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Background: In advanced or metastatic ovarian cancer patients, the therapeutic impact of molecular targeted agents and immunotherapy is limited, and current chemotherapeutic algorithm is still far from personalized medicine. We recently demonstrated that intraperitoneal carboplatin with dose-dense paclitaxel (ddTCip) therapy is a promising front-line chemotherapy even in the patients with residual peritoneal tumors, which led us to this theranostic study for biomarker discovery to realize the precision medicine (ID: UMIN000001713 on Feb 16 th , 2009). Methods: We first validated previously suggested markers (41 genes and 3 predictive models for the therapeutic efficacy and 31 polymorphisms for the toxicity), sought out more active effective biomarkers through genome-wide transcriptome and genotyping analyses, and then developed multiplex statistical prediction models for progression free-survival (PFS) and toxicity. Multiple regression analysis following forward stepwise method and Classification and Regression Trees (CART) algorithm were mainly employed to develop multiplex prediction models. Results: The association analyses with PFS in 76 patients followed by the validation study using data sets in 189 patients published in The Cancer Genome Atlas revealed that SPINK1 expression could be a possible predictive biomarker of ddTCip efficacy even when used alone, and multiple regression analyses provided a potent efficacy prediction model using expression data of 5 genes. SPINK1 appeared to be a critical resistant determinant of ddTCip therapy, which indicates the potential of SPINK1 also to be a novel therapeutic target. As for the toxicity prediction, ABCB1rs1045642 and ERCC1rs11615 polymorphisms appeared to closely associate with grade2-4 hematologic toxicity and peripheral neuropathy, respectively. We further successfully composed robust multiplex prediction models for the adverse events-CART models using a total of 4 genotype combinations and further powerful multiple regression models using 15 polymorphisms on 12 genes-. Conclusions: We newly proposed SPINK1 expression as a powerful predictive biomarker of the efficacy for ddTCip therapy and confirmed the predictive values of ABCB1 and/or ERCC1 polymorphisms for the toxicity. Multiplex prediction models composed herein were also found to work well for the prediction of therapeutic response. These may raise the potential to realize a precision medicine in the essential treatment for metastatic ovarian cancer patients.

Background: In advanced or metastatic ovarian cancer patients, the therapeutic impact of molecular targeted agents and immunotherapy is limited, and current chemotherapeutic algorithms are still far from personalized medicine. We recently demonstrated that intraperitoneal carboplatin with dose-dense paclitaxel (ddTCip) therapy is a promising front-line chemotherapy even in patients with residual peritoneal tumors, which led us to this theranostic study for biomarker discovery to realize precision medicine (ID: UMIN000001713 on Feb 16th, 2009). Methods: We first validated previously suggested markers (41 genes and 3 predictive models for therapeutic efficacy and 31 polymorphisms for toxicity), sought out more active effective biomarkers through genome-wide transcriptome and genotyping analyses, and then developed multiplex statistical prediction models for progression-free survival (PFS) and toxicity. Multiple regression analysis following the forward stepwise method and the classification and regression tree (CART) algorithm were mainly employed to develop multiplex prediction models. Results: The association analyses with PFS in 76 patients followed by the validation study using data sets in 189 patients published in The Cancer Genome Atlas revealed that SPINK1 expression could be a possible predictive biomarker of ddTCip efficacy even when used alone, and multiple regression analyses provided a potent efficacy prediction model using expression data of 5 genes. SPINK1 appeared to be a critical resistant determinant of ddTCip therapy, which indicates the potential of SPINK1 as a novel therapeutic target. For toxicity prediction, ABCB1 rs1045642 and ERCC1 rs11615 polymorphisms appeared to be closely associated with grade 2-4 hematologic toxicity and peripheral neuropathy, respectively. We further successfully composed robust multiplex prediction models for adverse events - CART models using a total of 4 genotype combinations and further powerful multiple regression models using 15 polymorphisms on 12 genes-. Conclusions: We newly proposed SPINK1 expression as a powerful predictive biomarker of the efficacy of ddTCip therapy and confirmed the predictive values of ABCB1 and/or ERCC1 polymorphisms for toxicity. The multiplex prediction models composed herein were also found to work well for the prediction of therapeutic response. These findings may raise the potential to realize precision medicine in the essential treatment for metastatic ovarian cancer patients.

Background We evaluated the efficacy of intraperitoneal (IP) carboplatin in combination with dose-dense paclitaxel (ddTCip) for suboptimal residual ovarian cancer. Methods This was a phase 2 study to evaluate ddTCip. Patients with stage II–IV ovarian carcinoma, who underwent primary cytoreductive surgery and had radiologically evaluable disease after surgery, were eligible to participate in this study. IP carboplatin (AUC = 6) was administered on day 1, and intravenous paclitaxel (80 mg/m2) was administered on days 1, 8 and 15. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Interval- debulking surgery followed by the same regimen was allowed when indicated. Results A total of 117 patients were considered eligible for this study prior to surgery and temporarily registered. Of the 117 patients, 76 patients met the inclusion criteria and were enrolled in this study. Fifty-nine (83.1%) patients had objective clinical responses. Median PFS and OS were 18.3 and 55.5 months, respectively. Sixty-four (84.2%) patients had grade 3/4 neutropenia, 43 (56.5%) patients had anaemia and 17 (22.4%) patients had thrombocytopenia. Port-related adverse events occurred in nine (11.8%) patients. Conclusions Front-line chemotherapy with ddTCip therapy appears safe and effective, even for patients with suboptimal residual ovarian cancer. Trial registration UMIN Clinical Trials Registry (ID: UMIN000001713) on February 16th, 2009.

Objective Paclitaxel is known to produce the “platelet-sparing effect” that prevents the carboplatin-induced decrease in platelet count. We conducted a pilot study to assess whether the addition of low-dose paclitaxel to carboplatin-based combination chemotherapy prevents thrombocytopenia. Methods Patients with platinum-sensitive recurrent ovarian cancer received intravenous (IV) paclitaxel at 60 mg/m2 followed by IV carboplatin at an area under the curve of 6 and IV pegylated liposomal doxorubicin at 30 mg/m2 on day 1 in a 28-day cycle (DC-LOP) or IV gemcitabine at 1000 mg/m2 on days 1 and 8 in a 21-day cycle (GC-LOP). Results During May 2011 to December 2011, 7 patients received 29 cycles of DC-LOP; during January 2012 to May 2013, 15 patients received 88 cycles of GC-LOP. Grade 3/4 thrombocytopenia occurred in 2 (33%) of 6 and 9 (56%) of 16 patients in the DC-LOP and GC-LOP groups, respectively. No grade 3/4 nonhematological toxicity was observed. Only one patient who received GC-LOP had grade 2 sensory and motor peripheral neuropathy. Paclitaxel-related toxicities, including muscle pain, arthralgia, and peripheral neuropathy, were consistently rare and mild. The response rates of DC-LOP and GC-LOP were 33% (0, complete response; 2, partial response; 3, stable disease; 1, progression disease) and 50% (2, complete response; 6, partial response; 7, stable disease; 1, progression disease), respectively. Conclusions Although low-dose paclitaxel addition did not alleviate thrombocytopenia in the setting of this pilot study, the results do not deny the existence of the “platelet-sparing effect” by low-dose paclitaxel. Further investigation of the carboplatin-based combination chemotherapy including a drug with mild hematological toxicity is warranted.

The characteristic morphology called broccoli sign combines a stalk and prolapsed tumor and is a useful diagnostic indicator of prolapsed tumor of the uterine body. Magnetic resonance (MR) imaging findings of broccoli sign are common for uterine submucosal leiomyomata but not well described for other tumors of the endometrial cavity, such as endometrial polyp, atypical polypoid adenomyoma, endometrial carcinoma, carcinosarcoma, and adenosarcoma. Both benign and malignant masses of the uterine body can show broccoli sign. The MR imaging features of prolapsed uterine tumor with broccoli sign resemble those of usual uterine body tumors, but the location is different. We describe the MR imaging features of prolapsed uterine tumors with broccoli sign.

ObjectiveThis study aimed to evaluate intravenous (IV)/intraperitoneal (IP) paclitaxel and IP carboplatin (TCipTip therapy) feasibility in epithelial ovarian (EOC), fallopian tube (FTC), or peritoneal carcinoma (PC) patients.MethodsFrom December 2007 to August 2010, 20 women with histologically confirmed stage IC to IV EOC, FTC, or PC received 6 TCipTip cycles after the primary cytoreductive surgery. Intravenous paclitaxel was administered at 135 mg/m2followed by IP carboplatin based on the area under the curve = 6 on day 1; IP paclitaxel at 60 mg/m2was administered on day 8. The toxicity grade was determined by CTCAE version 3.0. The institutional review board requested we reduce the IP paclitaxel dose in the first cycle to ensure safety.ResultsTwenty women, including 18 with EOC, 1 with stage IIC FTC, and 1 with stage IV primary PC, received TCipTip therapy. There were 12 serous, 5 endometrioid, 1 mucinous, 1 clear cell adenocarcinoma, and 1 mixed carcinoma (clear cell and endometrioid) cases. Eleven women achieved optimal status at primary surgery. Grade 3/4 hematologic toxicity incidence was 73% (neutrocytopenia), 9% (thrombocytopenia), and 24% (anemia). Grade 3/4 nonhematologic toxicities were observed in 5 patients (4 with grade 3 allergy and 1 with grade 3 ileus). Twelve patients (60%) completed more than 6 chemotherapy cycles. Reasons for interruption included paclitaxel allergy, grade 2 abdominal pain, carboplatin allergy during the seventh cycle, disease progression, pleural embolism, ileus, and address change.ConclusionsToxicities for TCipTip therapy were acceptable; this therapy is feasible for EOC, FTC, or PC patients. Further TCipTip therapy evaluation is warranted.

Aim: To evaluate toxicity, response and progression-free survival of single nedaplatin chemotherapy in women with platinum/taxane-resistant/refractory epithelial ovarian, tubal and peritoneal cancer. Methods: Seventeen patients with platinum/taxane-resistant/refractory epithelial ovarian, fallopian tube or primary peritoneal cancer who were treated with a single nedaplatin regimen at 90 mg/m2 administration on day 1 of a 28-day cycle in our institution between 2005 and 2007 were retrospectively investigated. Results: Ten of 17 patients (59%) had measurable disease. Seven patients were evaluated according to cancer antigen (CA) 125 levels. The overall response was 24% (complete response, 2 patients; partial response, 2 patients). Two of these 4 patients had measurable disease. Stable disease and progressive disease was noted in 6 (35%) and 7 (41%) patients. Median progression-free survival was 8 months (range 3–11) in patients who responded to therapy and 4 months (range 2–6) in patients with stable disease. Mean platinum-free interval due to treatment without using platinum analogues after developing platinum-resistant/refractory disease was 11 months (range 8–12) in patients who responded to nedaplatin regimen and 3 months (range 1–11) in patients who did not (P

Background In current Gynecologic Oncology Group studies, serum creatinine level is adjusted to 0.6 mg/dL in patients with levels Patients and Methods Carboplatin clearance was estimated in 115 patients with serum creatinine Results The carboplatin clearance calculated by the Jelliffe formula was significantly larger than the other 2 formulae ( P Conclusion Despite adjusting the serum creatinine level, the Adjusted-Jelliffe formula overestimates the creatinine clearance when compared with the Cockcroft-Gault formula.

OBJECTIVE We evaluated the feasibility of combination chemotherapy with paclitaxel, doxorubicin and cisplatin without prophylactic granulocyte colony-stimulating factor injection for intermediate-to-high-risk or recurrent endometrial cancer. METHODS Women with histologically confirmed FIGO Stages I-II with >1/2 myometrial invasion, Stage III/IV or recurrent endometrial cancer were enrolled. Patients received intravenous doxorubicin (45 mg/m(2)), followed by cisplatin (50 mg/m(2)) on Day 1 and intravenous paclitaxel (160 mg/m(2)) on Day 2. Granisetron (75 µg) was administered depending on neutrophil counts on Days 3 and 8. Treatment was repeated every 21 days for six cycles or until disease progression or unacceptable toxicity. The primary endpoint was the completion rate of the scheduled chemotherapy; secondary endpoints were Grade 3/4 toxicity and response rate in patients with measurable lesions. RESULTS From September 2010 to December 2012, 35 women, including 7 with FIGO Stage I, 4 with Stage II, 13 with Stage III, 10 with Stage IV and 1 with recurrent endometrial cancer, were enrolled. There were 26 endometrial carcinomas (Grade 1, 16; Grade 2, 6; Grade 3, 4), 4 carcinosarcomas, 2 serous adenocarcinomas, 1 neuroendocrine carcinoma, 1 poorly differentiated carcinoma and 1 mixed carcinoma. Twenty-five patients (71%) completed six chemotherapy cycles. Grade 3/4 hematological toxicities included neutrocytopenia (97%), thrombocytopenia (6%) and anemia (34%). Three patients (9%) experienced neutropenic fever. Grade 3/4 non-hematological toxicities were observed in 13 patients. In 15 patients with evaluable lesions, the response rate was 80%. CONCLUSIONS Combination chemotherapy with paclitaxel, doxorubicin and cisplatin without prophylactic granulocyte colony-stimulating factor injection is feasible.

5504Background: Although intraperitoneal (IP) chemotherapy with cisplatin and paclitaxel demonstrated better survival advantage for optimally debulked stage III ovarian cancer, it has not been wide...

To evaluate toxicity, response and progression-free survival of single nedaplatin chemotherapy in women with platinum/taxane-resistant/refractory epithelial ovarian, tubal and peritoneal cancer.Seventeen patients with platinum/taxane-resistant/refractory epithelial ovarian, fallopian tube or primary peritoneal cancer who were treated with a single nedaplatin regimen at 90 mg/m(2) administration on day 1 of a 28-day cycle in our institution between 2005 and 2007 were retrospectively investigated.Ten of 17 patients (59%) had measurable disease. Seven patients were evaluated according to cancer antigen (CA) 125 levels. The overall response was 24% (complete response, 2 patients; partial response, 2 patients). Two of these 4 patients had measurable disease. Stable disease and progressive disease was noted in 6 (35%) and 7 (41%) patients. Median progression-free survival was 8 months (range 3-11) in patients who responded to therapy and 4 months (range 2-6) in patients with stable disease. Mean platinum-free interval due to treatment without using platinum analogues after developing platinum-resistant/refractory disease was 11 months (range 8-12) in patients who responded to nedaplatin regimen and 3 months (range 1-11) in patients who did not (P0.01), whereas mean treatment-free interval was 3 months (range 1-5) in responders and 1 month (range 1-3) in non-responders, which did not show a significant difference. Grade 4 hematological toxicity was observed in 2 of 17 patients (12%). No grade 3 or 4 non-hematological toxicity occurred. All toxicities were managed on an outpatient basis.Single nedaplatin treatment for platinum/taxane-resistant/refractory ovarian, tubal and peritoneal cancer patients is the candidate of salvage chemotherapy with comparable effectiveness and less toxicity to other approved regimens.

The objective of this study was to retrospectively assess the efficacy and safety of combination chemotherapy of intraperitoneal (IP) carboplatin and intravenous (IV) paclitaxel in suboptimally debulked ovarian cancer. Between March 1998 and March 2006, 44 patients with histologically confirmed epithelial ovarian carcinoma or peritoneal carcinoma with a residual mass greater than 1 cm received combination chemotherapy of IV paclitaxel and IP carboplatin. Administration of IV paclitaxel at 175 mg/m2 immediately followed by IP carboplatin at an area under the curve of 6 was scheduled every 3 weeks for at least six cycles. The diagnosis and stage were ovarian carcinoma stage II in 8, III in 25, and IV in 6 cases, and peritoneal carcinoma stage III in 5 cases. Eighty-three percent of patients completed more than six cycles of chemotherapy. The incidences of grade 3/4 hematologic toxicities were 41 (93%) for neutrocytopenia, 10 (41%) for thrombocytopenia, and 18 (23%) for anemia. Observed grade 3/4 nonhematologic toxicities were 1 (2%) for allergy, 1 (2%) for fatigue, 1 (2%) for vomiting, 1 (2%) for liver dysfunction, and 4 (9%) for peripheral neuropathy. Two patients (5%) encountered catheter problems (one obstruction and one infection). Overall response rate was 80% (16 complete response, 19 partial response, 3 stable disease, and 6 progressive disease). Median progression-free survival and overall survival were 24 and 31 months, respectively. Combination chemotherapy of IP carboplatin and IV paclitaxel is effective and safe in suboptimally debulked ovarian cancer, and further evaluation is warranted.

Background: Suboptimal ovarian and peritoneal cancer patients with stage II-IV are regularly received TC chemotherapy using 180 mg/m2 paclitaxel (TXL) and AUC 5-6 of iv carboplatin (CBDCA) tri-weekly. The response rate of the TC is ∼60% and thus a further improvement is urgently required. So far, two modified TC regimens, i.e., 1) IP administration of CBDCA, and 2) application of dose-dense weekly 80 mg/m2 TXL have resulted in favorable prognostics as compared with the authentic one. We then commenced phase II clinical trials of weekly TXL/ IP CBDCA for these patients since 2009 under approval of each IRB. Since weekly administration of TXL has been reported to show higher rate of adverse effects such as hematotoxicity, establishment of tailored-therapy is needed for the regimen based on the individuals’ genetic background and cancer characteristics. Methods: Plasma TXL concentrations at 0, 2, 8, and 24 hrs after the administration were measured at a single laboratory, SRL (Tokyo). Forty-seven Japanese patients who were eligible for the TXL concentrations as of June 2011 were included for the analysis. Genotypes of ABCB1 (rs3213619, rs1128503, rs2032582, rs1045642), ABCC1 (rs60782127, rs4148356), ABCC2 (rs3740066), CYP1B1 (rs1056836), CYP2C8 (rs10509681, rs11572080, rs1058930, rs11572093), CYP3A4 (rs12721627, rs4646438, rs55951658, rs55901263, rs55785340), CYP3A5 (rs776746, rs10264272) and GSTP1 (rs1695) were determined using TaqMan® SNP genotyping assay (Applied Biosystems). Deletion polymorphisms of GSTT1 and GSTM1 were analyzed using PCR amplification and agarose gel electrophoresis. Results: Among the tested polymorphisms, only absence of GSTM1 was associated with the higher levels of TXL AUC (P=0.016) in the univariate analysis. When stratified by the GSTM1 status, other SNPs also showed some associations: In the presence of GSTM1, a combination of CYP2C8 rs11572093, CYP3A4 rs12721627 and CYP3A5 rs776746 enabled classification of patients with altered levels of AUC and CL of TXL (P=0.0037 and 0.0003, respectively); combined genotypes using ABCB1 rs11278503 and ABCC1 rs4148356 were useful for identifying patients with higher AUC and Cmax (P=0.036, 0.0031, respectively) in the absence of GSTM1. Conclusion: Stratification of patients with GSTM1 status and combinations with certain SNPs of cytochrome P450s and drug pumps were useful for identifying patients with altered pharmacokinetics parameters for TXL. This finding suggested a possible involvement of GSTM1 enzyme in the metabolism of TXL, though no conjugate of TXL has been reported thus far. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1883. doi:1538-7445.AM2012-1883

5054 Background: The purpose of this study is to evaluate the feasibility of IV / IP paclitaxel and IP carboplatin (TCipTip therapy) in patients with epithelial ovarian, fallopian tube or peritoneal carcinoma. Methods: From December 2007 to August 2010, the women with histologically confirmed, stage Ic-IVepithelial ovarian carcinoma, fallopian tube carcinoma or peritoneal carcinoma were received 6 cycle of TCipTip therapy after primary cytoreductive surgery. IV paclitacxel was administered at 135 mg/m2 followed by IP carboplatin administration based on the AUC = 6 on day1, and IP paclitacxel was administered at 60 mg/m2 on day 8. The toxicity grade was determined by CTCAE version 3.0. Progression free survival and Overall survival were estimated using Kaplan-Meier method. This study had been approved by the institutional review committee. The institutional review board required us to administer 45mg/m2 of IP paclitaxel at first cycle for the first 3 women to make sure the safety. Results: Twenty women ent...

e13118 Background: The objective of the current study was to determine the feasibility of TCipTip therapy in patients with epithelial ovarian carcinoma, fallopian tube carcinoma, or peritoneal carc...

e16549 Background: This is a feasibility study for a future trial to assess the feasibility of intravenous (IV) paclitaxel, intraperitoneal (IP) carboplatin and IP paclitaxel (TCipTip therapy) in patients with epithelial ovarian carcinoma, fallopian tube carcinoma or peritoneal carcinoma. Methods: The patients eligible for this study had histologically confirmed, stage IC-IV epithelial ovarian carcinoma, fallopian tube carcinoma or peritoneal carcinoma. IV paclitaxel was administered at 135 mg/m2 followed by IP carboplatin administration based on the area under the curve =6 on day1, and IP paclitaxel was administered at 60 mg/m2 on day 8. To ensure the safety, the three initial patients received 45 mg/m2 of IP paclitaxel on day 8. The toxicity grade was determined by CTCAE version 3. This study has been approved by the institutional review committee. Results: During November 2007 and December 2008, 10 patients were entered in this study. The patients included 7 epithelial ovarian carcinoma (stage IC, 2; stage IIIC, 5), 2 stage IIIC primary peritoneal carcinoma, and 1 stage IIA fallopian tube carcinoma. There were 7 serous adenocarcinoma, 2 endometrioid adenocarcinoma, 1 clear cell adenocarcinoma. The incidences of grade 3/4 hematological toxicities were 48% for neutropenia, 28% for thrombocytopenia, and 48% for anemia. Grade 3/4 neurotoxicity, abdominal pain nor IP catheter related toxicity was not observed. IP paclitaxel at 2nd or 3rd cycle was skipped in 4 patients by grade 3/4 neutropenia (grade 3, 3; grade 4, 1 ). Conclusions: TCipTip therapy is feasible for patients with epithelial ovarian carcinoma, fallopian tube carcinoma or peritoneal carcinoma. No significant financial relationships to disclose.

16560 Background: This is a pilot study to assess the efficacy and safety of combination chemotherapy of intraperitoneal (IP) carboplatin and intravenous (IV) taxane (paclitaxel or docetaxel) in ad...