Neoadjuvant Cisplatin Research Articles

Impact of Neoadjuvant Chemotherapy on the Administration of Concurrent Chemoradiation for Locally Advanced Nasopharyngeal Carcinoma

ObjectivesThe standard of care for locally advanced nasopharyngeal carcinoma (NPC) is concurrent cisplatin chemoradiotherapy. Neoadjuvant chemotherapy can be administered to downsize tumors before concurrent treatment to optimize radiation volumes. Our hypothesis was that the use of cisplatin in the neoadjuvant phase could limit the amount of cisplatin that patients could tolerate in the concurrent phase of treatment.MethodsThis is a retrospective analysis of Canadian NPC patients who received neoadjuvant chemotherapy with the intention to downsize locally advanced tumors prior to concurrent cisplatin plus radiation. Baseline demographic and treatment data were obtained from institutional databases and chart review; all data were analyzed with SPSS (SPSS Inc. Released 2005. SPSS for Windows, Version 14.0. Chicago: SPSS Inc.) Overall survival (OS), disease-specific survival (DSS), and local/regional relapse-free survival (LRRFS) were analyzed using Kaplan-Meier survival functions. Univariate and multivariate models were used to determine factors associated with the total dose of concurrent chemotherapy.ResultsForty-six patients were identified as receiving neoadjuvant chemotherapy before concurrent chemoradiotherapy. In the univariate and multivariate analyses of patients who received concurrent chemotherapy, receiving over 200 mg/m2 concurrent cisplatin with radiation was associated with a higher neoadjuvant dose of chemotherapy received. The median follow-up time was 2.6 years (range, 0.17 years to 10.6 years). At three years, the OS was 83%, DSS was 86%, and LRRFS was 74%.ConclusionsNPC patients have been treated with neoadjuvant chemotherapy at this center with favorable outcomes. Most patients could tolerate concurrent chemotherapy after radiotherapy. Receiving higher doses of concurrent chemotherapy was associated with also having higher doses of neoadjuvant cisplatin. This suggests that neoadjuvant cisplatin is not a limiting factor in the delivery of full-dose concurrent chemotherapy.

A Phase I Clinical Trial of AZD1775 in Combination with Neoadjuvant Weekly Docetaxel and Cisplatin before Definitive Therapy in Head and Neck Squamous Cell Carcinoma

Purpose: The WEE1 tyrosine kinase regulates G2-M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. Thus, a need arises to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel.Patients and Methods: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with stage III/IVB HNSCC with borderline-resectable or -unresectable disease, but who were candidates for definitive chemoradiation. Escalating AZD1775 was administered orally twice a day over 2.5 days on the first week, then in combination with fixed cisplatin (25 mg/m2) and docetaxel (35 mg/m2) for 3 additional weeks. The primary outcome measure was adverse events to establish MTD. Secondary measures included response rates, pharmacokinetics (PK), pharmacodynamics, and genomic data.Results: The MTD for AZD1775 was established at 150 mg orally twice per day for 2.5 days. RECISTv1.1 responses were seen in 5 of 10 patients; histologic adjustment revealed three additional responders. The only drug-limiting toxicity was grade 3 diarrhea. The PK C8hr target of 240 nmol/L was achieved on day 4 at all three doses tested. Pharmacodynamic analysis revealed a reduction in pY15-Cdk, and increases in γH2AX, CC3, and RPA32/RPA2 were noted in responders versus nonresponders.Conclusions: The triplet combination of AZD1775, cisplatin, and docetaxel is safe and tolerable. Preliminary results show promising antitumor efficacy in advanced HNSCC, meriting further investigation at the recommended phase II dose. Clin Cancer Res; 24(12); 2740-8. ©2018 AACR.

Efficacy of split schedule (SS) vs conventional schedule (CS) neoadjuvant cisplatin-based chemotherapy for muscle-invasive bladder cancer (MIBC).

4545Background: Neoadjuvant cisplatin (70mg/m2) based chemotherapy (NAC) prior to cystectomy is standard of care for MIBC. Many patients (pts) cannot receive cisplatin due to impaired renal functio...

A phase I study of neoadjuvant cisplatin (C), docetaxel (D) and nintedanib (N) for resectable non-small cell lung cancer (NSCLC).

8555Background: Major pathologic response (mPR) in resected NSCLC following neoadjuvant chemotherapy correlates with long-term survival. This phase 1 study assessed the safety and efficacy of N add...

Neoadjuvant Bleomycin, Etoposide, and Cisplatin (BEP) Chemotherapy in the Treatment of Extensively Advanced Yolk Sac Tumors: A Single Center Experience.

This study aimed to investigate the role of neoadjuvant bleomycin, etoposide, and cisplatin (BEP) regimen in patients with extensively advanced yolk sac tumors (YSTs). Between July 1982 and December 2015, a total of 58 patients with YST were initially treated at our institution, among which 18 were evaluated to be inoperable and received neoadjuvant BEP regimen. They were either too debilitated by the disease [Eastern Cooperative Oncology Group Performance Status Scale (ECOG ps) ≥2] to undergo a major surgery or were with too extensively disseminated lesions to be optimally debulked. This cohort of patients was retrospectively reviewed. One or 2 cycles of BEP regimen were prescribed to the majority of patients preoperatively. At the completion of neoadjuvant chemotherapy, 17 of them had ECOG ps of 1 or less. Seventeen (94.4%) exhibited clinical partial tumor regression, and 1 (5.6%) had clinical stable disease. Pathological complete tumor regression was observed in 2 (11.1%) patients, whereas the remaining 16 (88.9%) had nearly complete pathological regression. Seventeen patients were cytoreduced to no macroscopic residual disease; the remaining 1 was cytoreduced to macroscopic residual disease of 2 cm or less. No major surgical complications occurred. After a median follow-up of 83.5 months, 17 patients were free of recurrence. Five-year disease-free survival and overall survival were both 94.4%. Fertility-sparing surgery was carried out in all the 17 patients with the desire to preserve their fertility, and 5 infants were delivered in 6 patients who attempted conception. One or 2 cycles of neoadjuvant BEP regimen followed by cytoreductive surgery offer a chance for cure in extensively advanced patients with YSTs and help pave the way for fertility-sparing surgery.

MP78-12 DOES NEOADJUVANT CHEMOTHERAPY WITH GEMCITABINE AND CISPLATIN IN BLADDER CANCER INCREASE THE COMPLICATIONS AT RADICAL CYSTECTOMY IN HIGH AGE PATIENTS?

You have accessJournal of UrologyBladder Cancer: Invasive VI1 Apr 2018MP78-12 DOES NEOADJUVANT CHEMOTHERAPY WITH GEMCITABINE AND CISPLATIN IN BLADDER CANCER INCREASE THE COMPLICATIONS AT RADICAL CYSTECTOMY IN HIGH AGE PATIENTS? Keishiro Fukumoto, Eiji Kikuchi, Suguru Shirotake, Kyohei Hakozaki, Yasumasa Miyazaki, Takahiro Maeda, Gou Kaneko, Shunsuke Yoshimine, Nobuhiro Tanaka, Kunimitsu Kanai, Masafumi Oyama, Yosuke Nakajima, Tetsuo Momma, and Mototsugu Oya Keishiro FukumotoKeishiro Fukumoto More articles by this author , Eiji KikuchiEiji Kikuchi More articles by this author , Suguru ShirotakeSuguru Shirotake More articles by this author , Kyohei HakozakiKyohei Hakozaki More articles by this author , Yasumasa MiyazakiYasumasa Miyazaki More articles by this author , Takahiro MaedaTakahiro Maeda More articles by this author , Gou KanekoGou Kaneko More articles by this author , Shunsuke YoshimineShunsuke Yoshimine More articles by this author , Nobuhiro TanakaNobuhiro Tanaka More articles by this author , Kunimitsu KanaiKunimitsu Kanai More articles by this author , Masafumi OyamaMasafumi Oyama More articles by this author , Yosuke NakajimaYosuke Nakajima More articles by this author , Tetsuo MommaTetsuo Momma More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2560AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although the survival benefit of neoadjuvant chemotherapy (NAC) for bladder cancer is well known, the safety for high age patients has not been fully evaluated. The aim of this study was to evaluate the effect of age on the safety of NAC with gemcitabine and cisplatin. METHODS We collected 419 patients who had undergone radical cystectomy for clinical anyTN0M0 bladder cancer from 2005 to 2015 at 7 institutions. Overall 251 (59.9%), 132 (31.5%), and 36 (8.6%) patients had cT2 or lower, cT3, and cT4 disease, respectively. All NACs were performed with gemcitabine and cisplatin. The complication was recorded according to the Clavien-Dindo classification. RESULTS The number of patients of < 60 age, 60-69 age, 70-79 age and ≥ 80 age were 58 (13.8%), 130 (31.0%), 173 (41.3%), and 58 (13.8%). NAC was performed in 16 (27.6%), 41 (31.5%), 50 (28.9%) and 9 (15.5%) patients in < 60 age, 60-69 age, 70-79 age and ≥ 80 age. The number of patients with >cT2 was 112 (37.0%) in non-NAC group, which was significantly lower than their counterparts (48.3%, 0.035). There were no other significant differences in clinical features according to NAC. In < 60 age group, the number of patients with complications, ileus, infections and wound troubles were 13 (31.0%), 4 (9.5%), 8 (19.0%) and 5 (11.9%) in non-NAC group. Those were 4 (25.0%), 2 (12.5%), 3 (18.8%) and 0 (0.0%) in NAC group. These differences were not significant (p=0.460, 0.534, 0.647 and 0.186, respectively). In 60-69 age group, the number of patients with complications, ileus, infections and wound troubles were 40 (44.9%), 15 (16.9%), 18 (20.2%) and 7 (7.9%) in non-NAC group. Those were 17 (41.5%), 6 (14.6%), 10 (24.4%) and 4 (9.8%) in NAC group. These differences were not significant (p=0.710, 0.749, 0.591 and 0.477, respectively). In 70-79 age group, the number of patients with complications, ileus, infections and wound troubles were 53 (43.1%), 16 (13.0%), 30 (24.4%) and 9 (7.3%) in non-NAC group. Those were 15 (30.0%), 2 (4.0%), 11 (22.0%) and 3 (6.0%) in NAC group. These differences were not significant (p=0.110, 0.079, 0.738 and 0.525, respectively). In ≥ 80 age group, the number of patients with complications, ileus, infections and wound troubles were 29 (59.2%), 14 (28.6%), 17 (34.7%) and 4 (8.2%) in non-NAC group. Those were 5 (55.6%), 1 (11.1%), 4 (44.4%) and 3 (33.3%) in NAC group. These differences were not significant (p=0.559, 0.257, 0.419 and 0.067, respectively). CONCLUSIONS NAC in bladder cancer can be performed safety regardless of age. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1041-e1042 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Keishiro Fukumoto More articles by this author Eiji Kikuchi More articles by this author Suguru Shirotake More articles by this author Kyohei Hakozaki More articles by this author Yasumasa Miyazaki More articles by this author Takahiro Maeda More articles by this author Gou Kaneko More articles by this author Shunsuke Yoshimine More articles by this author Nobuhiro Tanaka More articles by this author Kunimitsu Kanai More articles by this author Masafumi Oyama More articles by this author Yosuke Nakajima More articles by this author Tetsuo Momma More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Choline-phosphate cytidylyltransferase-α as a possible predictor of survival and response to cisplatin neoadjuvant chemotherapy in urothelial cancer of the bladder

Objectives: The aim of this study was to test choline-phosphate cytidylyltransferase-α (CCT-α) protein as a biomarker for neoadjuvant cisplatin chemotherapy response in a bladder tumor setting.Materials and methods: A total of 238 patients with T2–T4 bladder cancer enrolled into two prior randomized trials comparing neoadjuvant cisplatin-based chemotherapy (NAC) plus cystectomy with cystectomy only (no-NAC) were used as discovery and validation cohorts. Protein expression was determined with immunohistochemistry and assessed with Histo (H)-scoring.Results: In the discovery cohort, comprising 61 patients, the survival ratio after NAC treatment for CCT-α-negative patients was significantly increased (p = 0.001) while there was no survival advantage in the CCT-α-positive patient group. Similarly, in the validation cohort with 177 patients, NAC treatment improved survival only in the CCT-α-negative group (p = 0.006). Although there was a tendency for a good NAC response with negative CCT-α status, the interaction variable between biomarker and treatment was not significant (p = 0.24). In the cystectomy-only group, patients with positive CCT-α expression had a better survival than CCT-α-negative patients. This prognostic effect of CCT-α expression remained significant after adjusting for well-known prognostic factors in a multivariate analysis. In a pooled database of both patient data sets, multivariate analyses showed CCT-α status as an independent factor for overall survival (p = 0.018; hazard ratio = 1.80, 95% confidence interval 1.11–2.93).Conclusion: CCT-α status was not predictive of outcome of NAC response; however, in the control group with cystectomy only it was found to have prognostic value.

Effects of Neoadjuvant 5-Fluorouracil and Cisplatin Therapy in Patients with Clinical Stage II/III Esophageal Squamous Cell Carcinoma.

Neoadjuvant chemotherapy (NAC) with 5-fluorouracil and cisplatin (FP) has been administered to patients with clinical stage II or III esophageal squamous cell carcinoma (ESCC). We aimed to confirm the clinical efficacy and outcomes of NAC with FP. The clinicopathological features and survival of 152 patients with clinical stage II/III ESCC who received NAC with FP followed by radical esophagectomy were analyzed. The R1/2 resection rate was higher (p=0.06) and the high histological response rate was significantly lower (p=0.05) in those with clinical stage III disease. Invasion depth significantly improved in those with less than cT3 (17/30. 57%), but did not in more invasive cases (35/122, 29%) (p=0.004). T Factor was frequently improved in those with clinical stage II (p=0.08). Five-year survival rates in clinical stage II and III were 73% and 41%, respectively. A multivariate analysis identified clinical stage (p=0.01) and residual tumor (p<0.01) as independent prognostic factors. NAC with FP is effective for patients with clinical stage II ESCC, while its potency may be lower for those with clinical stage III or cT3 disease.

Neoadjuvant Dose Dense MVAC versus Gemcitabine and Cisplatin in Patients with cT3-4aN0M0 Bladder Cancer Treated with Radical Cystectomy

Level I evidence supports the usefulness of neoadjuvant cisplatin based chemotherapy for muscle invasive bladder cancer. Since dose dense MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) has mostly replaced traditional MVAC, we compared pathological response and survival rates in patients with locally advanced bladder cancer who received neoadjuvant chemotherapy with dose dense MVAC vs gemcitabine and cisplatin. We retrospectively reviewed the records of patients with urothelial cancer who received neoadjuvant chemotherapy and underwent cystectomy at a total of 20 contributing institutions from 2000 to 2015. Patients with cT3-4aN0M0 disease were selected for this analysis. The rates of ypT0N0 and ypT1N0 or less were compared between the gemcitabine and cisplatin, and dose dense MVAC regimens. Two multivariable Cox proportional hazards regression models of overall mortality were generated using preoperative and postoperative data. Of the patients who underwent neoadjuvant chemotherapy and radical cystectomy during the study period 319 met our inclusion criteria. A significantly lower rate of ypT0N0 was observed in the gemcitabine and cisplatin arm than in the dose dense MVAC arm (14.6% vs 28.0%, p = 0.005). The rate of ypT1N0 or less was 30.1% for gemcitabine and cisplatin compared to 41.0% for dose dense MVAC (p = 0.07). The mean Kaplan-Meier estimates of overall survival in the gemcitabine and cisplatin, and dose dense MVAC groups were 4.2 and 7.0 years, respectively (p = 0.001). On multivariable cox regression analysis based on preoperative data patients who received gemcitabine and cisplatin were at higher risk for death than patients who received dose dense MVAC (HR 2.07, 95% CI 1.25-3.42, p = 0.003). Lymph node invasion (HR 1.97, 95% CI 1.15-3.36, p = 0.01) and hydronephrosis (HR 2.18, 95% CI 1.43-3.30, p <0.001) were also associated with higher risk of death. In our retrospective cohort of patients with locally advanced bladder cancer dose dense MVAC was associated with higher complete pathological response and improved survival rates compared to gemcitabine and cisplatin. A clinical trial is warranted to validate these hypothesis generating results to test the superiority of neoadjuvant dose dense MVAC in patients with locally advanced bladder cancer.

871P - Identification of genomic features underlying response of muscle-invasive bladder cancer (MIBC) to neoadjuvant sorafenib, gemcitabine, and cisplatin (SGC) in an open-label, single-arm, phase 2 study

871P - Identification of genomic features underlying response of muscle-invasive bladder cancer (MIBC) to neoadjuvant sorafenib, gemcitabine, and cisplatin (SGC) in an open-label, single-arm, phase 2 study

Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial

SummaryBackgroundNeoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen.MethodsOE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 109 cells per L, platelet count at least 100 × 109 platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m2 intravenously on day 1] and fluorouracil [1 g/m2 per day intravenously on days 1–4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] intravenously on day 1, and capecitabine [1250 mg/m2] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4–6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed.FindingsBetween Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6–26·3) with CF and 26·1 months (22·5–29·7) with ECX (hazard ratio 0·90 (95% CI 0·77–1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis.InterpretationFour cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma.FundingCancer Research UK and Medical Research Council Clinical Trials Unit at University College London.

Phase II trial of neoadjuvant chemotherapy followed by chemoradiation in locally advanced cervical cancer

ObjectiveCervical cancer is a global public health challenge. Since 1999, platin based chemoradiation (CRT) is the standard treatment for those patients with locally advanced disease. However, this population still has a dismal prognosis and, alternatives approaches such as adjuvant chemotherapy are controversial, especially because of increased toxicity. Neoadjuvant chemotherapy (NACT) could be an option for more intensive treatment with manageable toxicity. MethodsA phase II, prospective, non-randomized trial was conducted at a reference center in Recife, Brazil. Locally advanced cervical cancer patients (Ib2–IVa) were treated with neoadjuvant cisplatin 35mg/m2 and gemcitabine 1000mg/m2 D1 and D8, for 2cycles. Then, they received CRT (50.4Gy) with weekly cisplatin 40mg/m2 followed by brachytherapy. Response rate (RR) and toxicity were the primary endpoints. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. ResultsBetween Sep/2013 and Oct/2015, 50 patients were initiated on NACT and CRT. RR was 81% at the end of treatment. Hematological and gastrointestinal toxicity were most common. Grade 3/4 toxicity was 20% during NACT and 44% during CRT. Late adverse events were present in 20% of patients. PFS at 1 and 3-years were 73.4% (IC 58.7–83.6) and 53.9% (IC 36.9–68.3), respectively; and, OS at 1 and 3-years were 93.9% (IC 82.4–98.0) and 71.3% (IC 53.3–83.3), respectively. ConclusionIn our hands NACT in locally advanced cervical cancer patients did not show a meaningful improvement in ORR. Nevertheless, we believe it should be further explored in prospective trials.

Abstract 832: In vitro characterization and clinical correlation of BRCAness as a personalized biomarker for radiosensitization with homologous recombination-directed therapies

Abstract Introduction: BRCA1 and BRCA2 are involved in double-strand break (DSBs) repair via homologous recombination (HR). Clinically, BRCA1/2 mutant tumors show sensitivity to cisplatin, a cross-linking agent, but only mild sensitivity to ionizing radiation (IR). The addition of cisplatin to IR has been one of the largest advances in improving patient outcomes with radiotherapy in the past 50 years. Recently, BRCAness has been described wherein sporadic deficits in HR are observed in the absence of germline BRCA1/2 mutations. We hypothesize that BRCAness tumors also exhibit sensitivity to the combination of cisplatin + IR, and are a significant driver of the observed clinical benefit of combination therapy. Methods: Sensitivity to cisplatin + IR was examined in vitro and correlated with clinical data. Functional HR deficiency (HRD) was assessed in isogenic BRCA1 (H1299; lung) and BRCA2 (DLD1; colon) knockout pairs using 3 assays: the Rad51 foci assay, a flow-based DRGFP assay (DSB reporter assay) and clonogenic survival assays (CSA) with cisplatin +/- IR. Cancer Cell Line Encyclopedia (CCLE) data was used to identify breast cancer cell lines with sporadic, non-BRCA1/2 mutations. Functional HRD in 4 breast cancer cell lines was assessed with the same 3 assays used for the BRCA1/2 isogenic pairs. We also examined 14 triple-negative breast cancer (TNBC) patients treated with neoadjuvant cisplatin + IR. Nine of the 14 had available tissue, which was stained for Rad51 foci. Results: Functional HRD is observed in the BRCA1/2 isogenic pairs, as demonstrated by the Rad51 foci and DRGFP assay results. Increased sensitivity to cisplatin + IR is observed in the BRCA1/2 knockout lines in CSA results compared to isogenic controls. A genomic scar score, LST (large scale transition), was generated for each line based on CCLE data, with higher LST scores suggesting increased genomic instability and therefore HRD. Four cell lines were selected for further study. Similar functional HRD and cisplatin + IR sensitivity is observed in 2 breast cancer cell lines with high LST scores, as compared to 2 with low LST scores. Epistasis was observed upon siBRCA1 knockdown in the 2 cell lines with high LST scores. Half of the 14 TNBC patients demonstrated pathological complete response to neoadjuvant cisplatin + IR. Nine of the 14 patients had available tissue, of which 4 demonstrated functional HRD by the Rad51 foci assay. Conclusions: Multiple in vitro assays suggest that HRD tumors are much more sensitive to the widely used combination of cisplatin + IR as compared with HR proficient tumors. Data from our small cohort of triple-negative breast cancer patients appear concordant with these findings. Reliable determination of “BRCAness” tumors should identify a subpopulation of non-germline BRCA1/2-mutated breast cancer patients who may benefit from targeted therapy with cisplatin + IR. Citation Format: Jennifer Ma, Andrew C. Bell, Jeremy Setton, Justin Haseltine, Marcher Thompson, Rachna Shah, Benjamin H. Lok, Robert Delsite, Rebecca Aft, Nadeem Riaz, Simon Powell. In vitro characterization and clinical correlation of BRCAness as a personalized biomarker for radiosensitization with homologous recombination-directed therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 832. doi:10.1158/1538-7445.AM2017-832

Molecular markers of DNA damage and repair in cervical cancer patients treated with cisplatin neoadjuvant chemotherapy: an exploratory study.

Neoadjuvant (or induction) chemotherapy can be used for cervical cancer patients with locally advanced disease; this treatment is followed by radical surgery and/or radiation therapy. Cisplatin is considered to be the most active platinum agent drug for this cancer, with a response rate of 20%. In order to understand how the cisplatin treatment affects the stress response, in this work, we performed an exploratory study to analyze a number of stress proteins before and after cisplatin neoadjuvant chemotherapy. The study involved 14 patients; the pre- and post-chemotherapy paired biopsies were examined by hematoxylin and eosin staining and by immunohistochemistry. The proteins evaluated were p53, P16/INK4A, MSH2, nuclear protein transcriptional regulator 1 (NUPR1), and HSPB1 (total: HSPB1/t and phosphorylated: HSPB1/p). These proteins were selected because there is previous evidence of their relationship with drug resistance. The formation of platinum-DNA adducts was also studied. There was a great variation in the expression levels of the mentioned proteins in the pre-chemotherapy biopsies. After chemotherapy, p53 was not significantly affected by cisplatin, as well as P16/INK4A and MSH2 while nuclear NUPR1 content tended to decrease (p=0.056). Cytoplasmic HSPB1/t expression levels decreased significantly following cisplatin therapy while nuclear HSPB1/t and HSPB1/p tended to increase. Since the most significant changes following chemotherapy appeared in the HSPB1 expression levels, the changes were confirmed by Western blot. The platinum-DNA adducts were observed in HeLa cell in apoptosis; however, in the tumor samples, the platinum-DNA adducts were observed in morphologically healthy tumor cells; these cells displayed nuclear HSPB1/p. Further mechanistic studies should be performed to reveal how HSPB1/p is related with drug resistance. When the correlations of the markers with the response to neoadjuvant chemotherapy were examined, only high pre-chemotherapy levels of cytoplasmic HSPB1/p correlated with a poor clinical and pathological response to neoadjuvant cisplatin chemotherapy (p=0.056) suggesting that this marker could be useful opening its study in a larger number of cases.

Treatment of high-grade osteoblastic osteosarcoma of the humerus in a 5-year-old boy with cystic fibrosis: A case report.

Antineoplastic treatment of osteoblastic osteosarcoma in a patient with cystic fibrosis (CF) may harbor a high risk of neutropenia-associated complications, and, to the best of our knowledge, has not been previously reported. Diagnosis of CF was confirmed in a 6-week-old boy following pathological newborn screening. The patient had a stable course of CF under standardized continuous therapy. At the age of 5 years, osteosarcoma of the left proximal humerus was diagnosed without evidence of metastases. Neoadjuvant chemotherapy, including doxorubicin, cisplatin and methotrexate, was administered for 10 weeks. The patient tolerated this therapy relatively well, with a continuous antibiotic prophylaxis of cefuroxime without experiencing major complications; in particular, no pulmonary exacerbations were observed as a consequence of immunosuppression or mucosal toxicity. The tumor responded well, and amputation of the limb was avoided via the use of 'clavicle per humerus' osteosynthesis. Postoperatively, compartmental syndrome occurred, requiring management by fasciotomy. Adjuvant chemotherapy was applied thereafter again, without major toxicity that would have required dose reduction. Under intensive physiotherapy, the mobility of the left arm and hand was deemed to be satisfactory. The coincidence of CF with osteosarcoma is extremely rare, and, to the best of our knowledge, has not been previously described. Under antibiotic prophylaxis, antineoplastic treatment was possible without major complications during neutropenia.

Standard of care for MIBC is becoming more standard.

e16011 Background: Despite consensus guideline recommendations, the management of muscle invasive bladder cancer (MIBC) varies dependent on institution setting. The risk of recurrence of localized bladder cancer after cystectomy is substantial and associated with stage. The current standard of care for possibly T2 and certainly T3-T4 MIBC is neoadjuvant cisplatin (NAC) based chemotherapy followed by cystectomy. As recent as 2011, only 12% of patients in this category actually received NAC (Feifer et al. 2011). Similar statistics have been confirmed in the US and Canada. Given there is a 13% reduction in risk of death with use of NAC, the adherence to this recommendation needs to improve. We hypothesize that in a multispecialty community practice where barriers to care are reduced that the percentage of eligible patients receiving NAC is significantly higher than previously reported. Methods: After IRB exemption obtained, patients from 2012-2015 with MIBC who underwent cystectomy were examined. Data collection included age, sex, date of consultation, dates and type of chemotherapy received, eGFR, date of surgery and surgical pathology report staging. Data were analyzed using Kolmogorov-Smirnov, Shapiro-Wilk, Mann-Whittney and Kruskal-Wallis statistical tests. Results: The average patient age was 69 years old with a male predominance. Approximately 54% of patients received neoadjuvant chemotherapy; however, three of those patients did not receive the recommended cisplatin based regimen. Fifty percent of patients received NAC and 57% of cisplatin eligible (age &lt; 80, eGFR &gt; 30) patients received NAC. The average time to cystectomy was 171 days among those receiving NAC, with a decrease in time to cystectomy correlating with age. Conclusions: In a community group practice, adherence to standard of care recommendations for higher stage MIBC patients to receive NAC are significantly higher than recently reported values, 50% vs 12%, respectfully. This was achieved while maintaining acceptable time to cystectomy. This supports our hypothesis that when barriers to care are decreased in a community group practice, high quality standards of care can be effectively delivered. In the future, 5 year overall survival will also be important to evaluate in this population.

A phase I clinical trial of AZD1775 in combination with neoadjuvant weekly cisplatin and docetaxel in borderline resectable head and neck squamous cell carcinoma (HNSCC).

6034 Background: The WEE1 tyrosine kinase regulates G2/M transition and maintains genomic stability. In TP53-deficient tumors (via mutation or HPV inactivation), inhibiting WEE1 with AZD1775 can lead to unrestrained mitosis and cell death. We conducted a Phase I clinical trial of AZD1775 in combination with chemotherapy to define the toxicity profile, establish the maximal tolerated dose (MTD) and assess preliminary efficacy in borderline resectable HNSCC. Methods: Stage III/IVB HNSCC deemed borderline resectable by a multidisciplinary team were enrolled in a phase 1, 3 + 3 design to evaluate escalating doses of AZD1775 starting at 125 mg PO BID x 2.5 days alone as lead-in and in combination with cisplatin (25mg/m2) and docetaxel (35 mg/m2) for three additional weeks. Tumors were sequenced with UWOncoPlex (262 cancer genes); HPV status assessed via p16 IHC; toxicities graded with CTCAE v. 4.04; responses measured via RECIST 1.1 and through pathologic assessment when available. Trial is open but primary endpoints were met. Results: Eleven patients were screened; 10 enrolled and were evaluable for toxicities. The most common Grade ≥ 2 toxicities were diarrhea (4), fatigue (4), neutropenia (3) and nausea (3). The drug-limiting toxicity was Grade 3 diarrhea (2). The MTD was established at 150mg PO BID x 2.5 days, alone and in combination with neoadjuvant cisplatin and docetaxel. Two patients were HPV+/TP53wt, 1 was HPV+/ TP53 mut; 6 were TP53mut/HPV-; 1 was TP53 wt/HPV-. Seven out 10 patients had a response. Two patients dropped out after the first week with AZD1775, one due to an allergic reaction to docetaxel and another due to non-compliance. Eight completed neoadjuvant therapy and 7 of those converted to surgery: 2 had pathologic CRs (both HPV+/TP53wt); 4 had PR (all TP53 mutants); 1 (TP53wt/HPV-) had a PR by RECIST, but SD by pathology and 1 had PD. Conclusions: AZD1775 is safe and tolerable in combination with neoadjuvant cisplatin and docetaxel. Results show this combination to have promising anti-tumor efficacy in borderline resectable HNSCC with TP53 deficiency, and merits further investigation with the established MTD as the recommended Phase II dose. Clinical trial information: NCT02508246.

Molecular features underlying response to neoadjuvant gemcitabine, cisplatin, and sorafenib (S-GC) in muscle-invasive urothelial bladder carcinoma (MIBC): Insights for trials of new agents combined with chemotherapy in the field.

e16018 Background: S-GC neoadjuvant chemotherapy (NACT) was active in a phase 2 trial in MIBC, showing a response rate (downstaging to pT &lt; 2) of 54.3% in 46 pts within a single-arm, phase 2 trial ( Necchi et al, GU ASCO 2017). The addition of S to GC may help investigators unravelling key molecular features underlying response in MIBC. Methods: Analyses were made on pre- and post-treatment TURB and cystectomy (Cy) specimens (10µm sections) and matched germline DNA of 29/46 pts. Analyses included measurements of ERCC1 (by immunohistochemistry, IHC) on TURB specimens, baseline circulating VEGF levels (ELISA), copy number variations (CNV, Affymetrix), and next generation sequencing (NGS, custom gene panels through the Ion AmpliSeq Library Kit2.0™ and the Ion Torrent Personal Genome Machine™ platform). Results: We analyzed TURB samples from 15 responders (R) and 4 non-R (NR). An additional 10 Cy samples were used for NR. Baseline VEGF levels were not associated with PFS or OS on univariable analyses (p = 0.943 and p = 0.669, respectively). Differences in R vs. NR pts were found according to CNVs and NGS. CN gains on regions of chromosome (chr) 18 and 20 and loss in chr 5 were found in 56-60% of R and in none of the NR. Gains on regions of chr 3 and losses in chr 1 and 20 were more frequent in the NR ( &gt; 50%) vs. R ( &lt; 20%). The median number of somatic mutations (mut) per sample was 3 (range, 0-19). Missense mut in DNA-repair genes ( POLK; FANCM; PRKDC; BLM; MSH2; MSH6; RAD50) were found in 63.6% R vs 16.7% NR, in RAS-RAF pathway genes ( CDKN2A; RAC1; KRAS; NF1) in 45.4% vs 7.1%, in chromatin-remodelling genes ( ARID1A; ARID2; KDM5C; SMARCA4; ATRX; KMT2C; DAXX; SETD2) in 54.5% vs 16.7%, and in HER-family genes in R only (36.4%). ERCC1 IHC expression was found in 55.6% R vs 93.3% NR (p = 0.047). Conclusions: We identified distinct molecular features of R vs NR to S-GC in MIBC. These features may be linked to a potentially-additive effect of S and CT. The identification of the targets of CNVs will further elucidate the underlying biology. These results may help developing personalized medicine in MIBC with new more potent targeted agents with CT. Clinical trial information: NCT01222676.

174 - Neoadjuvant sorafenib, gemcitabine, and cisplatin (SGC) for muscle-invasive urothelial bladder cancer (MIUBC): Final results and translational findings of an open-label, single-arm, phase 2 study

174 - Neoadjuvant sorafenib, gemcitabine, and cisplatin (SGC) for muscle-invasive urothelial bladder cancer (MIUBC): Final results and translational findings of an open-label, single-arm, phase 2 study

Neoadjuvant sorafenib, gemcitabine, and cisplatin (SGC) for muscle-invasive urothelial bladder cancer (MIUBC): Final results and translational findings of an open-label, single-arm, phase II study.

345 Background: Despite cisplatin-based chemotherapy (CT) is recommended in MIUBC, an unmet need is to identify new drugs or combinations to improve the outcomes. SGC combination was evaluated in an open-label, single-arm, phase 2 trial (NCT01222676). Methods: After TURB, pts with T2-T4a N0 MIUBC received 4 cycles of cisplatin 70 mg/m2 d1, gemcitabine 1000 mg/m2d1 and 8, q3 wks. Sorafenib 400 mg q12h was administered daily from day 1 until radical cystectomy. In a Simon’s 2-stage design, the primary endpoint was pathologic complete responses (pT0). Residual carcinoma in situ was considered pT0. ITT analysis was applied. Statistical hypothesis assumed H0: ≤0.20 and H1: ≥0.40 (α and β of 5% and 10%). ERCC1 immunohistochemistry (IHC) and next-generation sequencing (NGS) of TURB tissue, and measurement of baseline circulating VEGF levels, were planned. Results: From 04/2011-06/2016, 45 pts were enrolled. 28 pts (62.2%) had macroscopical residual disease after TURB, 17 (37.8%) presented with clinical stage T3-4. pT0 was obtained in 19 pts (42.2%, 95%CI: 27.6-57.9); pT≤1 in 24 (53.3%, 95%CI: 37.9-68.3). After median follow-up of 35 months, median PFS was not reached (IQR: 29.4-NE), like median OS (IQR: 30.3-NE). Pathological response (pT0 vs pT≤1 vs other) predicted for both PFS (p=0.015) and OS (p=0.046). Hematologic (hem) G3-4 adverse events (AE): platelet 28.9%, neutrophils 15.6%, Hb (4.4%). Extra-hem AEs were seen in 9 pts (20%). 24 (53.3%) pts needed S temporary interruption (5 cases discontinuation). Tumor samples were available from 23 pts for ERCC1-IHC, 24 for NGS: ERCC1 IHC expression was associated with non response (pT≥2, p=0.033). ERBB2/ERBB3 mutations were found only in responders (pT≤1, 20%). PIK3CA/AKTmutations (missense, and newly-identified mutations) were more frequent in pT≥2 pts (35.7% vs 20%). Baseline VEGF levels did not predict for PFS/OS. NGS of the remaining pts of the trial is ongoing. Conclusions: SGC combination was active and effective in MIUBC. Translational analyses are providing information to develop combination of CT with new more potent and selective TKIs, possibly in more selected pts. Clinical trial information: NCT01222676.