Combined CTX Research Articles

SIRT1 as a potential key regulator for mediating apoptosis in oropharyngeal cancer using cyclophosphamide and all-trans retinoic acid

Although cyclophosphamide (CTX) has been used for recurrent or metastatic head and neck cancers, resistance is usually expected. Thus, we conducted this study to examine the effect of adding all-trans retinoic acid (ATRA) to CTX, to increase efficacy of CTX and reduce the risk of resistance developed. In this study, we investigated the combined effect of ATRA and CTX on the expression of apoptotic and angiogenesis markers in oropharyngeal carcinoma cell line (NO3), and the possible involved mechanisms. ATRA and CTX in combination significantly inhibited the proliferation of NO3 cells. Lower dose of CTX in combination with ATRA exhibited significant cytotoxicity than that of CTX when used alone, implying lower expected toxicity. Results showed that ATRA and CTX modulated oxidative stress; increased NOx and MDA, reduced GSH, and mRNA expression of Cox-2, SIRT1 and AMPK. Apoptosis was induced through elevating mRNA expressions of Bax and PAR-4 and suppressing that of Bcl-xl and Bcl-2, parallel with increased caspases 3 and 9 and decreased VEGF, endothelin-1 and CTGF levels. The primal action of the combined regimen on inflammatory signaling highlights its impact on cell death in NO3 cell line which was mediated by oxidative stress associated with apoptosis and suppression of angiogenesis.

Pattern of practice for postoperative management of endometrial cancer in Korea: a survey by the Korean Gynecologic Oncology Group and the Korean Radiation Oncology Group (KGOG 2028-KROG 2104).

This study aimed to investigate the current status of postoperative management of uterine endometrial cancer (EC) in Korea. A mail survey was administered to members of the Korean Gynecologic Oncology Group and Korean Radiation Oncology Group. A total of 38 gynecologic cancer surgeons (GYNs) and 31 radiation oncologists (RO) in 43 institutions was responded. The questionnaire consisted of general questions for clinical decision and clinical case questions. The GYN and RO responses were compared using chi-square statistics. The 2 expert groups had similar responses for clinical decision based on the results of the Gynecologic Oncology Group (GOG)-249 and Postoperative Radiation Therapy for Endometrial Carcinoma-III trials in the early-stage EC. In contrast, the responses based on GOG-258 results differed, as GYNs most frequently opted for sequential chemotherapy (CTx) and radiotherapy (RT), while ROs preferred concurrent chemoradiotherapy in locally advanced stage (p<0.05). Based on the GOG-258, GYNs preferred CTx alone for adjuvant treatment of serous or clear cell adenocarcinoma histology, whereas ROs advocated for combined CTx and RT (sequential or concurrent). Among the clinical case questions, GYNs were more likely than ROs to choose CTx alone rather than the combination of CTx and RT (sequential or concurrent) as the answers to case questions representing patients with locally advanced stage or unfavorable histology (all p<0.05). The present study showed several different opinions of GYNs and ROs regarding adjuvant treatment for EC, particularly for adjuvant RT in advanced stage or unfavorable histology.

Bone biomarkers and overall survival (OS) in men with advanced hormone-sensitive prostate cancer (HSPC): Results from SWOG S1216, a phase III trial of ADT +/- orteronel.

5071 Background: Circulating bone biomarkers (BB) are strongly prognostic for OS in castration-resistant PC (CRPC). We prospectively evaluated BB in men with HSPC in S1216, a trial that established new OS benchmarks. We sought to identify patient (pt) subsets with differential OS outcomes as defined by BB. Methods: Markers of bone resorption [CTx;PYD] &amp; formation [CICP;BAP] were assessed. Pts were randomly divided into training (1/3) &amp; validation (2/3) sets. In the training set, recursive partitioning of OS was used to identify the ideal dichotomous cutpoint for each BB &amp; for a combination of biomarker split points to define prognostic groups. In the validation set, Cox PH models were used to assess impact of BB on OS, adjusted for pt &amp; tumor characteristics. Adjusted odds ratios for 3-year OS based on BB &amp; baseline clinical factors were developed using logistic regression to estimate receiver operating characteristic (ROC) curves. Results: Of 1,279 men, 949 had baseline BB. Median age–68y; median PSA-28 ng/dL; Gleason&gt;7: 60%; Zubrod PS 0/1-97%. Values of BB at the median &amp; at cutpoints maximized for OS were identified. For 3 of the BB, the cutpoint was at the ̃85th %ile; for PYD it was at the median. Recursive partitioning algorithms applied to the training set identified 4 groups with differential OS based on a dichotomous split of CTx in combination with additional CICP splits within each group. Hazard ratios (HR) for OS based on elevated BBs are shown. ROC analysis showed that only BAP &amp; PYD had significantly higher AUC(0.73;0.74) compared to AUC of baseline clinical factors(0.71) w/ p=0.02 and 0.03 respectively. There was no evidence of BB x treatment interaction (all p&gt;=0.2). Conclusions: In men initiating ADT for HSPC, elevated BB are strongly prognostic for worse OS. BB levels alone &amp; in combination with pt/tumor characteristics identify unique subsets of men with high probability of being alive at 3 years from ADT initiation. These results validate the clinical value of BB in the HSPC state, extending BB utility beyond CRPC. Clinical trial information: NCT01809691. [Table: see text]

Efficacy of second-line chemotherapy after standard combination chemotherapy in patients with metastatic pancreatic cancer: The results from the NAPOLEON study.

661 Background: Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX) have been established as standard first-line combination chemotherapy (CTx) for patients with metastatic pancreatic cancer (MPC). However, the efficacy of second-line CTx and the significance of combination CTx in clinical practice are unclear. We therefore investigated the efficacy of second-line CTx in patients with MPC. Methods: Data were collected from CTx-naive MPC patients treated with first-line combination CTx at 14 hospitals in the Kyushu area of Japan from December 2013 to June 2018. The median overall survival (mOS) from second-line treatment was compared between patients who received second-line CTx (CT group) and those who received best supportive care (BSC group). Furthermore, in the CT group, the mOS was compared between the patients who received combination CTx and those who received mono-CTx. To control potential bias in the selection of second-line treatment, we also conducted a propensity score-adjusted analysis. Results: A total of 255 patients received GnP or FFX as first-line CTx. Of these, there were 156 (61%) in the CT group and 77 (30%) in the BSC group. The number of patients who received FFX/GnP as first-line CTx was 79 (51%)/77 (49%) in the CT group and 15 (20%)/62 (80%) in the BSC group, respectively (P &lt; 0.01). The mOS in the CT group was significantly longer than that in the BSC group (5.2 vs. 2.7 months; hazard ratio [HR] 0.42; 95% confidence interval [CI] 0.31-0.57; p &lt; 0.01 and 5.2 vs. 2.6 months; adjusted HR 0.39; 95% CI 0.28-0.55; p &lt; 0.01). In the CT group, 89 (57%) patients received combination CTx, and 67 (43%) received mono-CTx. There was no significant difference in the mOS between the combination CTx and mono-CTx patients (5.5 vs. 4.4 months; HR 0.88; 95% CI 0.62-1.26; p = 0.88 and 5.6 vs. 4.4 months; adjusted HR 0.85; 95% CI 0.56-1.30; p = 0.47). Conclusions: Among patients with MPC receiving second-line treatment, the CT group had a significantly longer mOS than the BSC group, but combination CTx conferred no improvement in the survival duration compared with mono-CTx.

A phase II trial of pembrolizumab in combination with cisplatin or carboplatin and etoposide in chemotherapy naive patients with metastatic or unresectable high-grade gastroenteropanncreatic or lung neuroendocrine carcinoma.

TPS635 Background: Combination chemotherapy (CTx) is the mainstay of treatment for patients with advanced high-grade gastroenteropancreatic neuroendocrine carcinoma (GEPNECs) and large cell neuroendocrine carcinomas (LCNECs) of the lung. Pembrolizumab (PEM) is a humanized antibody to the programmed cell death receptor (PD-1), which blocks the interaction with its cognate ligands, PD-L1 and PD-L2. PEM blocks the protective mechanism of cancer cells and allows the immune system to destroy them. Combination Ctx and immunotherapy has shown efficacy in other malignancies including small cell lung cancer. The purpose of this study is to test the efficacy, safety, and tolerability of combination CTx with PEM in patients with high-grade GEPNEC or LCNEC of the lung who are CTx naïve. Methods: This is an open label, phase II, single institution, multi-site trial using PEM in combination with either cisplatin or carboplatin and etoposide in patients with high grade GEPNECs or LCNEC of the lung who are CTx naïve. Patients with a histologic diagnosis of a GEPNECs with a Ki-67 of 55% or higher or a LCNEC of the lung will be eligible. Patients must be metastatic or unresectable; chemotherapy naïve; have at least one measurable lesion per RECIST 1.1, have an ECOG performance score of 0-1; and have a predicted life expectancy &gt; 3 months. Approximately 36 GEPNEC and 6 LCNEC of the lung patients will be enrolled. Patients will receive PEM 200mg IV in combination with cisplatin 80 mg/m2 or carboplatin AUC 6 on day 1 and etoposide 100mg/m2 on days 1-3 of a 21-day cycle. Tumor response will be assessed by CT scan every 6 weeks using RECIST 1.1. Those patients who have responsive or stable disease after 4-6 cycles of platinum-based CTx will move to maintenance PEM every 3 weeks for up to 2 years. The primary endpoint will be progression free survival. Results: This study is open to enrollment. Clinical trial information: NCT03901378.

The effect of everolimus and low-dose cyclophosphamide on immune cell subsets in patients with metastatic renal cell carcinoma: results from a phase I clinical trial

For the treatment of metastatic renal cell cancer several strategies are used among which the mTOR inhibitor everolimus. As mTOR plays an important role in the immune system, e.g., by controlling the expression of the transcription factor FoxP3 thereby regulating regulatory T cells (Tregs), it plays a key role in the balance between tolerance and inflammation. Previous reports showed stimulatory effects of mTOR inhibition on the expansion of Tregs, an effect that can be considered detrimental in terms of cancer control. Since metronomic cyclophosphamide (CTX) was shown to selectively deplete Tregs, a phase 1 clinical trial was conducted to comprehensively investigate the immune-modulating effects of several dosages and schedules of CTX in combination with the standard dose of everolimus, with the explicit aim to achieve selective Treg depletion. Our data show that 50 mg of CTX once daily and continuously administered, in combination with the standard dose of 10 mg everolimus once daily, not only results in depletion of Tregs, but also leads to a reduction in MDSC, a sustained level of the CD8+ T-cell population accompanied by an increased effector to suppressor ratio, and reversal of negative effects on three peripheral blood DC subsets. These positive effects on the immune response may contribute to improved survival, and therefore this combination therapy is further evaluated in a phase II clinical trial.

Abstract OT2-05-02: A phase II study of metronomic daily oral vinorelbine as first-line chemotherapy in advanced/metastatic hormone receptor positive (HR+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer resistant to endocrine therapy - VinoMetro

Abstract Background Chemotherapy (CTx) is a cornerstone in HR+/HER2- advanced/metastatic breast cancer (a/mBC) after failure of endocrine treatment. In this indication, vinorelbine (VRL) is a well-established cytotoxic drug. There is a high medical need for new options that prolong the time between endocrine failure and intensive CTx, which is commonly associated with impaired quality of life and serious side effects. Metronomic CTx was shown to induce disease control in a/mBC with a favorable safety profile. This innovative approach involving continuous daily dosing of oral VRL, which could provide anti-angiogenic and immune-modulatory properties, has not been investigated so far in this indication. Trial Design VinoMetro is an open-label, single-arm, phase II study (Simon two-stage minimax) of metronomic daily oral VRL (30 mg/day) as first-line CTx. The study involves strict safety monitoring with an initial safety run-in. It is accompanied by a steering committee and supervised by an independent data safety and monitoring board (DSMB). The main objectives are to estimate efficacy in terms of clinical benefit rate after 24 weeks of treatment (primary endpoint) and the progression-free survival, amongst others, as well as the assessment of safety and quality of life. Patients with HR+/HER2- a/mBC having failed or being no candidate for endocrine therapy (targeted combinations allowed) and being naïve to palliative CTx are eligible, if they exhibit ECOG 0-1. The main exclusion criteria are prior vinca-alkaloids, aggressive disease requiring combination CTx and CNS involvement. Until 2017-05-31, 7 patients were enrolled. It is planned to include 45 (39 evaluable) patients at 8 German sites until 09/2018. Scheduled completion date is 09/2019. Two interim analyses are planned (first analysis: safety evaluation based on the 10 initial patients with predefined stopping rules). Depending on recruitment, it is planned to include the interim safety data in the congress presentation. VinoMetro is an investigator initiated trial (NCT03007992) sponsored by the University Medical Centre of Johannes Gutenberg-University Mainz, Germany, and supported by an unrestricted grant provided by Pierre Fabre Pharma GmbH (Freiburg, Germany). Citation Format: Schmidt M, Decker T, Fehm T, Fuxius S, Harbeck N, Juhasz-Böss I, Thomssen C, Seehase M, Schollenberger L, Ruckes C, Möbus V. A phase II study of metronomic daily oral vinorelbine as first-line chemotherapy in advanced/metastatic hormone receptor positive (HR+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer resistant to endocrine therapy - VinoMetro [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-05-02.

The Internal Coherence of Breast Cancer Patients Is Associated with the Decision-Making for Chemotherapy and Viscum album L. Treatment.

Objective In the present observational study, the influence of internal coherence on shared decision-making for chemotherapy (CTX) and Viscum album L. extracts (VA) treatment in breast cancer patients was evaluated. Methods Breast cancer patients with a guideline-oriented advice from the tumor board for CTX were included in the study. At first diagnosis (T0) and 6 months later (T1), a questionnaire, the internal coherence scale (ICS), was administered and evaluated. Prior to analysis, patients were classified retrospectively depending on their treatment decision. Results 64 primary nonmetastasized breast cancer patients (median age 54.8 years, IQR: 46.3-65.3) were analyzed in this study. At T0, adjusted multivariable linear regression analyses revealed significant low ICS scores in patients rejecting CTX, especially in the ICS subscale “thermo coherence” (p = 0.006). The decision for add-on VA-therapy was associated with low scores for the ICS subscale “inner resilience coherence”, in particular low for the item “courage”. At T1, in the CTX+VA-group the thermo coherence increased significantly (p(d) < 0.01), while in contrast, in the CTX-only group the thermo coherence decreased significantly (p(d) = 0.02). Conclusion Add-on VA-applications in CTX treatment support the thermo coherence of breast cancer patients, revealing a decision option to encourage patients to undergo CTX in combination with additional VA-treatments.

Benefit of second-line chemotherapy for advanced biliary tract cancer.

e15621 Background: Second-line chemotherapy (2LCTX) is increasingly applied in patients (pts) with advanced biliary tract cancer (aBTC), although no randomized trial has so far demonstrated the benefit of this intervention over best supportive care (BSC) alone. In the absence of randomized data, we thus conducted a comparative effectiveness analysis of survival outcomes in aBTC pts treated with BSC±2LCTX. Methods: In this single-center cohort study, we retrospectively included 80 pts with metastatic, recurrent, or inoperable aBTC who completed 1st-line CTX at our department between 2003 and 2016. Thirty-eight of these pts (48%) received 2LCTX+BSC (Fluoropyrimidine (FP) mono: n = 26 (68%), FP-based combination CTX: n = 9 (24%), Others: n = 3 (8%)). Primary endpoint was 18-month overall survival (OS). An inverse-probability-of-treatment-weighted analysis (IPTW) was implemented to rigorously account for imbalances in prognostic variables between the two study groups. Results: During a median follow-up of 14.8 months, we observed 49 deaths. Six-month, 12-month, and 18-month OS estimates were 77%, 53% and 23% in the BSC+2LCTX group, and 29%, 21%, and 14% in patients in the BSC group, for a univariable hazard ratio (HR) for OS of 0.36 (95%CI: 0.20-0.64, p = 0.001). However, pts receiving 2LCTX+BSC had a significantly higher prevalence of favorable prognostic variables, such as a higher Karnofsky Index (p = 0.0001), lower serum bilirubin (p = 0.03), higher hemoglobin (p = 0.002), and higher serum albumin (p = 0.0007). After careful adjustment for these imbalances using IPTW, 2LCTX+BSC was not associated with an OS benefit over BSC alone (Adjusted HR = 0.62, 95%CI: 0.30-1.29, p = 0.201). In IPTW analysis, 6-, 12-, and 18-month OS were 51%, 33% and 14% in the BSC+2LCTX group, and 35%, 29%, and 19% in patients in the BSC group. The beneficial association of 2LCTX with OS was highly time-dependent, with IPTW HRs of 0.07 (p = 0.002), 0.42 (p = 0.05), and 0.53 (p = 0.11) after 3, 6, and 12 months, respectively. Conclusions: Within the limitations of a non-randomized study, our data support the concept that 2LCTX is associated with a short-term OS benefit in pts with aBTC.

Initial gemcitabine/nab-paclitaxel (GA) followed by sequential (S) mFOLFIRINOX or alternating (A) mFOLFIRI in metastatic pancreatic cancer (mPC): The SEENA-1 study.

359 Background: GA, FOLFIRINOX and FOLFIRI are standard chemotherapy (CTX) regimens for mPC.The optimal introduction of these regimens following GA is not known. This phase II study evaluated 2 different approaches to this question. Methods: Eligibility criteria included 1) untreated mPC, 2) ECOG PS 0/1, 3) organ function adequate for Rx. Patients (pts) were treated according to one of 2 methods following GA given per standard dose/schedule: FOLFIRINOX (bolus 5-FU omitted) for up to 12 cycles at 24 weeks or at time of disease progression (S); or GA alternating with FOLFIRI q8 weeks up to 48 weeks total Rx (A). Results: 54 evaluable pts (28S, 26A) were enrolled . Pt characteristics included median age 65, M/F 48/52% , liver involvement 89%. 17/53 pts (31%) did not achieve disease control at 8 weeks (8 toxicity/complications , 6 disease progression, 3 declined further protocol therapy). Of the remaining 37 pts, 24/13 were treated with S/A regimens, respectively. Grade ≥ 3 treatment toxicities reported while on study with frequency ≥ 10% included anemia 21%, neutropenia 43%, thrombocytopenia 15%, and fatigue 22%. Grade ≥ 3 neuropathy occurred in 8% of pts. For all 54 pts using RECIST 1.0, CR/PR/SD/DC was 2 (4%)/20 (37%)/19 (35%)/41(76%). Ca19.9 response ≥ 90% was seen in 20/37 (54%). For all pts, median OS was 12.3 months ( 95% CI 8.6-14.5 mo); 12 and 24 mo OS was 51% and 11%, respectively. For the 37 pts with DC on GA at 8 weeks (calculated from start Rx) median OS was 13.5 mo (95% CI 10.7-15.4 mo); 12 and 24 mo OS was 55% and 16% , respectively. No statistically significant differences were seen between S and A with respect to toxicity, response or survival. Conclusions: 1) As opposed to introduction of 5FU-based CTX at the time of disease progression/prohibitive toxicity, introduction prior to that time may be at least comparable regarding both toxicity and OS. 2) This approach may further enhance OS in pts who achieve DC on GA at 8 weeks. 3) Neither S nor A method of 5FU-based CTX introduction following GA was clearly superior in this study. 4) How best to combine 5FU-based combination CTX following GA in mPC merits further study. Supported by the Seena Magowitz Foundation.

Clinical application of Tacrolimus to infant steroid-resistant nephrotic syndrome

Objective To analyze the peculiarity of infants steroid-resistant nephrotic syndrome (SRNS) and to assess the efficacy, side-effect and relapse of various of Tacrolimus prescribed in infants SRNS. Methods A total of 76 case of infant SRNS from August 2012 to August 2015 in Guangzhou Weman and Children′s Medical Center grouped into oral Tacrolimus(TAC group), Methyprenisolone pulse therapy (MP group) and Methyprenisolong combined Cyclophosphamide(CTX) pulse therapy(MP+ CTX group), were observed for 1 year, and the urine protein excretion, renal function(CCr), blood glucose(BG), urine retinal-binding-protein(URBP), lymphocyte count etc.were recorded and the situation of infection and relapse regularly were monitored regularly.The data were retrospectively analyzed by the statistical method. Results All SRNS children underwent kidney biopsy, and 36 cases of minimal change disease, 32 cases of mesangial proliferative glomerulonephritis and 8 cases of focal segmental glome-rulosclerosis were contained in the patients.The pathological constituent ratios were not obviously different among these 3 groups.By 6-month follow-up, the complete remission ratio of TAC group was 63.64%, the total remission ratio was 95.45%, which were remarkably higher than those of MP group(26.09%, 60.87%) and MP+ CTX group(41.94%, 74.19%); the urine protein excretion of TAC group [(7.8±8.6) mg/(kg·d)] was distinctly lower than that of pretreatment and lower than that of MP group[(144.2±118.3) mg/(kg·d)], and lower than that of MP+ CTX group[(91.3±87.4) mg/(kg·d)], and the difference was significant(F=22.69, P<0.05). The remission time of TAC group was about 2 months, that of other two groups was about 3 months.By 1-year follow-up, the lymphocyte counts including total T-cell(CD3+ ), the helper T-cell(CD4+ ) and the inhibited T-cell(CD8+ ) of TAC group decreased obviously(all P<0.01), which were extremely lower than those of the MP group and MP+ CTX group, and there were significant differences(all P<0.05). By 1-year follow-up, the person-time of infection existed superior to the other 2 groups, TAC group was compared with MP plus group, the rank sum was 348.5(U=-3.69, P<0.01); compared with MP+ CTX plus group, the rank sum was 369.5(U=-4.18, P<0.01). During the observation the URBP of TAC group was distinctly higher than that of the MP group and the MP+ CTX group [(13.77±19.19) mg/L vs.(2.50±1.77) mg/L, (2.06±3.63) mg/L], and the differences were significant(t=3.16, 2.99, all P<0.05); the TAC group with BG and CCr maintained stably. Conclusions Tacrolimus shows its own advantages of more reliable effect and less side-effect in the infants with SRNS over MP therapy and MP combined CTX therapy, but it could not lessen the recurrence of the disease, and its long-term prognosis is still not very clear. Key words: Tacrolimus; Infant; Steroid-resistant nephrotic syndrome

Chemotherapy (Ctx) use and adoption of new agents in older versus younger patients (pts) with metastatic colorectal cancer (mCRC).

674 Background: The treatment of mCRC has changed substantially in the last 2 decades but adoption of new drugs has not been well studied in older pts. We explored the effect of age and comorbidities on the adoption of irinotecan (Iri) and oxaliplatin (Ox) in mCRC pts over a 15 year timespan. Methods: mCRC pts receiving 5-Fluorouracil (5FU) based Ctx between 1995-2009 were studied using the LifeLink Health Plan Claims Database, and evaluated based on age (&gt;70 vs ≤70y). Pts were identified by ICD-9 / HCPCS (J) codes. The fraction of pts receiving Ctx was calculated at yearly intervals and any other agent received with 5FU defined combination Ctx. Charlson Comorbidity Index (CCI) was used to assess comorbidity burden. Wilcoxon's and χ2test were used in univariate and logistic regression in multivariate analyses (MVA). Results: 16087 pts were identified with a median age of 61y and 55% males. The difference in proportions of older vs younger pts receiving Ctx for mCRC remained stable over the 15 year period. There was an increase in the fraction of pts with CCI&gt;1 over time (14% in 1996; 40% after 2004 (p&lt;0.05). Older pts had higher rate of CCI&gt;1 (Table). Use of single agent 5FU declined in both groups over time. After FDA approval, use of Iri was lower in older pts (15 vs 38% in 1998, p&lt;0.05), but this difference resolved by 2002 (62% both groups, p=0.9). Similarly, Ox was used more frequently in younger pts after initial approval (15% vs 22% in 2003), with decrease in this difference by 2009 (60% vs 64%,p=0.9). Older pts were less likely to get &gt;2 agents when compared to younger (15 vs 22%, 29 vs 39% and 11 vs 16% in 2003, 2006 &amp; 2009 respectively, p&lt;0.001). On MVA, likelihood of receiving combination Ctx increased over time [OR 1.2; 1.18-1.26; p&lt;0.01], but was lower in older pts [OR 0.65;0.59-0.71, p&lt;0.001] and pts with CCI&gt;1 [OR 0.84;0.77-0.91; p&lt;0.001]. Conclusions: In a group of commercially insured pts, a lower fraction of older pts are treated for mCRC and adoption of new agents into the treatment of older pts appears to lag behind that of younger pts. However, oncologists have become more comfortable treating older pts with comorbidities over time. [Table: see text]

Enhancement of cancer chemotherapeutic efficacy of cyclophosphamide by Curculigo orchioides Gaertn and its ameliorative effects on cyclophosphamide-induced oxidative stress.

Cyclophosphamide (CTX) is a synthetic antineoplastic drug with severe and life-threatening side effects. Studies in search of protective agents, preferably natural products, that can alleviate these side effects are valuable because they can contribute to improve current chemotherapeutic treatment strategies. Curculigo orchioides Gaertn (family Hypoxidaceae) is well known for its medicinal use in the Indian Ayurvedic system of medicine, and various studies have been reported that proved its immunomodulatory and anti-inflammatory properties. In this study, the tumor reduction capacity of CTX in combination with C orchioides methanolic extract was studied using Dalton's lymphoma ascites-induced solid tumor models. Effect of C orchioides on the reversal of the damage induced by CTX administration (intraperitoneally) was also determined in this study. For this, solid tumor volume, serum cytokine levels, hematolological parameters, intestinal histopathology, and serum and tissue biochemical parameters (Glutathione [GSH], alkaline phosphatase [ALP], glutamate pyruvate transaminase [GPT], lipid peroxidation [LPO]) were analyzed. Immune suppression and increased serum proinflammatory cytokine levels caused by CTX administration (25 mg/kg body weight) were reversed by C orchioides (20 mg/kg body weight). The alcoholic extract enhanced the tumor reduction capacity of CTX and reduced GPT and ALP levels in liver and serum, which were elevated by CTX administration. The LPO level was also lower in the CTX-administered animals when treated with the C orchioides extract. In conclusion, the plant extract when administered in combination with CTX, can result in enhanced anticancer properties; it also ameliorates the toxic side effects of CTX.

IS1-3 - Perspective of Systemic Chemotherapy for Gastric Cancer in Europe

Randomized trials showed that cytotoxic treatment prolongs survival and provides improved symptom control in advanced gastric cancer. Combination chemotherapy (CTx) with cisplatin and 5-FU is a preferred 1st-line CTx in Europe, but oxaliplatin has shown equivalent efficacy compared with cisplatin. Oral fluoropyrimidines, especially S-1 and capecitabine, can substitute for 5-FU. Modern doublet regimens are preferred in the majority of patients on the basis of a balanced benefit-risk ratio. In selected, fit and compliant patients, especially those with high tumor burden or potential secondary resectability, a third drug may be added as triple CTx led to higher responses rates and enhanced efficacy.Current study concepts evaluate the feasibility and efficacy of de-escalation protocols and maintenance treatment with less toxic drugs, e.g. S-1 monotherapy. This concept is currently studied following response induced by intensive induction CTx.The comprehension of tumor biology is increasing. In HER2 positive gastric cancer, the addition of the anti-HER2 monoclonal antibody trastuzumab to cisplatin and FU has prolonged survival. Novel anti-HER2-directed drugs like pertuzumab are being explored. More genetic alterations have been defined in subgroups of gastric cancer, like MET or FGFR amplification. Its role for therapeutic targeting remains to be elucidated.2nd-line CTx with single agents has now become a proven treatment option. Alternatively, anti-angiogenic treatment with ramucirumab has been published with positive data and will be made available.In conclusion, combination CTx is a European 1st-line standard for treating advanced gastric cancer. Molecularly targeted agents are further explored, preferably on the backbone of chemotherapy doublets. For further-line treatment, monotherapy with cytotoxics and - in the future - ramucirumab are the preferred options.

A national treatment survey on the chemotherapy (CTX) treatment for patients (Pts) with metastatic breast cancer (MBC) in Germany.

e17544 Background: The optimal CTX regimens and their sequence is the subject of ongoing debates esp. on the use of anthracycline/taxane (AT)-based adjuvant therapy (tx). Methods: Since 2004 a biennial survey is performed to evaluate routine CTX practice in MBC A total of 1,966 German sites were contacted. From 515 (26.2%) patient data were used for evaluation in order to achieve a representative sample for a chart review between June and August 2012. The current analysis is based on data from 291 sites on characteristics and tx of 741 pts undergoing first (1L), second (2L) or third (3L) line CTX for MBC in May 2012. Results: Data from 417 pts in 1L, 203 pts in 2L, and 121 pts in 3L were evaluated. Median age was 60 years (yrs). Patient characteristics were: 74% hormone receptor positive, 24% HER2-positive at primary diagnosis, 67% premenopausal, 60% had metastases in ≥ 2 organs, 66% had visceral disease. Prior tx (excluding M1 pts) was: no systemic tx 10%, endocrine tx only 13%, adjuvant CTX 58% (40% A and 44% AT-based), neoadjuvant CTX 20% (12% A and 75% AT-based). Median time from primary diagnosis to start of any treatment for MBC was 4.5 yrs for node-negative and 2.1 yrs for node-positive disease. Median time from primary diagnosis to current CTX was 4.9 yrs in 1L, 5.1 yrs in 2L and 5.8 yrs in 3L. Combination CTX was given in 21% of 1L, 12% of 2L and 9% of 3L pts, and its use decreased with increasing age. Agents used most frequently in 1L were taxanes in 61% (paclitaxel (P) 52%, docetaxel (D) 6%, nab-paclitaxel (Nab) 3%), capecitabine (X) 21%, vinorelbin (V) 19%, Epirubicin 6%, carboplatin 5%. 1L taxane tx was given to 73% of pts with prior A-based and 46% of pts with prior AT-based (neo-)adjuvant tx. Agents used most frequently in 2L were X 31%, P 20%, V 20%, gemcitabine (G) 7%, Nab 6% and in 3L V 27%, X 22%, eribulin 15%, Nab 12% P 7%, G 5%. Targeted tx was given in 54% of pts (20% trastuzumab, 4% lapatinib, and 30% bevacizumab), additional tx were bisphosphonates in 58%, and radiotherapy in 20%. Conclusions: The survey showed a high concordance of routine treatment and the existing national guidelines regarding CTX. Taxanes still dominate CTX in MBC including a significant amount of taxane rechallenge after their use in (neo-)adjuvant tx.

Abstract P2-12-11: Use of the DigniCap™ System to Prevent Hair Loss in Women Receiving Chemotherapy (CTX) for Stage I Breast Cancer (BC)

Abstract Background: Alopecia is a non-life threatening complication of adjuvant CTX for early stage BC. CTX induced hair loss affects quality of life and potentially impacts decisions regarding the risks and benefits of treatment. Scalp cooling (SC), used internationally by thousands of patients (pts) including a growing number in the U.S., is thought to prevent hair loss through decreased follicular metabolic rate and vasoconstriction resulting in reduced delivery and cellular uptake of drugs. The DigniCap™ System is a self-contained SC system with circulating coolant. We sought to evaluate feasibility and efficacy of the DigniCap™ System in pts with stage I BC. Methods: We performed an initial prospective feasibility study before a planned pivotal trial. The primary endpoint was feasibility, defined as &amp;lt;50% of pts discontinuing cap use due to cap-associated toxicity. Secondary endpoints included prevention of hair loss (HL) assessed by an independent panel (IP) consisting of a hairdresser, patient advocate, and dermatologist using photographs taken from 5 angles and blinded to pt and CTX cycle using the 5 point Dean's scale for HL: grade 0 (no HL), 1 (&amp;lt; 25% HL), 2 (25–50% HL), 3 (50–75% HL), and 4 (&amp;gt;75% HL). Pts assessed their own HL using the Dean's scale, and pt-assessed quality of life, time to and quality of hair re-growth, and impact of HL on treatment decisions were also evaluated. Successful prevention of alopecia was defined as &amp;lt; grade 2 HL by the Dean's scale. Eligibility included stage I disease and excluded use of anthracycline-taxane combination or sequential CTX. Results: 20 pts were enrolled. CTX regimens included: docetaxel and cyclophosphamide (TC) × 4–6 cycles (n = 16), weekly paclitaxel and trastuzumab × 12 (n = 2), and docetaxel, carboplatin, and trastuzumab (TCH) × 6 (n = 2). 19 of 20 pts (95%) completed all CTX using the DigniCap™ System. By IP assessment, 15 pts (75%) had a maximum of ≤ grade 2 HL; 2 pts (10%) and 3 pts (15%) had a maximum grade 3 or 4 HL respectively. By pt assessment, 11 pts (55%) reported ≤ grade 2 HL. 68% and 32% of pts reported grade 1 or 2 toxicity, respectively, including head/scalp pain, feeling chilled, and rash. 85% of pts reported that SC made decisions about CTX easier. At a median follow-up of 15.4 months, no scalp metastases have been observed. Conclusions: Use of the DigniCap™ System is feasible, effective in preventing CTX-induced alopecia in the majority of users, and safe with short-term follow-up in pts with stage I BC. Additional studies should help to define potential causes for cap failure. This is the first prospective US trial to evaluate the effect of SC using an expert IP and blinded photographs to assess extent of alopecia. A larger trial is planned to confirm these results in pts with stage I/II disease. Support for this trial was provided by the Tauber Foundation (UCSF), the Madonia and Cooper Funds (WFBH), and Dignitana. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-11.

Combination therapy with risedronate and teriparatide in male osteoporosis

Most studies of combination therapy with teriparatide and a bisphosphonate have not shown greater efficacy over monotherapy. The bisphosphonate risedronate, has not been studied in this context. The purpose of this proof-of-concept study was to assess whether combination risedronate and teriparatide increases bone mineral density (BMD) more than monotherapy with either drug alone. This was a randomized, double-blinded study of risedronate (35 mg weekly plus placebo injection), teriparatide (20 μg subcutaneously daily plus placebo tablet), or both risedronate plus teriparatide (combination) for 18 months in 29 men with low BMD. The primary endpoint was percentage change in lumbar spine (LS) BMD at 18 months. Secondary outcomes included changes in bone markers and BMD at other sites and interim time-points. All therapies increased LS BMD as compared with baseline (p < 0.05), but there were no between-group differences at 18 months. Total hip (TH) BMD increased to a greater extent in the combination group (mean ± SEM, 3.86 ± 1.1 %) versus teriparatide (0.29 ± 0.95 %) or risedronate (0.82 ± 0.95 %; p < 0.05 for both). Femoral neck (FN) BMD also increased more in the combination group (8.45 ± 1.8 %) versus risedronate (0.50 ± 1.7 %; p = 0.002), but was not different from teriparatide alone. In the combination group, P1NP and CTX increased rapidly, mirroring the teriparatide-alone arm. There were no between-group differences in adverse events. Combination teriparatide and risedronate increased BMD at the LS, TH as well as the FN and provided greater BMD increases at the TH than monotherapy. The results suggest combination risedronate and teriparatide therapy holds promise as a treatment for osteoporosis.

Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine

Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8(+) T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8(+) T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8(+) T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic antitumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8(+) T cells, which led to higher ratios of CD8(+)/Treg and CD8(+)/CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8(+) T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells.

The efficacy and toxicity of 3-weekly TS-1 containing chemotherapy in patients with unresectable advanced gastric cancer.

e14580 Background: TS-1 has shown good efficacy against unresectable advanced gastric cancer (AGC). Conventionally TS-1 containing chemotherapy (CTx) is performed on 5-weekly or 6-weekly basis. We lack robust evidence for the efficacy and safety of 3-weekly TS-1 containing CTx. In Korea, 3-weekly TS-1 containing CTx can be used as off-label under permission of Health Insurance Review and Assessment service (HIRA). We and HIRA conducted this study to confirm the efficacy and tolerability of 3-weekly TS-1 containing CTx in unresectable AGC. Methods: We retrospectively analyzed patients with unresectable AGC who received 3-weekly TS-1 containing CTx between June 2007 and January 2011. In 3-weekly TS-1 monotherapy, TS-1 40-60mg depending on patient’s body surface area was administered orally twice a day for 14 days followed by a 1-week rest every 3 weeks. In 3-weekly TS-1/cisplatin combination CTx, TS-1 40mg/m2 was given orally twice a day for 14 days followed by 1-week rest and cisplatin 60 mg/m2 on day 1 was given by intravenous infusion every 3 weeks. Results: A total of 1372 patients (TS-1 monotherapy: 265 (19.3%), TS-1/cisplatin : 1107 (80.7%)) were enrolled from 31 institutions. Response rate of 3-weekly TS-1 monotherapy was 18.1%. Progression-free survival (PFS) and overall survival (OS) were 5.2 months (95% C.I., 4.5-5.9) and 14.3 months (95% C.I., 10.6-17.9), respectively. Response rate of 3-weekly TS-1/cisplatin was 29.4%. PFS and OS of 3-weekly TS-1/cisplatin were 6.8 months (95% C.I., 6.3-7.4) and 16.1 months (95% C.I., 14.4-17.9) respectively. Common toxicities of TS-1 monotherapy included nausea/vomiting (N/V) (13.6%), anemia (13.2%) and neutropenia (10.2%). However, the incidences of more grade 3/4 toxicities were less than 3.0%. All grades of neutropenia, N/V and anemia occurred in 35.4%, 21.1% and 13.3% of patients receiving 3-weekly TS-1/cisplatin. However, grade 3/4 toxicities including neutropenia, N/V and anemia occurred in only 17.8%, 3.0% and 2.9%. Conclusions: Three-weekly TS-1 monotherapy or TS-1/cisplatin CTx showed good efficacy and well tolerability. Our study suggests that 3-weekly scheduled regimens may be a good treatment option for unresectable AGC patients.

PL2-1: Macrophages as Novel Targets for Therapy in Breast Cancer.

Abstract While BC has not historically been linked to underlying inflammation or infection, it exhibits tumor-associated inflammation marked by infiltration of innate and adaptive immune cells into developing tumors. In BC, macrophages are one of the most abundant innate immune cells present. BC-associated macrophages are regulated in part by colony stimulating factor 1 (CSF1), a key cytokine involved in monocyte/macrophage maturation, recruitment and activation, and its cognate receptor CSF1R. Macrophage presence in BC correlates with increased CSF1, increased vascular density, and worse clinical outcome. We reported that CD4+ T cells promote invasion and metastasis of mammary adenocarcinomas by directly regulating macrophage phenotype that in turn fosters invasive tumor growth, presence of circulating tumor cells and pulmonary metastasis. This preclinical data implied that women with BC heavily infiltrated by macrophages would have a worse clinical outcome as compared to tumors not heavily infiltrated with macrophages. We evaluated survival outcomes in 698 women with invasive BC treated with surgery alone and found that recurrence-free survival could be stratified based upon macrophage and T cell infiltration. Thus, we investigated CSF1 and CSF1R antagonists, in combination with standard-of-care chemotherapy (CTX) in mouse models of mammary carcinogenesis. We found that when macrophage infiltration in mammary adenocarcinomas was blocked, paclitaxel (PTX) chemosensitivity was increased, accompanied by development of productive anti-tumor immune responses and CD8+ cytotoxic T cell (CTL) infiltration. The combined effects of these changes were reduced primary tumor growth, 85% reduction in metastases and increased survival. In collaboration with clinical colleagues, we are currently evaluating the clinical benefit of macrophage modulation in preclinical models of BC to facilitate biomarker identification, and inform clinical trials of CTX in combination with macrophage-antagonists. Based on our preliminary data, we hypothesize that components of macrophage responses in BC can be identified to serve as biomarkers for risk stratification. And, that these components can be effectively targeted for therapeutic intervention, resulting in reduced late-stage BC development and metastasis when combined with CTX. LMC acknowledges generous support from the NIH/NCI (R01CA130980, R01CA13256, R01CA140943, R01CA15531), the Department of Defense (W81XWH-09-1-0342, W81XWH-10-BCRP-EOHS-EXP) and the Susan G Komen Foundation (KG111084) Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PL2-1.