Daniel R. Budman

An in-vitro 72-h assay using median effect analysis and curve shift analysis was used to evaluate the utility of potentially clinically useful combinations of agents for synergism or antagonism. Six human breast cancer cell lines, both receptor rich and receptor poor, were studied. Panobinostat (LBH-589), a pan histone deacetylase inhibitor with a multitude of biological effects, exhibits time-dependent synergistic effects in breast cancer cell lines with docetaxel, doxorubicin, or gemcitabine in clinically relevant concentrations. Survivin expression was markedly downregulated in the presence of panobinostat with gemcitabine. Bortezomib, a proteasome inhibitor, markedly enhanced the cytotoxic effects of panobinostat combined with gemcitabine. Panobinostat did not demonstrate universal enhancement of cytotoxic drugs, and therefore, synergy was dependent on the second agent selected. No synergy was noted with anti-Her2 agents in Her2 overexpressing cell lines. Metformin combined with panobinostat demonstrated no synergy in this test system. These effects were confirmed by an apoptosis assay and caspase-3 production. A positive drug interaction was identified. The triplet of panobinostat with either doxorubicin/carboplatin or gemcitabine/carboplatin was especially potent in all cell lines. As all these agents are clinically available, further studies of the potent combinations are warranted.

9130 Background: Cancer patients have a significant risk of VTE. Recurrent VTE rates of 9-17% occur (Lee NEJM 2003) despite the use of therapeutic anticoagulation (AC). Low molecular weight heparins (LMWH) afford several advantages over warfarin. Nevertheless, even with LMWHs more than 20% of patients have VTE propagation. Completeresolution and partial resolution of DVTs occur in up to 38% and 54%, respectively, after 6 months of AC (Prandoni Ann Intern Med 2002, Piovella Haematologica 2002), and thrombi remaindetectable in half of non-cancer patients after a year (Kearon Circulation 2003). Recently, Factor Xa inhibitors have become available and require further study to determine if they offer therapeutic improvements in this patient population. As part of the CAT (Cancer and Thrombosis) trial, we prospectively evaluated complete resolution rates with the Factor Xa inhibitor fondaparinux sodium (FS). Methods: Inclusion criteria included an acute VTE (DVT and/or PE) in patients with cancer and creatinine clearance > 30 mL/min. Patients received FS [5mg SC for pts 65, 7.5mg SC for pts 50–100 kg and 10mg SC for pts >100 kg]. Imaging studies after baseline were repeated on days 14, 30, and 56 for DVTs, and on day 56 for PEs. Results: 64 patients were entered and 63 evaluated. Cancer types included: Lung (25%); Breast (18%), Colon (14%), Pancreas (14%), Lymphoma (8%), Ovarian (6%), and 15% with other cancers. Findings included: 107 DVT sites and 43 PEs. No patient had a recurrent DVT; 2 (3%) patients had new asymptomatic PEs. Major bleeding occurred in 3 patients (5%); minor bleeding occurred in 4 patients (6%). VTE resolution results are seen in the table. Conclusions: 1) The VTE complete resolution rate documented in this prospective trial with FS is among the highest reported in patients with cancer, and occurred within 8 weeks of starting AC. 2) VTE resolution could help tailor the duration of AC. These favorable results support future randomized trials to compare resolution rates of FS with LMWHs, and to evaluate if the optimal duration of AC depends on VTE resolution.

9063 Background: The efficacy and safety of IVCF addition to parenteral anticoagulation (AC) in treating cancer patients with VTE remains controversial and no RCTs have been conducted in this population. We initiated this prospective RCT to determine if the addition of IVCF placement is advantageous in cancer patients. Methods: 64 patients with a DVT (86%) and/or PE (55%) were randomly assigned (1:1) to receive AC with fondaparinux sodium (FS) [5mg, 7.5mg or 10mg] with or without an IVCF. Endpoints included: rates of complications by treatment arm; recurrent or residual DVTs or PEs on days 14, 30, and 56; and survival rates. Results: 64 patients were randomized and 63 evaluated. Cancer types included: lung (25%); breast (18%), colon (14%), pancreas (14%), lymphoma (8%), ovarian (6%), and 15% with other cancers. ECOG performance status: 0 or 1 in 44%; 2 in 47%; and 3 in 9%. 8 patients (12.5%) had stable brain metastases. Findings included: no patient had a recurrent DVT; 2 (3%) patients had new PEs (one in each treatment arm). Major bleeding occurred in 2 patients (6%) receiving AC only and 1 (3%) patient receiving AC+IVCF; minor bleeding occurred in 2 patients in each treatment arm. 2 (7%) patients had complications from the IVCF which included an occlusion requiring a thrombectomy and prolonged bleeding at the incision site requiring prolonged hospitalization. Median survivals were 493 days in the AC only arm 266 days for AC + IVCF (p<0.57). Conclusions: 1) No advantage was found for placement of an IVCF in addition to AC with FS. 2) While a trend toward lessened survival was seen in the IVCF+AC arm, it is difficult to say that this is treatment related due to the heterogeneous patient population. 3) With the cost and invasiveness of IVCF placement and without a benefit in recurrent PE rate or safety, IVCF should not routinely be added to AC for cancer patients with DVT or PE. This study is the only prospective RCT evaluating AC plus IVCF in cancer patients. Further studies would be needed to see if any subpopulation benefits from IVCF placement, although no such group was indicated in this trial.

The hereditary forms of breast cancer identified by BRCA1 and BRCA2 genes have a defect in homologous DNA repair and demonstrate a dependence on alternate DNA repair processes by base excision repair, which requires poly(ADP-ribose) polymerase 1 (PARP-1). siRNA and deletion mutations demonstrate that interference with PARP-1 function results in enhanced cell death when the malignancy has a defect in homologous recombination. These findings resulted in a plethora of agents in clinical trials that interfere with DNA repair, and these agents offer the potential of being more selective in their effects than classic chemotherapeutic drugs. An electronic search of the National Library of Medicine for published articles written in English used the terms "PARP inhibitors" and "breast cancer" to find prospective, retrospective and review articles. Additional searches were done for articles dealing with mechanism of action. A total of 152 articles dealing with breast cancer and PARP inhibition were identified. PARP inhibition not only affects nonhomologous repair, but also has several other nongenomic functions. Mutational resistance to these agents was seen in preclinical studies. To date, PARP-1 inhibitors were shown to enhance cytotoxic effects of some chemotherapy agents. This new class of agents may offer more therapeutic specificity by exploiting a DNA repair defect seen in some human tumors with initial clinical trials demonstrating antitumor activity. Although PARP inhibitors may offer a therapeutic option for selected malignancies, the long-term effects of these agents have not yet been defined.

Although platinum based therapy has improved short term survival of patients with metastatic ovarian cancer, the majority of patients continue to relapse and eventually die of their disease. Currently, a plethora of agents are in development, but how to combine them to enhance efficacy remains largely empiric. We have used short in vitro culture of defined cell lines with application of promising agents and analysis for cell death using a MTT assay to identify potentially useful combinations. Using median effect analysis, curve shift analysis and apoptosis assays, we can identify when agents are synergistic or antagonistic when applied together. Up to three agents can be studied in combination. Using three cell lines: SK-OV3, CaOV-3, and ES-2 (a clear cell tumor), we have identified that panobinostat (LBH-589), a broad histone deacetylase inhibitor in clinical trials, demonstrates global synergy with gemcitabine, with paclitaxel, and additive to synergistic effects with 5′DFUR. The triplet of panobinostat, doxorubicin, and carboplatin is especially synergistic in these cell lines. These effects are cytotoxic and not cytostatic. As all these agents are used clinically, we have identified combinations which warrant further investigation.

The use of cytotoxic therapy in the fit elderly breast cancer patient has been tempered with concerns of age, physical function, and co-morbid illness. In the appropriate patient with biologically aggressive disease, such as receptor poor breast cancer, it is reasonable to consider combination chemotherapy as part of an adjuvant program. If this approach is to be employed, the physician must also consider the patient’s co-morbid conditions and status of function in society as potential indicators of toxicity or lack of benefit. In this case, a formal geriatric assessment is of value. A Cancer and Leukemia Group B (CALGB) trial of monotherapy vs combination cytotoxic therapy as adjuvant treatment for localized breast cancer patients over 65 years of age has determined that the combination approach is superior to single agent therapy. In an unplanned analysis of receptor rich and receptor poor tumors, the patients with receptor poor tumors seemed to achieve the greatest benefit from combination cytotoxic therapy. Adjuvant chemotherapy can also be considered for patients with high-risk receptor rich breast cancers. However, the use of chemotherapy in the elderly patient with breast cancer is largely based upon data emerging from trials in younger patients. Studies specifically for patients over 65 years of age are urgently needed in this population to provide evidence-based proof of the current approach.

Peer reviewed article authored by (Kit L Cheng, Thomas Bradley, Daniel R Budman). Read article or submit your manuscript for publishing.

20544 Background: Cancer-associated thrombosis is a major cause of death in patients (pts) with cancer. The 1-year survival in pts with cancer with VTE is 12% (vs. 36% without VTE). More than 20% of pts have VTE propagation and re-thrombosis on standard therapeutic anticoagulation (AC) (Prandoni 2007). The role of IVC filters in terms of efficacy, safety, prevention of pulmonary embolism (PE), and impact on survival remains controversial. Resolution of DVT takes an average of 6 months in non-cancer pts (Asbeutah 2004) and thrombi remain detectable in half of pts after a year (Kearon 2004). Methods: Pts with malignancy were eligible if they had an acute VTE (DVT and/or PE), and were randomized to standard fondaparinux sodium (FS) alone [5mg SC for pts 100 kg] vs FS+IVC filter. A total of 106 pts are planned. The primary endpoint is survival without recurrent VTE. Secondary endpoints include safety and clot resolution, given in this report. Due to safety review in pts ≥ 65 yrs, the dose of FS was reduced to 5mg during the conduct of the study. Pts were evaluated q 2 weeks for 4 weeks then q 4 weeks. Results: To date 33 pts were randomized and treated. All have stage IV extent, 94% are on chemotherapy; median age 67 (range 38–89%). Diagnoses include: lung (25%), GI (22%), and breast (19%); 9% have brain metastases. Of pts re-evaluated with DVTs: 15/20, 75% [95% CI: 44–90%] had complete clot resolution at an average of 45 days. Of those with PE: 8/9, 89% [95% CI: 52–100%] had complete clot resolution. Toxicities were more prominent in pts ≥ 65, 1 with marked ecchymosis and 1 with fatal hemorrhage into a brain metastasis. Conclusions: This study is ongoing and remains blinded as to treatment arm; however, current observations are important: 1) complete clot resolution has been observed in many, despite past studies using low molecular weight heparins not reporting such resolution in cancer patients; 2) the factor Xa inhibition may be responsible for this clot resolution effect; 3) the FS was well tolerated and appears safe in those over age 65 at a lower dose.

Medical oncology has undergone profound changes in the past decade, driven in part by the explosive growth in the field of molecular biology. In turn, drug development has progressed from empirical screening to combinatorial chemistry, computer-aided design, and rationally identified targets. At present, approximately 400 drugs for the treatment of cancer are in development, and a large number of standard cytotoxic agents and biologic agents for the treatment of cancer are commercially available. The editors of this fourth edition of Cancer Chemotherapy and Biotherapy have taken on the Herculean task of melding chemotherapy and biologic therapy, with an emphasis on clinical relevance. To a great degree, they have accomplished their goal.