Chemotherapy For Metastatic Disease Research Articles

The impact of chemotherapy on hospitalizations and emergency care in older adults with advanced cancer.

6545 Background: The benefits of systemic chemotherapy for metastatic disease vary by tumor type and must be weighed against potential side effects. In patients receiving chemotherapy for advanced ...

Ampulla of Vater Carcinoma in Real-World Clinical Practice: A Case Series

The aim of this report was to describe the way in which a rare and niche disease like ampulla of Vater carcinoma (AVC) was treated in real-world clinical practice. A retrospective analysis of consecutive patients with a diagnosis of AVC treated at our medical oncology unit between August 2004 and August 2013 was performed. We evaluated 8 consecutive patients with a median age of 60 years (range 56-84). At the last follow-up, 4 patients were alive without evidence of disease and 4 patients had died. The median follow-up time was 21.51 months (range 1-100.43), the median overall survival 23.19 months (range 7.07-102.2), and the median disease-free survival 18.26 months (range 0-102.2). Six patients underwent surgery, which consisted of pylorus-preserving pancreaticoduodenectomy, R0 in all cases. Tumor histology was adenocarcinoma in all patients. Two patients presented with locally advanced disease. Only 1 patient presented with metastases while 3 patients subsequently developed metastases. Two patients received chemotherapy for metastatic disease; in both cases disease progression was observed at the first disease evaluation. We can consider AVC as a pathology niche and pancreaticoduodenectomy as the effective treatment for these patients.

Abstract OT1-1-14: A phase 2, 2-stage, 2-cohort study of the oral PARP inhibitor BMN 673 in patients with germline BRCA mutation and locally advanced and/or metastatic breast cancer (ABRAZO study)

Abstract Background: Poly-ADP-ribose polymerase (PARP) represents a family of enzymes of which at least two (PARP1 and PARP2) play important roles in DNA repair. PARP inhibition induces synthetic lethality in tumor cells bearing mutations in the genes BRCA1 and BRCA2, both of which are key components in the homologous recombination DNA double-strand breaks repair pathway. BMN 673 is the most potent preclinical PARP inhibitor described to date with the highest efficiency at trapping PARP-DNA complexes (Murai et al, 2014). BMN 673 has shown promising single-agent anti-tumor efficacy in several tumor types in an ongoing Phase 1/2 clinical study. Methods: The purpose of this Phase 2 trial (ABRAZO) is to evaluate the safety and efficacy of BMN 673 in patients with locally advanced or metastatic breast cancer with a deleterious germline BRCA 1 or BRCA 2 mutation. This study is an open-label, 2-stage, 2-cohort Phase 2 study using a Southwest Oncology Group (SWOG) 2-stage design. Eligible subjects will be assigned to either Cohort 1 (n=70) or 2 (n=70) based on prior chemotherapy exposure for metastatic disease: Cohort 1) Subjects who have previously responded to a platinum-containing regimen for metastatic disease with disease progression > 8 weeks following the last dose of platinum; or Cohort 2) Subjects who have received > 2 prior chemotherapy regimens and who have had no prior platinum therapy for metastatic disease. The primary objective is to determine the objective response rate (ORR) of BMN 673 as a single agent for each cohort. The secondary objectives of the study are to determine the following for each cohort: clinical benefit rate (CBR), duration of response (DOR), progression free survival (PFS), and overall survival (OS). Health-related quality of life assessment is an exploratory objective. Patients may be eligible if they are 18 years or older, have histologically or cytologically confirmed carcinoma of the breast, locally advanced and/or metastatic disease, deleterious or pathogenic germline BRCA1 or BRCA2 mutation, prior chemotherapy for metastatic disease based on the above Cohort 1 or Cohort 2 inclusion criteria, ECOG performance status ≤ 1, and no central nervous system (CNS) metastasis except adequately treated brain metastasis documented by baseline CT or MRI scan that has not progressed since previous scans and that does not require corticosteroids for management of CNS symptoms. Eligible patients will receive BMN 673 oral capsules once daily (1.0 mg/day) continuously in 21-day cycles until disease progression or unacceptable toxicity. This trial is enrolling patients from the United States and European countries (NCT02034916). Citation Format: Nicholas C Turner, Judith Balmana, Susan M Domchek, Frances Visco, Charlie Zhang, Nathalie A Lokker, Debra L Lounsbury, Mark E Robson. A phase 2, 2-stage, 2-cohort study of the oral PARP inhibitor BMN 673 in patients with germline BRCA mutation and locally advanced and/or metastatic breast cancer (ABRAZO study) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-14.

Abstract OT2-2-07: A phase II study of S-1 (14 days' administration followed by 7 days' rest) for metastatic breast cancer

Abstract Background S-1, an orally administered fluorinated pyrimidine (FP), improves overall survival in the adjuvant setting of gastric and pancreatic cancer. It is also effective for metastatic breast cancer (Yamamoto et al. Anticancer Res 30:3827-32, 2010). Although S-1 is usually administered for 28 days followed by 14 days’ rest, severe adverse events are often observed by Day 15. By altering the schedule into 14 days’ administration followed by 7 days’ rest, discontinuation of treatment can often be avoided in daily practice. This schedule maintains the same dose intensity. Equally, an anti-tumor effect and fewer adverse events are observed in 14 days’ administration followed by 7 days’ rest than in 28 days’ administration followed by 14 days’ rest for the treatment of squamous cell carcinoma of the head and neck (Tsukuda et al. Br J Cancer 93:884-889, 2005). In order to reduce the occurrence and severity of adverse events of S-1, we paid attention to dose reduction according to the renal function of patients. S-1 is comprised of tegafur, 5-chloro-2, 4-dihydroxy-pyridine(CDHP) and potassium oxonate. CDHP enhances the serum concentration of 5-FU by inhibiting dihydropyrimidine dehydrogenase (DPD), and it is excreted by the kidneys. Therefore, an accumulation of DPD in patients with renal dysfunction escalates the serum concentration of 5-FU and induces more severe adverse events. Thus, the dosage of S-1 should be reduced according to renal function. Trial design This is a phase II trial to evaluate the efficacy and toxicity of S-1 (14 days’ administration followed by 7 days’ rest) for metastatic breast cancer. S-1 is administered orally twice daily at a dose of 40-60 mg depending on the BSA and creatinine-clearance from Days 1 to 14, which is followed by 7 days’ rest. This treatment is repeated until disease progression. (Trial registration :UMIN 000014096) Eligibility criteria Patients with histologically confirmed breast cancer, and recurrent and /or metastatic disease are included. Patients with HER2-positive (IHC:3+ or FISH+) tumor are excluded. Patients within 2 lines of previous chemotherapy for metastatic disease are allowed. Eligible patients are aged between 20 years and 80 years with a performance status of 0 to 2 and adequate organ function. Specific aims The primary endpoint is the response rate, and the secondary endpoints are disease control rate, progression-free survival, time to failure, toxicities and feasibility. Statistical methods The sample size was calculated using the Simon method, with a type I error of 5% and a study power of 90%. The unpromising response rate was 15% and the promising rate was 42%. The required number of patients was estimated to be 23. Target accrual Accrual of 25 patients was planned to produce a minimum of 23 evaluable patients. Patient accrual started in June 2014. Citation Format: Akira Hirano, Akinori Hattori, Kaoru Ogura, Hiroaki Inoue, Fumie Okubo, Mari Kamimura, Shiho Sakaguchi, Jun Kinoshita, Reiko Miyamoto, Norie Jibiki, Yoshihiko Naritaka, Tadao Shimizu. A phase II study of S-1 (14 days' administration followed by 7 days' rest) for metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-2-07.

Abstract P3-10-06: Real-world efficacy and safety outcomes of nab-paclitaxel (nab-P) in patients (pts) with metastatic breast cancer (MBC): Results from a US health insurance database

Abstract Background: nab-P, an albumin-bound formulation of paclitaxel, was approved in 2005 for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 mo of adjuvant chemotherapy based on clinical trials. nab-P demonstrated efficacy and safety when administered weekly in phase II trials and every 3 weeks (q3w) in an international phase III trial. Little is known about the treatment patterns and outcomes of nab-P in the real-world setting. Using health insurance claims data, this study was conducted to characterize efficacy and safety of nab-P in pts with MBC treated in US clinical practices. Methods: This retrospective claims analysis used data in the Optum Research Database (United Health affiliate). Data were supplemented by Social Security Death Index sources. The analysis included women aged ≥ 18 y with MBC diagnosis (≥ 2 claims of BC diagnosis separated by ≥ 30 d and ≥ 2 claims of metastatic spread) prior to nab-P initiation. Pts had ≥ 6 mo of continuous enrollment in the health plan from January 2005-September 2012, complete medical coverage and pharmacy benefits, no other primary malignancy, and no prior chemotherapy. Cohorts were determined by line of therapy, nab-P regimen, and schedule. Endpoints included treatment patterns, time to next therapy or death (TNTD), overall survival (OS), and safety. Results: Of the 664 eligible pts, most were between 40-69 y of age (88%) and had received nab-P as ≥ second-line therapy (74%), monotherapy (61%), and weekly dosing (71%). In combination, nab-P was most often given with bevacizumab (58%) or human epidermal growth factor receptor 2 (HER2)–targeted therapy (24%) vs another cytotoxic agent (19%). Median TNTD and OS were 6.1 and 17.4 mo, respectively. By line of therapy (first, second, and ≥ third), TNTD was 7.1, 6.6, and 5.3 mo, and OS was 22.7, 17.4, and 15.1 mo. The OS data are comparable with published clinical trial results (Table). In a subgroup of pts (n = 400) with aggressive disease features (≤ 50 y of age or having ≥ 3 metastases), median OS was 15.6 mo. These data are comparable with a retrospective analysis of pts with visceral dominant metastasis (VDM) or a short disease-free interval (SDFI; Table). Toxicities reported in healthcare claims were consistent with those previously published. Conclusions: Consistent with clinical trial data, outcomes of this analysis demonstrated the efficacy and safety of nab-P across lines of therapy in a real-world population of patients with MBC. Clinical Trial Experience in MBC for Pts Treated With nab-PTrialnab-P dose (mg/m2) and schedulenMedian OS, moCA0121 (Ph III)ITT (all lines)260 q3w22915.0≥ second line260 q3w13113.0CA0242 (Ph II, first line)300 q3w7627.7100 qw 3/47622.2150 qw 3/47433.8Median OS, moSubgroups With Aggressive Disease FeaturesnVDMnSDFICA0123 (first line)260 q3w7415.14214.6CA0243 (first line)300 q3w6127.72016.6100 qw 3/46019.62119.1150 qw 3/45932.11418.6qw 3/4, weekly for the first 3 of 4 weeks. 1 Gradishar WJ, et al. J Clin Oncol. 2005;23:7794-7803. 2 Gradishar WJ, et al. Clin Breast Cancer. 2012;12:313-321. 3 O’Shaughnessy J, et al. Breast Cancer Res Treat. 2013;138:829-837. Citation Format: Debra A Patt, Caihua Liang, Ling Li, Amy Ko, Cindy Duval Fraser, Deyanira Corzo, Cheryl Enger. Real-world efficacy and safety outcomes of nab-paclitaxel (nab-P) in patients (pts) with metastatic breast cancer (MBC): Results from a US health insurance database [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-06.

Abstract P3-10-01: Randomized phase III trial of taxanes versus S-1 as first-line chemotherapy for metastatic breast cancer (SELECT BC: CSPOR- MBC01)

Abstract Background: Treatment goals of metastatic breast cancer (MBC) are to prolong survival and improve health-related quality of life (HRQOL). Current standard first-line chemotherapy for MBC are the taxanes or anthracyclines; however treatment-related adverse events greatly reduce HRQOL. S-1 is an oral 5-fluorouracil derivative, and phase II trials showed good clinical efficacy and tolerability. We conducted a phase III randomized controlled trial to establish non-inferiority of S-1 in overall survival (OS) and superiority in HRQOL to taxanes, when given as first-line chemotherapy for MBC. Methods: Patients with HER2-negative non-life-threatening MBC, naïve to chemotherapy for metastatic disease, were randomly assigned to the taxane or S-1 groups. In the taxane group, patients received docetaxel 60-75mg/m2 q3w, paclitaxel 80-100mg/m2 q1w, or paclitaxel 175 mg/m2 q3w according to institutional policy. In the S-1 group, patients received S-1 40–60 mg twice daily based on body surface area using a 28 days on;14 days off regimen. Treatment was repeated until tumor progression or for at least 6 cycles (taxane) or 4 cycles (S-1). After failure of the first-line protocol therapy, another cytotoxic agent was administered, based on the investigator’s discretion. HRQOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, the Patient Neurotoxicity Questionnaire (PNQ) and the EQ-5D at baseline and 3, 6, 12 months after the start of the treatment. The primary endpoint was OS. Secondary endpoints were time to treatment failure (TTF), adverse events, and HRQOL. Results: A total of 618 women were enrolled. After a median follow-up of 34.6 months, median OS was 37.2 months in the taxane group (n=309) and 35.0 months in the S-1 group (n=309) (hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.86–1.27, non-inferiority test p=0.015). Median TTF was 8.9 months in the taxane group and 8.0 months in the S-1 group (HR 1.10, 95% CI 0.93–1.30, p=0.022). The incidence of the following grade 3-4 adverse events, allergic reaction, edema and sensory neuropathy, were statistically significantly more frequent in the taxane group (p=0.038, 0.0013 and 0.0077, respectively). Hematologic and non hematologic toxicities except above did not differ significantly between the two groups. The results of the EORTC QLQ-C30 under study treatment indicated that the S-1 was better than the taxanes in global health status/QOL (p=0.044), physical functioning (p=0.002), role functioning (p=0.002), emotional functioning (p=0.004), cognitive functioning (p=0.026), social functioning (p<0.0001), pain (p=0.042) and financial difficulties (p=0.003). EQ-5D utility scores were significantly higher in the S-1 group (p=0.033) during the first year. PNQ sensory and motor scores were significantly better in the S-1 group (p<0.0001 and p=0.0002, respectively). Conclusions: This study clearly demonstrated that S-1 was superior to taxanes in terms of HRQOL and toxicity, without compromising the prolonged OS. S-1 should be considered as a new standard for first-line chemotherapy for MBC. We are conducting another similar trial (UMIN000005449) that compares first-line anthracycline with S-1 in terms of OS and HRQOL. Citation Format: Takanori Watanabe, Kojiro Shimozuma, Kentaro Imi, Hiroyoshi Doihara, Hiromitsu Akabane, Hiroaki Ueo, Shinji Ohno, Masahiro Kashiwaba, Atsushi Fukuuchi, Kenichi Watanabe, Michiko Tsuneizumi, Hirotsugu Isaka, Yukari Uemura, Yasuo Ohashi, Hirofumi Mukai. Randomized phase III trial of taxanes versus S-1 as first-line chemotherapy for metastatic breast cancer (SELECT BC: CSPOR- MBC01) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-01.

Abstract P3-10-02: Gemcitabine with cisplatin or paclitaxel in metastatic triple-negative breast cancer

Abstract Background: There is still no standard chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC). Our previous phase II pilot trial with first-line gemcitabine and cisplatin combination (GP) in patients with mTNBC (clinicaltrials.gov Identifier: NCT00601159) showed a median progression-free survival (PFS) of 6.2 months. In this Chinese Breast Cancer Study Group (CBCSG) 006 trial (clinicaltrials.gov Identifier: NCT01287624) we explored in a randomized trial the role of the less costly GP regimen versus the standard GT [Gemcitibine + paclitaxel] chemotherapy for the metastatic breast cancer as a first line treatment for mTNBC. Trial objectives: progression free survival [PFS]; overall survival [OS]; and toxicity. Methods: In the trial with a hybrid trial design incorporating a formal test of superiority as well as noninferiority, mTNBC patients with no previous chemotherapy for metastatic disease were randomly assigned to receive either GP regimen (G/P: 1250 mg/m2 d1,8/ 75 mg/m2 d1) or the GT regimen (same G; T: 175 mg/m2 d1). Results: Between Jan. 2011 and Nov., 2013, 236 patients were randomized [118 patients / arm], and all received at least one dose of assigned chemotherapy. As of Mar. 20, 2014, the intent-to-treat analysis showed 201 recurrences and 97 deaths. Objective response rates of GP vs GT were 67.9% vs. 50.4% (P= 0.008), with median PFS of 232 vs. 194 days (HR=0.692, 95% CI 0.523-0.915; P= 0.009). Overall survival of patients from the GP vs. the GT arms was median 672 vs. 556 days (HR=0.902, 95% CI 0.605-1.344; P= 0.611). Significant differences in grade 3/4 adverse events were seen for nausea, vomiting, anemia and thrombocytopenia [GP vs. GT, 6.8 vs. 0.8%; 11.0 vs. 0.8%; 33.1 vs. 51.0%; and 32.2 vs. 2.5%, respectively]. In addition, assessment of adverse events of any grade showed the GP regimen had more anorexia, constipation, hypomagnesemia and hypokalemia, while GT regimen had significantly more alopecia and peripheral neuropathy. The delivered relative dose intensity was > 90% for all three drugs, with the total number of delivered cycles of chemotherapy in GP and GT arms being 654 and 648 [average 5.54 and 5.49 /patient], respectively. Conclusions: 1.The Gemcitabine + Platinum is superior to Gemcitabine + Paclitaxel in terms of objective response rates and duration of PFS. 2.While grade 3 / 4 nausea & vomiting, and anemia, were heavier for the GP combination, the delivery of chemotherapy and average number of cycles delivered were comparable between the two arms. 3.Overall survival data will be updated on the conference to indicate the long-term effect of the somehow more toxic GP regimen, which shows nevertheless superiority of response rates and of the PFS over the more costly GT regimen. Citation Format: Xichun Hu, Binghe Xu, Li Cai, Zhonghua Wang, Biyun Wang, Jian Zhang, Yuee Teng, Zhongsheng Tong, Yueyin Pan, Yongmei Yin, Changping Wu, Zefei Jiang, Xiaojia Wang, Guyin Lou, Donggeng Liu, Jifeng Feng, Jianfeng Luo, Jiong Wu, Zhimin Shao, Joseph Ragaz. Gemcitabine with cisplatin or paclitaxel in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-02.

The impact of weight gain during adjuvant chemotherapy on survival in breast cancer.

Weight gain can be detected during adjuvant chemotherapy in breast cancer patients, leading to administration of lower drug doses than planned and a decrease in long-term survival. In this study, the effect of weight gain on survival in breast cancer patients was investigated. Breast cancer patients treated with adjuvant chemotherapy between May 2002 and May 2003 were prospectively included in the study. Patients treated with neoadjuvant chemotherapy or with chemotherapy for metastatic disease were excluded from the study. Data regarding patients' demographic, clinical and pathologic characteristics and chemotherapy protocols were recorded. Patients were grouped as those with weight gain less than or more than 3 kg, and those with a body mass index of less than or more than 30. The impact of weight gain on patients' disease-free and overall survival was investigated. Log-rank test and Cox regression analyses were utilized for survival analyses. P<0.05 value was accepted as statistically significant. Eighty-eight consecutive female patients with a median age of 46 (29-71) were included in the study. Patients received anthracycline based chemotherapy protocols. Weight gain was detected in 79 patients (89.8%), with more than 3 kg weight gain detected in 38 patients (43.2%). In a median follow-up time of 98 months (62-120), distant metastases were detected in 21 patients (23.9%), and 11 patients (12.5%) died. Mean disease-free survival of patients with a weight gain less than and more than 3 kg during chemotherapy was 89.1±3.9 and 84.7±4.2 months (p=0.007), whereas mean overall survival was 95.6±2.2 and 92.5±2.1 months (p=0.01), respectively. Mean disease-free survival of patients with a body mass index less than and more than 30 was 87.3±2.3 and 85.1±3.6 months (p=0.4), whereas mean overall survival was 94.2±2.3 and 92.1±1.1 months (p=0.35), respectively. Weight gain during adjuvant chemotherapy has a negative effect on both disease-free and overall survival in patients with breast cancer.

Safety of cisplatin in patients with urothelial carcinoma (UC) and renal dysfunction.

321 Background: Patients (pts) with UC and creatinine clearance (CrCl) &lt; 60 ml/min are considered cisplatin-ineligible. Since the safety of cisplatin use in patients with CrCl &lt; 60 has not been comprehensively studied, we conducted a retrospective study in this population. Methods: Data were requested and retrospectively collected from 5 collaborating institutions. All patients had stage 2 or higher UC and CrCl &lt; 60. Patient characteristics including age, sex, indication for chemotherapy (neoadjuvant, adjuvant or metastatic disease), schedule, total dose of cisplatin, adverse effects, renal function, blood cell counts and radiologic tumor response were collected. Descriptive statistics were employed with no baseline assumptions. Results: 104 patients were evaluable with a mean age of 63.7+ 8.1 yrs (range 41-77yrs) and 63.5% (n=66) were men. Mean CrCl by Cockroft-Gault formula was 50.8 + 8.0 ml/min (range 26-59 ml/min). Baseline ECOG performance status was 0 in 71.8% (n=74); 1 in 20.3% (n=21) and 2 in 7.8% (n=8) of patients. 40.4% (n=42) received chemotherapy for metastatic disease and the rest received perioperative chemotherapy. Of the patients with metastatic disease, 7.1% patient had complete response (CR), 40.5 % patients had partial response. Mean total dose of cisplatin used in all patients was 414.32±198.01 mg, with 81.7% (n=85) patients receiving ≥70mg/m2 dose per cycle. Percentage of patients with any toxicity with baseline CrCl &lt;45 and &gt;45 were 43.5% and 39.5%, respectively (p=0.81). Neutropenic infection occurred in 16.3% and thrombocytopenic bleed in 8.6%. Grade 3 renal toxicity was seen in only one patient (0.96%) and no toxic deaths were reported. Conclusions: This retrospective clinical experience in pts with UC with CrCl &lt;60 ml/min and mostly ECOG-PS 0-1 suggests that cisplatin-based chemotherapy is feasible and warrants exploration given CRs induced in metastatic disease. Incorporation of prophylactic growth factors and modified schedules may mitigate myelosuppression.

Survival for patients with resectable lung metastatic colorectal cancer (mCRC).

708 Background: Hepatic resection for CRC metastasis is now considered a standard of care and perioperative chemotherapy may improve outcomes. Resection of metastasis isolated to lung is also considered potentially curable, although there is still some variation in recommendations and no evidence for perioperative or adjuvant chemotherapy. Here, we explore patient characteristics and outcomes for patients undergoing lung resection for mCRC, with the liver resection group as the comparator. Methods: SA mCRC registry data were analysed to assess patient characteristics and survival outcomes between patients suitable for lung or liver resection. K-M survival analysis was used to assess OS. Results: 3,241 patient are registered on the database. 102 (3.1%) patients were able to undergo a lung resection compared to 420 (12.9%) a liver resection. Of the lung resection patients, 21% initially presented with liver only disease, 11% both lung and liver, and 7% brain or pelvic disease. 62 (61%) presented with lung only disease. Of these patients, 79% went straight to surgery and 34% had lung resection as the only intervention. When comparing the groups, they were balanced for age and sex, liver v lung; 67.7 years v 69.5 years, 63.6% v 57.8% male. There was no difference in pathological grade or KRAS MT rate when tested (36% liver v 32% lung). Compared to patients undergoing liver resection, those having lung resection were more likely to be metachronous (75.5% v 44%, p=&lt;0.0001) and have a rectal primary (43.1% v 30.7%, p=0.017). Chemotherapy for metastatic disease was given more often in liver resection patients (76.9% v 53.9%, p=0.17). Median overall survival is not reached for both arms and the lower hazard rate for lung than liver resection does not approach statistical significance (HR 0.82, 95% CI 0.54-1.24, p=0.33). The 3 and 5 year survival liver v lung as follows; 77% v 81% and 62% v 70%. Conclusions: Lung resection occurs less frequently than liver resection for metastatic disease as expected. There was no statistical difference in overall survival in patients suitable for lung or liver resection. These data support the potential for long term survival with resection of both lung and liver metastasis in mCRC.

Evaluation of 6 Patients with Genital Melanoma from Onset of Symptoms to Death: Evaluate the Factors Affecting the Prognosis of the Disease.

Background:Genital melanoma is a rare but deadly cancer in women and the prognosis is often poor.Purpose:This study assesses the impact of possible risk factors on the end prognosis of the patients, with the ultimate goal of improving survival of disease.Methods:This is a report of 6 patients diagnosed and treated as genital melanoma. Parameters reviewed included: age at diagnose, presenting symptoms, location size and Breslow depth of lesion, stage at diagnose, adjuvant therapies, hysterectomy and salpingo-oophorectomy, metastasis or recurrence in follow-up, chemotherapy for metastatic disease.Results:The mean age at the time of diagnosis, was 44.67 years, the average size of lesion was 2.91 cm; the average Breslow depth of lesion was 1.93 mm. The mean interval between the onsets of symptoms to diagnosis was 16.7 months; the average life expectancy was 23.5 months. There is no significant relationship between the initial location of the lesion and prognosis (P: 0.98). Patients diagnosed in < 7 months, were in lower stages at diagnose (P: 0.018), and the survival of them was better (P: 0.035). Patients diagnosed in early stages had better survival at last (P: 0.035) Adjuvant radiotherapy improves survival markedly (P: 0.018). Hysterectomy and salpingo-oophorectomy had no significant effect on prognosis (P: 0.7). Chemotherapy in metastatic disease had no significant effect on prognosis (P: 0.46).Conclusion:The survival markedly improved if the disease diagnosed in a short distance from onset of symptoms and specially in early stages. Adjuvant radiotherapy can improve the survival significantly, but for the early hysterectomy and salpingo-oophorectomy and also for chemotherapy in metastatic disease, the impact on prognosis is uncertain, but positive.

Therapeutic implications of Epstein-Barr virus infection for the treatment of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is highly endemic in certain regions including the People’s Republic of China and Southeast Asia. Its etiology is unique and multifactorial, involving genetic background, epigenetic, and environment factors, including Epstein–Barr virus (EBV) infection. The presence of EBV in all tumor cells, aberrant pattern of antibodies against EBV antigens in patient sera, and elevated viral DNA in patient circulation as well as nasopharyngeal site underline the role of EBV during NPC development. In NPC tumors, EBV expresses latency type II, where three EBV-encoded proteins, Epstein–Barr nuclear antigen 1, latent membrane protein 1 and 2 (LMP1, 2), are expressed along with BamH1-A rightward reading frame 1, Epstein–Barr virus-encoded small nuclear RNAs, and BamH1-A rightward transcripts. Among all encoded proteins, LMP1 plays a central role in the propagation of NPC. Standard treatment of NPC consists of radiotherapy with or without chemotherapy for early stage, concurrent chemoradiotherapy in locally advanced tumors, and palliative systemic chemotherapy in metastatic disease. However, this standard care has limitations, allowing recurrences and disease progression in a certain proportion of cases. Although the pathophysiological link and molecular process of EBV-induced oncogenesis are not fully understood, therapeutic approaches targeting the virus may increase the cure rate and add clinical benefit. The promising results of early phase clinical trials on EBV-specific immunotherapy, epigenetic therapy, and treatment with viral lytic induction offer new options for treating NPC.

Abound.Sqm: a Phase 3 Randomized Study of Maintenance Nab-Paclitaxel (Nab-P) After Induction Therapy with Nab-P Plus Carboplatin (C) in Patients (Pts) with Squamous Cell (Scc) Non-Small Cell Lung Cancer (Nsclc)

ABSTRACT Background: In a phase 3 trial, nab-P/C vs solvent-based paclitaxel + C demonstrated a 68% improvement in ORR (41% vs 24%; P Trial design: During induction, ≈ 540 pts will receive nab-P 100 mg/m2 IV (30-min infusion) on days 1, 8, and 15 plus IV C AUC 6 mg·min/mL on day 1 of a 21-day cycle. Eligibility criteria include no prior chemotherapy for metastatic disease, histologically confirmed stage IIIB/IV SCC NSCLC, Eastern Cooperative Oncology Group performance status (PS) ≤ 1, adequate organ function, peripheral neuropathy grade Disclosure: A. Ko: Amy Ko is an employee of Celgene and owns stock; H. West: Dr West has participated in advisory boards and received honoraria from the following: Novartis, Genetech/Roche, Foundation Medicine; E. Kim: Dr Kim is an advisor/consultant for the following companies: Celgene Eli Lilly Genentech/Roche; C. Reynolds: Dr Reynolds has participated in Ad Boards and received honoraria for the following: Celgene and Pfizer. All other authors have declared no conflicts of interest.

Sorafenib in advanced, heavily pretreated patients with soft tissue sarcomas

Therapeutic options for patients with advanced pretreated soft tissue sarcomas are limited. However, in this setting, sorafenib has shown promising results. We reviewed the data of 33 patients with soft tissue sarcoma treated with sorafenib within a named patient program in Austria. Twelve physicians from eight different hospitals provided records for the analysis of data. Among the 33 patients, the predominant histological subtype of sarcoma was leiomyosarcoma (n=18, 55%). Other subtypes were represented by only one or two cases. Fifteen patients presented with metastases at the time of diagnosis. Another 17 patients developed metastases later in the course of the disease (data on one patient are missing). Most of the 33 patients had undergone resection of the primary (n=29, 88%) and half of the patients had received radiotherapy (n=17, 52%). Chemotherapy for metastatic disease had been administered to 30 patients (91%). The majority had received two or more regimens of chemotherapy (n=25, 76%) before sorafenib treatment. The use of sorafenib resulted in a median time to treatment failure of 92 days in patients with leiomyosarcoma and 45 days in patients with other histological subtypes. One-third of the patients derived benefits from treatment: four patients were documented with partial response and six with stabilized disease. In terms of treatment-related toxicity, skin problems of various degrees and gastrointestinal disturbances were frequently reported. In this retrospective analysis of heavily pretreated patients with advanced soft tissue sarcomas, sorafenib was associated with some antitumor activity and an acceptable toxicity profile.

Phase I/IB trial of eribulin and everolimus in patients with triple-negative metastatic breast cancer.

TPS2637 Background: Eribulin mesylate is a synthetic analog of halichondrin B via tubulin-based anti-mitotic mechanism, leads to G2/M cell cycle arrest, disruption of mitotic spindles, apoptotic cell death and inhibits the phosphorylation of AKT in TNBC cells. Everolimus inhibits mTOR pathway. With mTOR inhibition, pAKT is enhanced, seen at 24 hours with everolimus alone in TNBC cell lines Ser473 and SKBR3. Combination of eribulin and everolimus suppressed both pAKT and pS6K1 at 24 hours. Based on our preclinical findings, we hypothesize that everolimus and eribulin will have a synergistic effect with inproved clinical activity in metastatic TNBC. Objectives: phase I/IB trial of everolimus plus eribulin in metastatic TNBC. Phase I determines the safety & tolerability and the recommended Phase II dose (RP2D), while the Phase IB will evaluate event free survival rate at RP2D. Methods: Eligibility: Metastatic TNBC who progressed on anthracyclines/taxanes, and previous chemotherapy for metastatic disease (up ...

Safety and efficacy of nab-paclitaxel (nab-P) in patients (pts) with metastatic breast cancer (MBC): Real-world results from a U.S. health insurance database.

1075 Background: nab-P is an albumin-bound formulation of paclitaxel approved in 2005 for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, based on an international phase 3 trial comparing nab-P with paclitaxel on an every 3 week (q3w) schedule. The objective of this study was to characterize safety and efficacy outcomes of nab-P in MBC in the United States using health insurance claims data. Methods: A retrospective claims analysis was conductedusing the Optum Research Database (United Health affiliate). The analysis included women aged ≥ 18 years diagnosed with MBC (≥ 2 claims of BC diagnosis separated by ≥ 30 days and ≥ 2 claims of metastatic spread) prior to nab-P initiation. Pts had ≥ 6 months of continuous enrollment in a US health insurance plan from January 2005 through September 2012, complete medical coverage and pharmacy benefits, no other primary malignancy, and no prior nab-P. Data were supplem...

Prognostic factors related with survival in patients with pancreatic adenocarcinoma.

The prognosis in patients with pancreatic cancer is poor and this cancer is the fourth leading cause of cancer-related death worldwide. Although surgical resection is the only curative treatment of choice for pancreatic cancer, the majority of patients are diagnosed at an advanced stage, thus only 10%-15% of them are suitable for curative resection and the overall survival is less than 5%. Chemotherapy for metastatic disease is to palliate symptoms of patients and to improve survival. Therefore, prognostic factors are important and a correct definition of poor prognostic factors may help to guide more aggressive adjuvant or aggressive treatment protocols in patients with pancreatic cancer. This article reviews the prognostic factors affecting survival of patients with pancreatic cancer in the light of recent advances in the literature.

Abstract P1-08-31: Putative role of genetic variants of eNOS in survival and toxicity of patients given antiangiogenic therapy

Abstract Background: The development of tumor angiogensis is mainly driven by vascular endothelial growth factor (VEGF), which is strongly overexpressed in many cancers. VEGF induces the expression of the endothelial nitric oxide (NO) synthase (eNOS) and the resultant overproduction of NO may be associated with recruitment of inflammatory cells, disruption of endothelial barrier, edema and impaired drug delivery within tumors (1). Functional polymorphisms in the eNOS gene, including -786C&amp;gt;T and 894G&amp;gt;T, have been associated with impaired production of NO and higher incidence of hypertension (HT) (2), diabetic nephropathy (3) and glaucoma (4). Since suppression of VEGF-eNOS signal transduction by antiangiogenic drugs may normalize tumor vasculature by restoring interstitial fluid pressure and drug distribution in tumors, but may induce HT in patients, the purpose of this study was to examine the association between the major eNOS variants -786C&amp;gt;T and 894G&amp;gt;T with treatment outcome and risk of HT in metastatic breast cancer (MBC) patients given bevacizumab. Methods: Sixty-five MBC patients given bevacizumab as per approved indication were enrolled. Main characteristics were: mean age 49.5 years (range 29-73) at first diagnosis, 53 years (range 34-74) at metastatic progression and PS 0-1. Four subjects with HT and 1 patient with compensated cardiovascular disease were also included. First-line chemotherapy for metastatic disease was taxol plus bevacizumab. Germline DNA was extracted from peripheral blood with the Qiamp Mini Kit (Qiagen, Milano, Italy) and examined for eNOS -786C&amp;gt;T and 894G&amp;gt;T variants by Real Time PCR (Life Sciences 7900HT platform) and automatic sequencing (Life Sciences 3100 Avant). The study was approved by the local Ethics Committee. Results: Genotype frequencies are reported below (Table 1). The presence of -786TT genotype was associated with longer PFS compared with the other genotypes (median PFS 95%CI, CC/CT = 9 vs TT = 12 months, Log-rank [Mantel Cox] test p = 0.0066), but not with any grade of HT. Also the 894GT/TT was associated with longer PFS compaed with the GG homozygous wild-type genotype (median PFS 95%CI, GG = 7,5 vs GT/TT = 10 months, Log-rank [Mantel-Cox] test p = 0,0497). The incidence and severity of HT did not vary among genotypes. Conclusion: Patients bearing deficient eNOS variant did not experience higher risk or severity of HT with respect to the wild-type allele but enjoied a longer PFS. Table 1. Genotype frequenciesSNPFrequencies%Frequencies%Frequencies%-786C&amp;gt;TCCCTTT 37%33.8%26.2%894G&amp;gt;TGGGTTT 41.5%53.8%4.6%

Abstract OT3-2-10: Phase 3, multicenter, randomized, double-blind, placebo-controlled trial of fulvestrant with or without PD-0332991 (palbociclib) ± goserelin in women with hormone receptor-positive, HER2-negative metastatic breast cancer (MBC) whose disease progressed after prior endocrine therapy

Abstract Background: Palbociclib (P) is a selective inhibitor of CDK 4/6 that prevents DNA synthesis by blocking G1-S phase cell cycle progression. Blockade of hormone signaling is synergistic with cell cycle arrest induction and results in significant clinical benefit. Combining P with anti-endocrine therapy is expected to have additive or synergistic effect on tumor growth and metastasis. In a randomized phase 2 study, postmenopausal women with hormone- sensitive ER+/HER2– advanced breast cancer had significantly longer progression-free survival (PFS) with P + letrozole (L) versus L. This study will assess efficacy of P + fulvestrant (F) in patients with endocrine-resistant MBC. Trial Design: In this double-blind phase 3 study, patients will receive F (500 mg given IM per standard of care) and be randomized 2:1 to receive P (125 mg/d orally for 3 wk followed by 1 wk off) + F (500 mg given per standard of care) or matched placebo + F. Pre- and perimenopausal women must also receive goserelin. Randomization will be stratified by documented sensitivity to prior endocrine therapy (yes vs no), menopausal status at study entry (pre-/peri- vs postmenopausal), and presence of visceral metastases (yes vs no). An external data monitoring committee will perform an early review of safety data from the first 40 randomized patients to confirm safety/tolerability, including pharmacokinetic data to explore potential drug-drug interactions. Eligibility Criteria: Eligible women are aged ≥18 y with ER+ and/or PR+, HER2– MBC, whose cancer has progressed during or within 12 mo of completing adjuvant therapy (with an aromatase inhibitor or tamoxifen if post-menopausal or pre-/perimenopausal, respectively) or while on or within 1 mo after the end of prior aromatase inhibitor therapy for their metastatic disease. One previous line of chemotherapy for metastatic disease is permitted. Patients must have measureable disease (per RECIST v1.1) or bone-only metastatic disease and be willing and able to provide tumor tissue for biomarker research. Aims: The primary endpoint will assess whether P + F vs placebo + F prolongs investigator-assessed PFS. Secondary endpoints include overall survival, objective response, duration of response, trough drug concentrations, patient-reported outcomes, biomarkers, and safety and tolerability. Statistical Methods: This study will have 90% power to detect an increase in PFS using 1-sided significance testing. One interim analysis is planned to re-estimate the sample size and assess patient safety as well as preliminary efficacy. Accrual: Target accrual is 417 patients (P + F, n = 278; placebo + F, n = 139). Contact Information: For further information, please contact the Director, Clinical Trials Disclosure Group, Pfizer Inc (marla.brickman@pfizer.com). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-10.

First FDA Approval of Dual Anti-HER2 Regimen: Pertuzumab in Combination with Trastuzumab and Docetaxel for HER2-Positive Metastatic Breast Cancer

On June 8, 2012, the U.S. Food and Drug Administration (FDA) approved pertuzumab (Perjeta, Genentech) for use in combination with trastuzumab (Herceptin, Genentech) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 808 patients with HER2-positive MBC. Patients were randomized (1:1) to receive pertuzumab (n = 402) or placebo (n = 406) in combination with trastuzumab and docetaxel. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). A statistically significant improvement in PFS (difference in medians of 6.1 months) was observed in patients receiving pertuzumab [HR, 0.62; 95% confidence interval (CI), 0.51-0.75; P < 0.0001]. A planned interim analysis suggested an improvement in OS (HR, 0.64; 95% CI, 0.47-0.88; P = 0.0053) but the HR and P value did not cross the stopping boundary. Common adverse reactions (>30%) observed in patients on the pertuzumab arm included diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. No additive cardiac toxicity was observed. Significant manufacturing issues were identified during the review. On the basis of substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns. Therefore, FDA approved pertuzumab but limited its approval to lots not affected by manufacturing problems. The applicant agreed to multiple manufacturing and testing postmarketing commitments under third-party oversight to resolve manufacturing issues.