Bone Health Outcomes from the International, Multicenter, Randomized, Phase 3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer.

INTRODUCTION: D-CARE, an international, phase 3, randomized, double-blind, placebo-controlled study in women with early-stage breast cancer at high risk of disease recurrence, failed to meet its primary endpoint-improvement in bone metastasis-free survival (BMFS) with adjuvant denosumab vs placebo injections. As a result of the limitations of assessing BMFS, which includes relapse in bone with and without extraskeletal recurrences and deaths from any cause, the prespecified exploratory bone endpoints' analysis may provide a more clinically meaningful effect of denosumab in this disease setting. METHODS: The study enrolled women (aged ≥ 18 years) with histologically confirmed stage II/III breast cancer. Patients treated with adjuvant/neoadjuvant chemotherapy meeting inclusion criteria were randomly assigned 1:1 to receive either denosumab (120 mg) or placebo subcutaneously every 3-4 weeks for about 6 months and then every 3 months for a total treatment duration of 5 years. Five prespecified exploratory bone endpoints and post hoc subgroup analysis based on age (< 50 and ≥ 50 years) and menopause status (premenopausal and postmenopausal) were evaluated. RESULTS: Overall, 4509 women with early-stage breast cancer were assigned to receive denosumab (N = 2256) or placebo (N = 2253). The baseline demographics and clinical characteristics were comparable between the two arms. The hazard ratio (HR) for time to first bone metastasis was 0.82 (95% CI 0.66-1.02; p = 0.068), with HRs of 0.70 (95% CI 0.52-0.94; p = 0.018) for patients < 50 years old and 0.74 (95% CI 0.55-0.98; p = 0.038) for premenopausal patients, favoring the denosumab group. The HRs for time to first on-study fracture and time to first on-study skeletal-related event were 0.76 (95% CI 0.63-0.92; p = 0.004) and 0.52 (95% CI 0.35-0.78; p = 0.001), respectively, again favoring the denosumab group. CONCLUSION: The exploratory bone endpoints indicate the benefits of denosumab treatment in patients with high-risk early breast cancer, supporting the expected bone health benefits contributed by denosumab. TRIAL REGISTRATION NUMBER: NCT01077154.

Malignancy in giant cell tumor of bone: analysis of an open-label phase 2 study of denosumab.

BACKGROUND: Giant cell tumor of bone (GCTB) is a rare osteoclastogenic stromal tumor. GCTB can rarely undergo malignant transformation. This post hoc analysis evaluated and classified malignancies in patients with GCTB who received denosumab. METHODS: This analysis was conducted on patients with pathologically confirmed GCTB and measurable active disease treated with denosumab 120 mg subcutaneously once every 4 weeks, with loading doses on study days 8 and 15, as part of a phase 2, open-label, multicenter study. We identified potential cases of malignancy related to GCTB through an independent multidisciplinary review or medical history, associated imaging or histopathologic reports, and disease course. The findings were summarized and no statistical analysis was performed. RESULTS: Twenty of five hundred twenty-six patients (3.8%) who received at least one dose of denosumab were misdiagnosed with GCTB that was later discovered to be malignancies: five primary malignant GCTB, five secondary malignant GCTB, four sarcomatous transformations, and six patients with other malignancies (giant cell-rich osteosarcoma, undifferentiated pleomorphic sarcoma, spindle cell sarcoma, osteogenic sarcoma, phosphaturic mesenchymal tumor of mixed connective tissue type, and fibrosarcoma/malignant fibrous histiocytoma). Many malignancies were present before denosumab was initiated (8 definitive cases, 7 likely cases), excluding potential involvement of denosumab in these cases. Signs associated with potential misdiagnoses of GCTB included poor mineralization with denosumab treatment, rapid relapse in pain, or a failure of the typical dramatic improvement in pain normally observed with denosumab. CONCLUSIONS: Although rare, GCTB can undergo malignant transformation, and rates in this study were consistent with previous reports. Signs of poor mineralization or lack of response to denosumab treatment may warrant close monitoring. TRIAL REGISTRATION: clinicaltrials.gov , ( NCT00680992 ). Registered May 20, 2008.

Denosumab Treatment for Giant Cell Tumor of the Spine Including the Sacrum.

STUDY DESIGN: This was a subanalysis of an international, multicenter, open-label study. OBJECTIVE: The aim of this study was to assess the efficacy and safety of denosumab in a subset of patients with giant cell tumors of bone (GCTB) of the spine including the sacrum from an international, open-label, single-arm, phase 2 study (ClinicalTrials.gov: NCT00680992). SUMMARY OF BACKGROUND DATA: Standard GCTB treatment is surgical removal, either by curettage or resection, combined with intraoperative adjuvant therapy; however, some sites may not be amenable to resection (e.g., skull, spine). METHODS: Adults or skeletally mature adolescents with pathologically confirmed GCTB of the spine including the sacrum, and radiologically measurable evidence of active disease, were included. Patients received denosumab (120 mg subcutaneously) once every 4 weeks during the treatment phase, with loading doses on days 8 and 15 of the first cycle. Patients had surgically unsalvageable GCTB (Cohort 1), had planned surgery expected to result in severe morbidity (Cohort 2), or were enrolled from a previous GCTB study (Cohort 3). RESULTS: Overall, 132 patients were included in the safety analysis (103 in Cohort 1, 24 in Cohort 2, and five in Cohort 3); 131 patients were included in the efficacy analysis. Kaplan-Meier estimated probabilities of disease progression or recurrence were 3% (95% confidence interval [CI], 0.0-6.2) at year 1 and 7.4% (95% CI, 2.1-12.7) at years 3 and 5 in Cohort 1, and not estimable in Cohorts 2 and 3. Of 23 patients (Cohort 2) with surgery planned at baseline, 10 (43%) had on-study surgery; of these, one patient had reported disease progression or recurrence after the on-study surgery. Clinical benefit was reported in 83% of patients overall (all cohorts). CONCLUSION: Results from the analysis suggest that denosumab is potentially effective treatment for patients with GCTB of the spine including the sacrum. The adverse event profile was consistent with the full study population.Level of Evidence: 2.

Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer. METHOD: In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged ≥ 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3-4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with ClinicalTrials.gov, NCT01077154. FINDINGS: Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0·97, 95% CI 0·82-1·14; p=0·70). The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (<1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%). Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness. INTERPRETATION: Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer. FUNDING: Amgen.

Denosumab in patients with giant-cell tumour of bone: a multicentre, open-label, phase 2 study.

BACKGROUND: Giant-cell tumour of bone (GCTB) is a rare, locally aggressive osteoclastogenic stromal tumour of the bone. This phase 2 study aimed to assess the safety and activity of denosumab in patients with surgically salvageable or unsalvageable GCTB. METHODS: In this multicentre, open-label, phase 2 study done at 30 sites in 12 countries we enrolled adults and skeletally mature adolescents (aged ≥12 years) weighing at least 45 kg with histologically confirmed and radiographically measurable GCTB, Karnofsky performance status 50% or higher (Eastern Cooperative Oncology Group status 0, 1, or 2), and measurable active disease within 1 year of study enrolment. Patients had surgically unsalvageable GCTB (cohort 1), had surgically salvageable GCTB with planned surgery expected to result in severe morbidity (cohort 2), or were enrolled from a previous study of denosumab for GCTB (cohort 3). Patients received 120 mg subcutaneous denosumab once every 4 weeks during the treatment phase, with loading doses (120 mg subcutaneously) administered on study days 8 and 15 to patients in cohorts 1 and 2 (patients in cohort 3 did not receive loading doses). The primary endpoint was safety in terms of the type, frequency, and severity of adverse events; secondary endpoints included time to disease progression from cohort 1 and the proportion of patients without surgery at month 6 for cohort 2. The safety analysis set included all enrolled patients who received at least one dose of denosumab. This study is registered with ClinicalTrials.gov, number NCT00680992, and has been completed. FINDINGS: Between Sept 9, 2008, and Feb 25, 2016, 532 patients were enrolled: 267 in cohort 1, 253 in cohort 2, and 12 in cohort 3. At data cutoff on Feb 24, 2017, median follow-up was 58·1 months (IQR 34·0-74·4) in the overall patient population, and 65·8 months (40·9-82·4) in cohort 1, 53·4 months (28·2-64·1) in cohort 2, and 76·4 months (61·2-76·5) in cohort 3. During the treatment phase, the most common grade 3 or worse adverse events were hypophosphataemia (24 [5%] of 526 patients), osteonecrosis of the jaw (17 [3%], pain in extremity (12 [2%]), and anaemia (11 [2%]). Serious adverse events were reported in 138 (26%) of 526 patients; the most common were osteonecrosis of the jaw (17 [3%]), anaemia (6 [1%]), bone giant cell tumour (6 [1%]), and back pain (5 [1%]). 28 (5%) patients had positively adjudicated osteonecrosis of the jaw, four (1%) had atypical femur fracture, and four (1%) had hypercalcaemia occurring 30 days after denosumab discontinuation. There were four cases (1%) of sarcomatous transformation, consistent with historical data. Ten (2%) treatment-emergent deaths occurred (two of which were considered treatment-related; bone sarcoma in cohort 2 and sarcoma in cohort 1). Median time to progression or recurrence for patients in cohort 1 during the first treatment phase was not reached (28 [11%] of 262 patients had progression or recurrence). 227 (92%; 95% CI 87-95) of 248 patients who received at least one dose of denosumab in cohort 2 had no surgery in the first 6 months of the study. INTERPRETATION: The types and frequencies of adverse events were consistent with the known safety profile of denosumab, which showed long-term disease control for patients with GCTB with unresectable and resectable tumours. Our results suggest that the overall risk to benefit ratio for denosumab treatment in patients with GCTB remains favourable. FUNDING: Amgen.

Response to Comment-Osteonecrosis of the Jaw in Myeloma Patients Receiving Denosumab or Zoledronic Acid. Comment on Pivotal Trial by Raje et al. Published in Lancet Oncology.

We read the commentary by Fusco et al [...].

Epidemiology of benign giant cell tumor of bone in the Chinese population.

BACKGROUND: Quantifying the incidence of giant cell tumor (GCT) of bone is challenging because it is a rare, histologically benign bone tumor for which population-level statistics are unavailable in most countries. We estimated the 2017 incidence of GCT in China using a direct (registry-based) approach with available population-based data. MATERIALS AND METHODS: The most recent age- and sex-specific incidence rates of GCT recorded in the Bone Tumor Registry in Japan (2015) were applied to 2017 age- and sex-matched populations projected by the United Nations for China in order to estimate 2017 incidence. An adjustment factor calculated using registry data suggesting that GCT may represent a greater proportion of bone tumors in China than in Japan (Guo, 1999) was applied to provide secondary estimates. RESULTS: Annual GCT incidence was estimated to be 1.49 per million population or 2094 new cases in China for 2017. A comparison of this estimated incidence with Japan (1.25 per million) and the United States (1.38 per million) indicates that the incidence is somewhat higher in China using identical methods. Secondary estimates suggest that GCT incidence in China may be as high as 2.57 per million or 3625 new cases in 2017. The corresponding 3-year limited-duration prevalence of GCT in China using a registry-based approach and general age-specific mortality is 6276 (secondary estimate: 10,876). CONCLUSIONS: Leveraging unique population-based registry data, we estimated that GCT is a rare disease in the Chinese population with an incidence ranging between 1.49 and 2.57 cases per million persons per year. Possible differences in diagnostic classification of GCT, urban-rural demographics, and the younger demographic distribution of the Chinese population may underlie observations that GCT, a condition that primarily affects young individuals (20-40 years of age), accounts for a higher proportion of skeletal tumors in China than in other regions.

A multicenter case registry study on medication-related osteonecrosis of the jaw in patients with advanced cancer.

PURPOSE: This observational case registry study was designed to describe the natural history of cancer patients with medication-related osteonecrosis of the jaw (ONJ) and evaluate the ONJ resolution rate. METHODS: Adults with a diagnosis of cancer and with a new diagnosis of ONJ were enrolled and evaluated by a dental specialist at baseline and every 3 months for 2 years and then every 6 months for 3 years until death, consent withdrawal, or loss to follow-up. The primary endpoint was the rate and time course of ONJ resolution. Secondary endpoints included frequency of incident ONJ risk factors, ONJ treatment patterns, and treatment patterns of antiresorptive agents for subsequent ONJ. RESULTS: Overall, 327 patients were enrolled; 207 (63%) were continuing on study at data cutoff. Up to 69% of evaluable patients with ONJ had resolution or improvement during the study. ONJ resolution (AAOMS ONJ staging criteria) was observed in 114 patients (35%); median (interquartile range) time from ONJ onset to resolution was 7.3 (4.5-11.4) months. Most patients (97%) had received antiresorptive medication before ONJ development, 9 patients (3%) had not; 68% had received zoledronic acid, 38% had received denosumab, and 10% had received pamidronate (56% had received bisphosphonates only, 18% had received denosumab only, and 21% had exposure to both). CONCLUSIONS: These results are consistent with those observed in clinical trials evaluating skeletal-related events in patients with advanced malignancy involving bone. Longer follow-up will provide further information on ONJ recurrence and resolution rates between medically and surgically managed patients.

Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin.

HER2/neu positive breast tumors predict a high mortality and comprise 25%-30% of breast cancer. We have shown that Flavokawain A (FKA) preferentially reduces the viabilities of HER2-overexpressing breast cancer cell lines (i.e., SKBR3 and MCF7/HER2) versus those with less HER2 expression (i.e., MCF7 and MDA-MB-468). FKA at cytotoxic concentrations to breast cancer cell lines also has a minimal effect on the growth of non-malignant breast epithelial MCF10A cells. FKA induces G2M arrest in cell cycle progression of HER2-overexpressing breast cancer cell lines through inhibition of Cdc2 and Cdc25C phosphorylation and downregulation of expression of Myt1 and Wee1 leading to increased Cdc2 kinase activities. In addition, FKA induces apoptosis in SKBR3 cells by increasing the protein expression of Bim and BAX and decreasing expression of Bcl2, BclX/L, XIAP, and survivin. FKA also downregulates the protein expression of HER-2 and inhibits AKT phosphorylation. Herceptin plus FKA treatment leads to an enhanced growth inhibitory effect on HER-2 overexpressing breast cancer cell lines through downregulation of Myt1, Wee1, Skp2, survivin, and XIAP. Our results suggest FKA as a promising and novel apoptosis inducer and G2 blocking agent that, in combination with Herceptin, enhances for the treatment of HER2-overexpressing breast cancer.

A phase I pharmacokinetic study of intraperitoneal bortezomib and carboplatin in patients with persistent or recurrent ovarian cancer: An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: Intraperitoneal (IP) therapy improves survival compared to intravenous (IV) treatment for women with newly diagnosed, optimally cytoreduced, ovarian cancer. However, the role of IP therapy in recurrent disease is unknown. Preclinical data demonstrated IP administration of the proteasome inhibitor, bortezomib prior to IP carboplatin increased tumor platinum accumulation resulting in synergistic cytotoxicity. We conducted this phase I trial of IP bortezomib and carboplatin in women with recurrent disease. METHODS: Women with recurrent ovarian cancer were treated with escalating doses of IP bortezomib - in combination with IP carboplatin (AUC 4 or 5) every 21days for 6cycles. Pharmacokinetics of both agents were evaluated in cycle 1. RESULTS: Thirty-three women participated; 32 were evaluable for safety. Two patients experienced dose-limiting toxicity (DLT) at the first dose level (carboplatin AUC 5, bortezomib 0.5mg/m2), prompting carboplatin reduction to AUC 4 for subsequent dose levels. With carboplatin dose fixed at AUC 4, bortezomib was escalated from 0.5 to 2.5mg/m2 without DLT. Grade 3/4 related toxicities included abdominal pain, nausea, vomiting, and diarrhea which were infrequent. The overall response rate in patients with measurable disease (n=21) was 19% (1 complete, 3 partial). Cmax and AUC in peritoneal fluid and plasma increased linearly with dose, with a favorable exposure ratio of the peritoneal cavity relative to peripheral blood plasma. CONCLUSION: IP administration of this novel combination was feasible and showed promising activity in this phase I trial of heavily pre-treated women with ovarian cancer. Further evaluation of this IP combination should be conducted.

Molecular targeted approaches to cancer therapy and prevention using chalcones.

There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3-diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α, ß-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, ß-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ and ß-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy.

Expression of the Wnt antagonist Dickkopf-3 is associated with prognostic clinicopathologic characteristics and impairs proliferation and invasion in endometrial cancer.

OBJECTIVE: Emerging evidence implicates the Wnt antagonist Dickkopf-3 (Dkk3) as a tumor suppressor and potential biomarker in solid tumors. We investigated whether Dkk3 plays an important role in the carcinogenesis of endometrial cancer (EC). METHODS: We analyzed Dkk3 mRNA expression via real-time RT-PCR in twenty-seven human primary EC tissues, and six matched normal endometrial controls. Dkk3 levels were correlated with various clinicopathologic characteristics. Additionally, enforced Dkk3 expression was examined in proliferation and tumorigenesis in vitro and in vivo, using MTT, soft agar assay, invasion assay, a xenograft mouse model, and a ß-catenin-responsive SuperTopFlash luciferase assay. RESULTS: Compared with matched normal endometrial cases, Dkk3 was down-regulated in EC (p<0.0001). Among cancer cases, Dkk3 expression was significantly reduced in patients with higher stage (p=0.002), positive pelvic lymph nodes (p=0.0004), non-endometrioid histology (p=0.02), and cytology-positive ECs (p=0.02). Enforced expression of Dkk3 in EC cell lines showed reduced proliferation (p<0.0001), anchorage-independent growth (p=0.005), invasion (p=0.02), and reduced TCF activity (p=0.04), confirming Dkk3 as a negative regulator of the ß-catenin/Wnt signaling pathway. Tumor growth in Dkk3-injected mice was not statistically different, though did plateau towards the end, and was associated with increased lymphoid infiltration and tumor necrosis. CONCLUSION: Dkk3 gene expression is frequently downregulated in endometrial cancer, and is associated with poor prognostic clinicopathologic markers. The results also identify a role for Dkk3 as a tumor suppressor in EC, affecting both proliferation and invasiveness. These findings may prove to be important in the design of novel biomarkers and treatment modalities for advanced EC.

Cisplatin-loaded porous Si microparticles capped by electroless deposition of platinum.

The loading and release of the anti-cancer drug platinum cis-dichlorodiamine (cisplatin) from mesoporous silicon (pSi) microparticles is studied. The pSi microparticles are modified with 1-dodecene or with 1,12-undecylenic acid by hydrosilylation, and each modified pSi material acts as a reducing agent, forming a deposit of Pt on its surface that nucleates further deposition, capping the mesoporous structure and trapping free (unreduced) cisplatin within. Slow oxidation and hydrolytic dissolution of the Si/SiO(2) matrix in buffer solution or in culture medium leads to the release of drugs from the microparticles. The drug-loaded particles show significantly greater toxicity toward human ovarian cancer cells (in vitro), relative to an equivalent quantity of free cisplatin. This result is consistent with the mechanism of drug release, which generates locally high concentrations of the drug in the vicinity of the degrading particles. Control assays with pSi particles loaded in a similar manner with the therapeutically inactive trans isomer of the platinum drug, and with pSi particles containing no drug, result in low cellular toxicity. A hydrophobic pro-drug, cis,trans,cis-[Pt(NH(3))(2)(O(2)C(CH(2))(8)CH(3))(2)Cl(2)], is loaded into the pSi films from chloroform without concomitant reduction of the pSi carrier.

The role of the N-terminus of mammalian copper transporter 1 in the cellular accumulation of cisplatin.

The mammalian copper transporter 1 (CTR1) is responsible for the uptake of copper (Cu) from the extracellular space, and has been shown to play a major role in the initial accumulation of platinum-based drugs. In this study we re-expressed wild type and structural variants of hCTR1 in mouse embryo fibroblasts in which both alleles of mCTR1 had been knocked out (CTR1(-/-)) to examine the role of the N-terminal extracellular domain of hCTR1 in the accumulation of cisplatin (cDDP). Deletion of either the first 45 amino acids or just the (40)MXXM(45) motif in the N-terminal domain did not alter subcellular distribution or the amount of protein in the plasma membrane but it eliminated the ability of hCTR1 to mediate the uptake of Cu. In contrast it only partially reduced cDDP transport capacity. Neither of these structural changes prevented cDDP from triggering the rapid degradation of hCTR1. However, they did alter the potency of the cDDP that achieved cell entry, possibly reflecting the fact that hCTR1 may mediate the transport of cDDP both through the pore it forms in the plasma membrane and via endocytosis. We conclude that cDDP interacts with hCTR1 both at (40)MXXM(45) and at sites outside the N-terminal domain that produce the conformational changes that trigger degradation.

Tumor platinum concentration following intraperitoneal administration of cisplatin versus carboplatin in an ovarian cancer model.

OBJECTIVE: Current intraperitoneal (IP) regimens for the treatment of ovarian cancer rely on cisplatin (DDP) whereas intravenous regimens rely on carboplatin (CBDCA). A major question in the field is whether CBDCA can replace DDP for IP treatment. We compared the uptake of IP administered DDP and CBDCA into human ovarian carcinoma nodules of various sizes growing on the peritoneal surface of nu/nu mice. METHODS: Human 2008 cells expressing GFP were inoculated IP in nu/nu mice. When small tumor nodules became visible by external imaging, a maximum tolerated dose of DDP, or either an equimolar or equitoxic dose of CBDCA, was injected IP. Platinum (Pt) concentration in tumor nodules was measured by inductively coupled plasma mass spectrometry. RESULTS: A total of 749 tumors harvested from 33 mice were analyzed for Pt concentration. DDP produced a 3.4-fold higher level of Pt in tumor nodules when compared to an equimolar dose of CBDCA (p=0.02). However, when DDP and CBDCA were injected at doses that were equitoxic to the mice, tumor Pt levels were equivalent (p=0.63). Although Pt concentrations of equal-sized nodules were highly variable, tumor Pt content (ng Pt/mg tumor) decreased with increasing nodule size following IP DDP, an effect not seen with IP administration of equitoxic doses of CBDCA (p<0.001). CONCLUSIONS: These results suggest that IP CBDCA has comparable or better drug penetration when compared to DDP given at equitoxic doses, and thus provide support for replacing DDP with CBDCA in the IP treatment of patients with ovarian cancer.

Enhanced delivery of cisplatin to intraperitoneal ovarian carcinomas mediated by the effects of bortezomib on the human copper transporter 1.

PURPOSE: The copper transporter 1 (CTR1) is a major influx transporter for platinum drugs. However, the accumulation of cisplatin in human ovarian carcinoma cells is limited by the fact that cisplatin triggers the down-regulation and proteasomal degradation of CTR1, thereby limiting its own uptake. We sought to determine whether proteasome inhibition using bortezomib would prevent human CTR1 (hCTR1) degradation and increase platinum accumulation in ovarian cancer cells. EXPERIMENTAL DESIGN: The effects of bortezomib on human hCTR1 expression and cisplatin accumulation were measured by Western blot, flow cytometric, and confocal digital imaging analyses. Platinum accumulation was measured by inductively coupled plasma mass spectrometry and bortezomib concentrations by liquid chromatography/mass spectrometry. RESULTS: Bortezomib blocked the cisplatin-induced down-regulation of hCTR1 in a concentration-dependent manner and increased cisplatin uptake 1.6- to 2.4-fold. Median effect analysis showed a combination index of 0.37 at 50% cell kill, indicating a high level of synergy. The effect of bortezomib was muted in cells lacking both alleles of CTR1, showing that bortezomib was working primarily through its effect on blocking hCTR1 degradation. I.p. administration of bortezomib produced a peritoneal/plasma area under the curve ratio of 252 in a murine model. I.p. administration of bortezomib before i.p. cisplatin increased platinum accumulation in peritoneal tumors by 33% (P = 0.006). CONCLUSIONS: Proteasomal inhibition prevented cisplatin-induced down-regulation of hCTR1 in ovarian cancer cells and enhanced drug uptake and cell killing in a synergistic manner. Bortezomib shows a large pharmacologic advantage when administered i.p. There is a strong rationale for the combined i.p. administration of bortezomib and cisplatin.

Laparoscopic colostomy in gynecologic cancer.

STUDY OBJECTIVE: The purpose of our study was to report on our case series of 7 patients with gynecologic cancer who underwent laparoscopic colostomy for elective fecal diversion. Our aim was to retrospectively estimate feasibility, safety, and efficacy of the laparoscopic approach in the setting of gynecologic malignancy, given the high incidence of earlier abdominal surgery and pelvic radiation treatment in this select population. DESIGN: Retrospective chart review (Canadian Task Force classification I). SETTING: University of Texas, M.D. Anderson Cancer Center. PATIENTS: All patients with a history of gynecologic cancers who underwent laparoscopic colostomy during the study period. INTERVENTIONS: We retrospectively reviewed all patients who underwent elective laparoscopic diverting colostomy in our department of gynecologic oncology. Surgical indications, medical history, operative and stomal complications, estimated blood loss, return of bowel function, and length of hospital stay were collected. MEASUREMENTS AND MAIN RESULTS: Seven patients underwent laparoscopic colostomy during the study period. Six of these patients underwent an end descending colostomy, and 1 patient underwent a loop colostomy. Indications included rectovaginal fistula (n = 5), colonic/pelvic fistula (n = 1), or large bowel obstruction (n = 1). No intraoperative or postoperative complications occurred, nor did any conversions to laparotomy. The median blood loss was 50 mL (range 10-75). Median operative time was 102 minutes (range 69-159). Six (86%) patients had a history of pelvic radiation. In addition, 3 (43%) patients had a history of laparotomy. The median patient weight was 59.8 kg (range 47.1-82.2). The median time to tolerance of a regular diet was 2 days (range 1-3) and the median length of hospital stay was 3 days (range 2-4). No immediate or delayed stomal complications were noted with a median follow-up of 6 months (range 1-15). CONCLUSION: Laparoscopic colostomy in advanced gynecologic cancer may be a safe and feasible technique with minimal morbidity, rapid return of bowel function, and short hospital stay.

Birth outcomes in teenage pregnancies.

OBJECTIVE: To evaluate and characterize the racial/ethnic differences in obstetric outcomes of early and late teenagers in California. METHODS: A data-set linking birth and death certificates with maternal and neonatal hospital discharge records in California was utilized to identify nulliparous women (11 to 29 years of age) who delivered between January 1,1992 and December 31,1997. Pregnancy outcomes of early (11-15 year) and late (16-19 year) teenagers were compared to those of a control group of women aged 20-29. RESULTS: Early (n = 31 232) and late teens (n = 271 470) demonstrated greater neonatal and infant mortality and major neonatal morbidities (delivery < 37 weeks of gestation and birthweight < 2500 g) when compared to pregnancies in the older control women (n = 662 752). Ethnicity adversely affected outcome with African-Americans of all ages having worse outcomes than whites. The higher rate of adverse obstetric outcomes among the teenage pregnancies occurred despite a lower cesarean section rate and was consistent across all ethnic groups. CONCLUSIONS: When compared to women aged 20-29, all teen pregnancies were associated with higher rates of poor obstetric outcomes. Other factors besides teen pregnancy appear to be responsible for poor outcomes in certain ethnic groups.