSA measurement. Further studies are needed to test the value of this factor in comparison to and coupled with other prognostic parameters.

This report describes the clinical characteristics, treatment associated toxicity, and follow-up of fifty-eight patients with plasma cell--dyscrasias treated with high dose chemotherapy and total body irradiation (TBI) at a single institution. Following TBI, 36 patients received anti-B cell monoclonal antibody (MoAb)-treated autologous bone marrow, 21 patients received anti-CD6 cell MoAb-treated allogeneic bone marrow to deplete T cells, and one patient received unpurged bone marrow from a syngeneic donor. Evaluation after high dose chemotherapy and bone marrow transplantation (BMT) demonstrated 26 complete responses (CR), 26 partial responses (PR), 2 non-responders, 1 not yet evaluated, and three toxic deaths. Fourteen of 36 patients who underwent autologous BMT are alive free from progression at 18 (range 5 to 68) months post transplant (post-BMT); of these, 11 remain in continuous complete response at 16 (range 5 to 68) months post-BMT. Seven of 21 patients who underwent allogeneic BMT are alive free from progression at 30 (range 4 to 44) months post-BMT; of these, three patients remain in continuous complete response at 43 (range 33 to 45) months post-BMT. These data suggest that high dose chemotherapy with TBI followed by MoAb purged BM can be performed with acceptable toxicity and high tumor response rates.

The mortality associated with multiple myeloma is due to the progressive accumulation of a clonal population of plasma cells in the bone marrow. Tumor cells may also be found in the blood and other extramedullary sites, especially in the terminal stages of the disease. During disease progression, numerous effects lead to significant morbidity, including immunosuppression, increased bone turnover, anemia, and renal deterioration. For more than two decades it has been realized that chemotherapy and radiotherapy could provide effective temporary relief from the pain and suffering associated with this malignancy. Unfortunately, these benefits are usually short lived, and essentially all patients experience recurrent disease that is usually refractory to additional therapy.

5037 Background: GOG172 demonstrated improved survival for patients (pts) with ovarian cancer treated with intraperitoneal (IP) chemotherapy, as compared with standard IV dosing. Two ongoing phase III trials have added bevacizumab (bev) to upfront treatment and the next planned GOG study has been designed to include bev in conjunction with multiple IP regimens. A pilot trial done in collaboration between Ovarian SPORE sites was undertaken to evaluate the safety, tolerability and pharmacokinetics of such a regimen. Methods: Carboplatin AUC 6 on day 1 and paclitaxel 60 mg/m2 on days 1, 8, 15 was given, IV in cycle 1 and IP in the 5 subsequent 21-day cycles. The initial IV cycle was designed to allow for intra-patient IV vs. IP pk comparison. Pts received bev 15 mg/kg IV on day 8 in cycle 2 and day 1 in cycles 3-6. Results: Trial is complete with40 evaluable pts. Pts were able to complete most of the planned treatment, with 34 pts completing all 6 cycles. There was no progressive disease on trial. Toxicity w...

We have been developing tools to reproducibly correlate the expression of multidrug-resistance (MDR)-associated genes with response to chemotherapy in primary cancers. This study reports the results of a novel MDR gene expression analysis of primary serous carcinoma of the ovary utilizing a TaqMan Low Density Array (TLDA) chip which includes 380 previously characterized multidrug resistance (MDR)-associated genes that were initially identified in cultured cancer cells. Primary tumor samples from 133 patients from 4 sites were studied. All patients were subsequently treated with standard chemotherapy and had known clinical outcome. A 13 gene signature was identified whose expression added statistical power to the risk status of the patients based on standard clinical parameters (age, CA125, and success of surgical debulking) (log-rank statistic p=0.02). When subsets of patients with defined clinical risk were studied, we found that a subset of clinically high risk patients that had low expression of the 13 gene signature had a better outcome than would be predicted by purely clinical criteria. Similarly, clinically low risk patients with high expression of the 13 gene signature had a poorer prognosis. Since the mechanism of action of the 13 MDR genes involved in the signature are well-understood, it might be possible to devise therapeutic strategies to some of these targets with the goal of improving clinical outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-51.

5593 Background: Platinum remains the single most effective drug for the treatment of epithelial ovarian cancer; however with relapse and re-treatment most patients eventually become resistant to t...

LBA5529 Background: Canfosfamide (C) is a novel glutathione analog prodrug activated by glutathione S-transferase P1–1. C has single agent activity in P resistant OC and is synergistic with P. Methods: Pts with P resistant OC following ≤ 2 P regimens, measurable disease (RECIST) were eligible. Pts received C (750 mg/m2) and P (AUC 5) or D (50 mg/m2) IV q4wks until progression. Randomization was stratified by ECOG PS, best prior P response and bulky disease (≥ 5cm). Results: All 247 P refractory or resistant pts received 505/494 cycles median 3 (range 1–17), CP/D respectively. Most common toxicities for CP were hematologic and as expected for each drug alone. By independent radiologic review (IRR), 25% of pts discontinued treatment without documented progression. Overall ORR varied between clinician and IRR assessments. Overall median PFS was 3.5 mos for both CP and D. Overall median survival (MS) has not been reached. Planned analysis of the effect of time from last P dose to study treatment (TFP; not from time of recurrence) identified a P resistant subgroup for TFP ≥ 6 mos (med 7.1) [ Table ]. Subgroup ORR for CP was 31.6% vs 10.5% for D. Subgroup median PFS for CP has not been reached vs 3.5 mos for D (p=0.0099). Subgroup MS for CP has not been reached vs 11.1 mos for D(p=0.0014). Subgroup CP had superior QOL outcomes per FACIT-FACT-O. Conclusions: Primary endpoint of overall PFS was comparable. Subgroup TFP ≥ 6 mos reported large differences in ORR and QOL and statistical significance in PFS and survival for CP. OC trials with C in combination with other standard agents are in progress. [Table: see text] [Table: see text]

5081 Background: GM-CSF is a recombinant human cytokine, which increases the proliferation of granulocytes and monocytes. Experience with this agent, including adjuvant studies in melanoma, vaccine-based studies using autologous tumor vaccines that secrete human GM-CSF, and studies in prostate cancer using GM-CSF have all suggested that GM-CSF might provide anti-tumor activity in a subset of cancer patients. Methods: Open label phase II study performed in asymptomatic patients with recurrent mullerian malignancy without an indication for immediate systemic chemotherapy. Patients could have measurable or evaluable disease (defined as CA-125 >35 U/ml or 2 successively rising values with the most recent 3x the nadir value.) GM-CSF 250 mcg/m2 was administered subcutaneously on days 1–14 of a 28-day cycle. Monthly follow-up included interim history, physical exam and CA-125, with radiologic evaluation q 3 months. Results: Enrollment to this cohort is complete. Thirty-five women with a median age of 60 were enrolled; data are available on 33:30 women with ovarian and 3 with primary peritoneal cancers. To date 31 women are evaluable for response. Best overall response of patients who have completed the study includes 6 patients with stable disease (18%). Median time to treatment termination (TTT) was 76 days. Four patients remain on study, 2 with SD >6 months. Toxicity was generally mild, including injection site reaction, fatigue, and bone pain, however 2 patients experienced excessive toxicity and withdrew consent. There were 3 bowel obstructions thought related to disease but contribution of drug could not be ruled out. After 14 days of GM-CSF, CA-125 dropped in 23 of 33 women (70%) from their baseline on study value (median change -23%, range −48 to +158%). The magnitude of CA-125 drop during the first two weeks of therapy was significantly and positively correlated with day 15 WBC (p = 0.04.) Conclusions: GM-CSF is well tolerated and frequently associated with a decline in CA-125 that is correlated with leukocytosis. Although median TTT for the entire group is modest, a subset of women have had prolonged stable disease. Strategies to maintain and titrate leukocytosis are now being explored in a separate cohort. No significant financial relationships to disclose.

5020 Background: Vascular endothelial growth factor (VEGF) is a major promoter of tumor angiogenesis. Bevacizumab is a recombinant humanized monoclonal antibody that neutralizes VEGF and is active in several tumor types, including epithelial ovarian cancer. Methods: We are conducting a phase II trial of carboplatin, paclitaxel and bevacizumab (CPB) in newly diagnosed patients with chemotherapy naïve, stage ≥ IC, epithelial ovarian, fallopian, primary peritoneal, or uterine papillary serous (UPSC) tumors. Patients receive carboplatin AUC of 5 IV, paclitaxel 175 mg/m2 IV, and bevacizumab 15 mg/kg IV for 6–8 cycles on a 21-day cycle. Bevacizumab is omitted in the first cycle, and continued for one year’s consolidation. Principle endpoints include response rate and progression free survival. Results: Since 3/05, 35 patients have been enrolled. Of the 30 evaluable patients, 24 have ovarian, 4 peritoneal, 1 fallopian tube cancer, and 1 UPSC (1 stage IIB, 22 stage III, and 7 stage IV), and median age is 57 (range 18–77). 133 cycles of chemotherapy have been administered with acceptable toxicity. Grade IV neutropenia has been seen in 3 cycles with 1 episode of febrile neutropenia. Grade I, II, and III HTN was observed in 1, 3, and 4 cycles, and grade I (42% hematuria 45% epistaxis) and II bleeding observed in 36 and 1 cycle(s), respectively. There has been 1 nasal perforation, 2 delayed wound healing, and no bowel perforation. 1 woman withdrew consent (for PMH diverticulitis), and 3 women have been removed for toxicity (1 autonomic neurotoxicity, 1 HTN, and 1 PE). To date, 13 patients have completed the chemotherapy phase of treatment, and only one patient has come off study for progression on consolidation bevacizumab. Conclusion: First line CBP is a highly active regimen that has been well tolerated thus far. Updated toxicity and response data will be available in the spring of 2006. [Table: see text]

5008 Background: A phase III trial (GOG172) demonstrated improved survival for patients with newly diagnosed and optimally debulked ovarian cancer treated with intraperitoneal (ip) cisplatin and paclitaxel (P), given both as a 24 h iv infusion and ip, as compared with standard iv dosing. Studies to further enhance efficacy and minimize toxicity of ip taxane/platinum regimens are needed. Because adequate systemic drug exposure is thought to be essential for maximum therapeutic benefit of ip chemotherapy, the pharmacokinetics (PK) and bioavailability of ip P and carboplatin (C) were determined in this pt population in a phase II trial to evaluate dosing by the ip route alone. Methods: P 60 mg/m2 once a week and C at an AUC 6 every weeks were infused over 1 h, iv in cycle 1 and ip in the 5 subsequent 21-day cycles. Plasma samples were collected during week 1 of cycles 1, 2 and 6. P was measured by LC/MS and free platinum (fPt) was determined by flameless atomic absorption. Results: PK data is available for 14 pts receiving at least 1 cycle of ip therapy and for 7 pts who received all 5 cycles. When given ip, P achieved a peak conc. in plasma (Cmax) of 0.086 ± 0.034 μM (mean ± SD) at 6.4 ± 2.2 h, 22-times lower than Cmax for iv infusion (1.92 ± 0.80 μM). Thereafter, P plasma levels were comparable for both routes and decayed at similar rates with a half-life of 13.9 ± 4.1 h for iv and 13.7 ± 2.2 h for ip dosing. The systemic bioavailability of ip P was 53 ± 19% for the initial dose and 46 ± 10% in cycle 6. P plasma levels exceeded 0.05 μM, the pharmacologic threshold conc., for >20 h upon ip dosing in 67% (10/15) and 71% (5/7) of pts in cycles 2 and 6, respectively. C was rapidly absorbed into systemic circulation when given ip with a Cmax of 83 ± 11 μM for fPt at 1.6 ± 0.2 h in cycle 2. Consistent with prior reports, systemic availability of fPt exceeded 100% (133 ± 22% in cycle 2; 142 ± 47% in cycle 6). Conclusions: Weekly ip P 60 mg/m2 with ip C (AUC 6) every 3 weeks achieved a potentially effective pattern of systemic exposure to both agents in a majority of pts. The cumulative time that P plasma levels are >0.05 μM per cycle of therapy is likely to be longer than provided by the iv/ip dosing regimen for P (135 mg/m2 24 h iv infusion day 1; 60 mg/m2 ip day 8) used in GOG172. No significant financial relationships to disclose.

5063 Background: Both the selective aromatase inhibitor, anastrazole, (Arimidex) and Gefitinib (Iressa), an oral epidermal growth factor receptor tyrosine kinase inhibitor have demonstrated modest ...

5062 Background: Recurrent epithelial ovarian cancer (EOC) has come to be considered a chronic cancer frequently treated with multiple lines of chemotherapy. It remains unclear whether response to sequential treatment improves survival or simply reflects the biology of the disease. Methods: We reviewed 154 patients with EOC presenting in 1989–90 (n=72) and 1995–6 (n=82). The prognostic relevance of disease and treatment characteristics were examined in multivariate survival analysis. Results: Median overall survival (OS) was similar in the early (22.9) and late (22.3 months) cohorts (p=0.29). Median progression free survival (PFS) was apparently longer in the later cohort (9.4 (95%CI 7.1–13.1) vs. 14.9 (95%CI 11.8–20.7)) but did not reach statistical significance (p=0.88) Nearly twice as many patients received >3 lines of chemotherapy (22 vs. 12) for recurrent disease in the later cohort. Univariate and multivariate analysis showed that two parameters were associated with a longer survival time: early sta...

5010 Background: Previously we reported the use of three sequential doublets (Triple Doublets) in the treatment of women with newly diagnosed and advanced stage mullerian malignancies (Matulonis et...

3151 Background: A high proportion of ovarian tumors express the epidermal growth factor receptor (EGFR). Preclinical and clinical studies have demonstrated this receptor as a potential therapeutic...

2011 Background: STA-4783 (S) is a bis-thiobenzoylhydrazide that promotes induction of hsp70 and enhances paclitaxel (P) antitumor efficacy in xenograft models. Its mechanism appears to be immunolo...