Initial Chemoradiotherapy Research Articles

The Evolving Role of Tumor Treating Fields in Managing Glioblastoma: Guide for Oncologists.

Glioblastoma (GBM) is a devastating brain tumor with poor prognosis despite advances in surgery, radiation, and chemotherapy. Survival of patients with glioblastoma remains poor, with only 1 in 4 patients alive at 2 years, and a 5-year survival rate of about 5%. Recurrence is nearly universal and, after recurrence, prognosis is poor with very short progression-free survival and overall survival (OS). Various salvage chemotherapy strategies have been applied with limited success. Tumor Treating Fields (TTFields) are a novel treatment modality approved for treatment of either newly diagnosed or recurrent GBM. TTFields therapy involves a medical device and transducer arrays to provide targeted delivery of low intensity, intermediate frequency, alternating electric fields to produce antimitotic effects selective for rapidly dividing tumor cells with limited toxicity. In the phase 3 EF-14 trial, TTFields plus temozolomide provided significantly longer progression-free survival and OS compared with temozolomide alone in patients with newly diagnosed GBM after initial chemoradiotherapy. The addition of TTFields to standard therapy improved median OS from 15.6 to 20.5 months (P=0.04). In the phase 3 EF-11 trial, for recurrent GBM, TTFields provided comparable efficacy as investigator’s choice systemic therapy, with improved patient-reported quality of life and a lower incidence of serious adverse events. Primary toxicity associated with TTFields is skin irritation generally managed with array relocation and topical treatments including antibiotics and steroids. TTFields therapy has demonstrated proven efficacy in management of GBM, including improvement in OS for patients with newly diagnosed GBM, and is under current investigation in other brain and extracranial tumors.

Primary malignant lymphoma of the talus: A case report and review of the literature.

Malignant lymphoma commonly occurs in adults, with a peak incidence between the seventh and ninth decades of life. Although malignant lymphoma usually occurs in the lymph nodes, it rarely occurs primarily in the bone. We herein describe an extremely rare case of primary malignant lymphoma of the talus in a 74-year-old man. Although plain radiographs showed no abnormality, gadolinium-enhanced magnetic resonance imaging (MRI) revealed a well-circumscribed intra- and extraosseous tumor of the talus. 18F-fluorodeoxyglucose (FDG) positron emission tomography/MRI revealed a marked increase of FDG uptake in the right ankle and the right inguinal lymph nodes. As the tumor was diagnosed as diffuse large B-cell lymphoma by core needle biopsy, combination therapy with chemo- and radiotherapy was initiated. The patient achieved complete remission, with no sign of recurrence at 8 months after initial chemoradiotherapy. Since primary malignant lymphoma of the bone is chemo- and radiosensitive and has a good prognosis, accurate staging by radiological investigation as well as correct pathological diagnosis by biopsy are required for optimal treatment.

Which side is better? The impact of primary tumor side in early stage colorectal cancer (CRC).

e15106 Background: Multiple studies have indicated the prognostic and potential predictive significance of primary tumor side in metastatic CRC. To date, the few studies examining its impact in early stage disease have either combined data across multiple stages or restricted analysis to overall survival (OS) data. A by stage analysis of the impact of tumor side on recurrence risk is critical if it is to impact adjuvant therapy decisions. Methods: We examined data from a multi-site Australian registry of consecutive patients diagnosed from 2003-2016. Tumors at and distal to the splenic flexure, including the rectum, were considered a left primary (LP). Rectal patients treated with initial chemoradiation were excluded. Clinico-pathologic and outcome data were examined. Data analysis was provided by the healthcare group at IBM Research Australia. Results: A total of 6123 patients were identified, of which 1046 (17.1%) had initial stage I, 1892 (30.9%) had stage II, 1708 (27.9%) had stage III, and 1477 (24.1%) had stage IV disease. Most patients were male (55.2%), and had a LP (n = 3818, 62.4%). Median age at diagnosis was 68.8 years, was higher in patients with a right primary (RP) (71.6 versus 67.0 years for LP, p < 0.001), with more females in the RP group (51.1% vs 41.0% for LP, p < 0.001). The proportion of RP varied by stage, highest in stage II (44.9%), lowest in stage IV (31.5%). For all stage IV disease, including metachronous cases, OS was worse with a RP (HR 1.32, 95% CI 1.14-1.53). For early stage cases, distant recurrence free survival (DRFS) was similar for RP vs LP for stage I (HR 0.63, 95% CI 0.32-1.23), better for stage II RP (HR 0.72, 95% CI 0.55-0.95) and worse for stage III RP disease (HR 1.22, 1.01-1.48). OS did not differ for RP vs LP for stage I or II disease, but was worse for stage III disease with a RP (HR 1.39, 95% CI 1.13-1.70). Furthermore, post recurrence survival was poorer in stage III RP disease (HR 1.61, 95% CI 1.33-1.96). Conclusions: Primary tumor side has potential as an important prognostic marker in early stage CRC. Our novel finding of a variable impact by stage indicate that an assessment of cohorts where recurrence data is available is critical to fully understanding the implications of tumor side for adjuvant therapy decision making.

The outcome of responders to initial chemoradiotherapy or chemotherapy for locally advanced pancreatic cancer

The outcome of responders to initial chemoradiotherapy or chemotherapy for locally advanced pancreatic cancer

Abstract 611: A complex 3D model of glioblastoma for patient-specific drug response profiling

Abstract Approximately 70,000 new cases of brain tumors will be diagnosed this year with glioblastoma (GBM) accounting for about 17% of those cases. Unfortunately the median survival for patients with GBM is only 14.6 months due to the complexity of the tumor, the pattern of diffuse spread within the brain, and the lack of effective therapeutic options. Complex in vitro tumor models developed in 3D better mimic in vivo biology, and, when utilizing patient-derived cells, may offer robust platforms for new drug development and patient-specific drug response profiling. We have previously shown this to be true with both breast and ovarian cancer and we have adopted this approach to modelling GBM ex vivo. We hypothesize that primary derived GBM tissues and stem cells cultured in complex 3D microenvironments can recapitulate the intra-tumor heterogeneity and drug resistance similar to that found in the clinical. To this end, we have developed 3D models of GBM that incorporate tumor cells, endothelial cells, and macrophages within a complex extracellular matrix and cultured them for up to 2 weeks under perfusion flow. We have created these models using both cell lines and primary patient cells and these 3D tissues have been analyzed for changes in viability (PrestoBlue and PicoGreen), marker expression (flow cytometry, Luminex, and protein arrays), macrophage differentiation and invasion (flow cytometry, multiphoton microscopy, and IHC), and methylation patterns (ChIP on chip arrays and methylation specific PCR). Initial optimization work using cell lines has revealed that culturing with endothelial cells and/or macrophages has an effect upon proliferation dependent upon the differentiation state of the macrophages. Additionally, co-culture conditions affect protein secretion and phosphorylation along with patterns of gene methylation. We have also examined how changes in the tumor microenvironment affect these different metrics by examining the role of hypoxic growth conditions. Work using patient cells isolated from primary glioblastoma has focused upon drug response dependent upon the tumor microenvironment and the presence of cancer stem cells utilizing a neurosphere generation assay. We have demonstrated temozolamide resistance in tumors with early relapse after initial chemo-radiation, and sensitivity to EGFR inhibitor afatanib in tumors with EGFR amplication, suggesting clinical and molecular correlation or our ex vivo 3D drug response profiling using patient derived GBM models. Taken together, our data support the further development and use of complex, 3D co-cultures to better mimic GBM in a patient-specific manner. These models are currently being considered for preclinical assessment of novel therapies, including chimeric antigen receptor T cells, and may be a useful adjunct in precision medicine applications to improve patient outcomes. Citation Format: Tessa DesRochers, Lillia Holmes, Lauren O’Donnell, Qi Guo, David Schammel, Jeff Edenfield, Charles C. Kanos, Hal E. Crosswell. A complex 3D model of glioblastoma for patient-specific drug response profiling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 611.

Anal Adenocarcinoma: Outcomes in an Uncommon Malignancy

Adenocarcinoma is an uncommon malignancy of the anal canal. Although it is recognized as an aggressive disease, optimal management and long-term outcomes are not well established. Patients diagnosed with anal adenocarcinoma were identified from a cancer database. Their charts were reviewed for patient and disease characteristics, management, and outcomes. Eighteen patient charts from 1997 to 2012 were reviewed. Nine patients presented with stage II disease, five with stage III, three with stage IV, and one was inadequately staged before chemoradiation. One patient refused treatment, one patient went straight to abdominoperineal resection, 13 patients underwent initial chemoradiation therapy, and three underwent palliative chemotherapy. Of the 13 patients who received neoadjuvant therapy, eight underwent subsequent radical resection; three progressed during neoadjuvant and became unresectable, one had complete pathologic response and was observed, and one did not complete neoadjuvant and was lost to follow-up. Two patients with stage II disease were disease free over eight years, and one was disease free after 26 months; four patients had persistent or recurrent local disease, and 10 developed metastatic disease. Seven patients died with disease at a median 16 months, and the other seven were alive with disease at a median follow-up of 10 months. Patients with anal adenocarcinoma present at advanced stages, and cure is rare. Although chemoradiation followed by abdominoperineal resection is the most common management strategy, the potential for curative resection and long-term disease free survival is minimal, regardless of stage at presentation.

Risk-Adapted Adjuvant Chemotherapy After Concomitant Fluoropyrimidine–Radiotherapy Neoadjuvant Treatment for Patients With Resectable CT3-4 or N+ Rectal Cancer: Five-Year Disease-Free Survival Results of a Single-Center Series

BackgroundProviding adjuvant chemotherapy in locally advanced rectal cancer after neoadjuvant chemoradiation is currently a matter of debate. Recommendations from clinical guidelines range from offering no treatment to oxaliplatin-based combinations. We present a risk-adapted approach based on the response to initial chemoradiation as the strongest prognostic factor for disease-free survival (DFS). Patients and MethodsOne hundred one patients were treated at a single institution with preoperative long-course radiotherapy plus concurrent fluoropyrimidines. Patients with disease downstaged to pT0-2N0 received adjuvant fluoropyrimidines alone, while the remaining received an oxaliplatin-based combination. The primary study end point was 5-year DFS. ResultsOverall, the disease of 54 patients was downstaged to pT0-2N0 (53.5%), while that of 47 patients was staged as pT3-4 or N+ (46.5%) after surgery. In the intention-to-treat analysis, 5-year DFS for patients in the good-prognosis group (downstaging to pT0-2 N0) and for those with poor prognosis (pT3-4 or N+) were 79.4% and 66.3%, respectively (hazard ratio, 0.489; P = .043). Downstaging and pN+ were independent prognostic factors for DFS. ConclusionA risk-adapted adjuvant therapy strategy based on pathologic stage after neoadjuvant chemoradiation is feasible and achieves high rates of 5-year DFS. Patients with good prognostic factors can be treated with adjuvant fluoropyrimidines alone, thus permitting the avoidance of oxaliplatin-derived toxicities.

Early surgery for failure after chemoradiation in operable thoracic oesophageal cancer. Analysis of the non-randomised patients in FFCD 9102 phase III trial: Chemoradiation followed by surgery versus chemoradiation alone

BackgroundTwo randomised trials concerning thoracic oesophageal cancer concluded that for squamous cell carcinoma, chemoradiation alone leads to the same overall survival (OS) as chemoradiation followed by surgery. One of these trials, FFCD 9102, randomised only fit, compliant and operable responders to induction chemoradiation between continuation of chemoradiation and surgery. In the present analysis, the outcome in the patients not eligible for randomisation was calculated to determine if attempt of surgery should be recommended. MethodsEligible patients had operable T3-N0/N1-M0 thoracic oesophageal cancer. After initial chemoradiation, patients with no clinical response, or with contraindication to follow any attributed treatment, were not randomised. OS was studied first in the whole population of not randomised patients, and then specifically in clinical non-responders. The impact of surgery on OS was studied in these two populations. FindingsOf the 451 registered patients in the trial, 192 were not randomised. Among them, 111 were clinical non-responders. Median OS was significantly shorter for non-randomised patients (11.5months) than for randomised patients (18.9months; p=0.0024). However, for the 112 non-randomised patients who underwent surgery, median OS was not different from that in randomised patients: 17.3 versus 18.9months (p=0.58).Concerning clinical non-responders, median OS was longer for those who underwent surgery compared to non-operated patients: 17.0 versus 5.5months (hazard ratio (HR)=0.39 [0.25–0.61]; p<0.0001), and again was not different from that in responding, randomised patients (p=0.40). InterpretationIn patients with locally advanced thoracic oesophageal cancer, overall survival did not differ between responders to induction chemoradiation and patients having surgery after clinical failure of chemoradiation. Surgery should therefore be considered in those patients who are still operable.

Abstract IA27: Clinical trials in locally advanced pancreatic cancer (LAPC)

Abstract The role of radiation in locally advanced unresectable pancreatic cancer (LAPC) is more controversial now that ever. Perhaps the greatest impact on clinical practice in LAPC has come from the LAP07 trial, which evaluated the addition of erlotinib to gemcitabine and the role of consolitative chemoradiation. Results from the trial were presented at ASCO last year and showed no benefit to the use of consolidative chemoradiation after 4 months of gemcitabine based chemotherapy compared to 6 months of chemotherapy alone. Issues regarding the off protocol use of chemoradiation, compliance in the chemoradiation arm, and XRT quality assurance require further clarity. The publication of the full manuscript from the trial is expected this year. Two prior phase III trials comparing initial chemotherapy to initial chemoradiation have reported conflicting results. The Fédération Francophone de Cancérologie Digestive and Société Française de Radiothérapie Oncologique (FFCD-SFRO) showed superior survival of gemcitabine alone to a poorly tolerated experimental chemoradiation regimen (60 Gy to large fields with cisplatin and 5FU) that had not been tested in a phase I or II trial. The only other recent trial to compare initial chemotherapy to chemoradiation was conducted by the Eastern Cooperative Oncology Group (ECOG 4201). This trial compared gemcitabine-based chemoradiation followed by weekly gemcitabine to gemcitabine alone. A median survival benefit was seen in the chemoradiation arm. This benefit came at the cost of increased gastrointestinal toxicity. A number of U. S. cooperative group trials evaluating gemcitabine-based chemotherapy in advanced pancreatic cancer have included patients with locally advanced disease without planned radiotherapy. Median survival durations of between 9.1 and 9.9 months have been achieved in these subsets of patients, compared to between 12 and 14.3 months in the LAP07 and FFCD-SFRO trials. The reason for this difference is unclear. The rationale for the further study of the use of radiation therapy in locally advanced unresectable pancreatic cancer (LAPC) is based on clinical and autopsy data which indicate that 30% or more of patients die with disease confined to the primary site. Local tumor control rates at one year are commonly reported to be greater than 90%, but have fallen to below 50% at 2 years in studies that have reported longer median OS. As median survival durations improve in patients with locally advanced pancreatic cancer, local progression of disease will probably be revealed to more commonly limit long-term survival. RTOG 1201 is a randomized phase II trial that will address this limitation. It compares gemcitabine and abraxane alone to gemcitabine and abraxane followed by standard or high dose radiation using IMRT. It will also address the role of the use SMAD4 expression to predict the pattern of disease progression. Citation Format: Christopher H. Crane. Clinical trials in locally advanced pancreatic cancer (LAPC). [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA27.

Upfront treatment with temozolomide and bevacizumab (TEMOBEVA) in patients with bulky, multifocal glioblastoma and/or with severe neurological impairmen.

e13037 Background: Optimal treatment of patients with bulky or multifocal glioblastoma, or with severe neurological impairment is not well established. We evaluated here the impact of upfront Temozolomide (TMZ) and bevacizumab (BEV) in such patients. Methods: This retrospective study included 43 patients from 3 French centres between December 2010 and December 2014. Patients were considered not eligible for surgery or initial chemoradiation either due to tumor volume precluding an upfront chemoradiotherapy with TMZ, or due to multifocality or severe neurological impairment. Initial combination of TMZ (150 to 200 mg/m2/d, 5d every 28d) plus BEV (10mg/kg every 14d) was delivered. Responding patients received radiotherapy (60 Gy in 30 fractions) plus concomitant TMZ (75mg/m2/d), with or without BEV (10mg/kg every 14d). Results: Forty-three patients were analyzed (median age 60 years, median Karnofsky Performance Status (KPS) 70). Thirty-two patients (74%) were classified in the RTOG RPA group V-VI. Median nu...

A comparison of survival with chemoradiation therapy alone versus surgery and post-esophagectomy chemoradiation in patients with esophageal carcinoma

Background: Esophageal cancer is usually incurable. Aggressive treatments involving multimodality therapies have been offered to improve overall survival rates. It seems that various therapeutic approaches can have a different outcome and survival. The aim of our study was to compare survival with chemoradiation therapy (CRT) alone versus surgery and post-esophagectomy chemoradiation therapy (CRT-S) in patients with esophageal carcinoma. Methods: This historical cohort study assigned 226 patients with stage I to III esophageal cancer who referred to Radio-oncology clinic of Razi hospital from 2005-2011 for oncology treatment. Patients were categorized into two groups. One group treated by chemoradiation therapy (CRT) alone and other group treated with surgery and post-esophagectomy chemoradiation. Overall survival of two groups was compared. For statistical analysis SPSS was used and the comparison of groups was performed with Kaplan-Meier analysis and Log-rank test. Results: Of 266 patients with stage I to III esophageal cancer, 222 patients were in the CRT group and 44 patients were in the CRT-S group. 22 patients had stage I, 82 had stage II and 118 had stage III. Median survival was 17 month for the CRT group and 18 month for the CRT-S group. There was no significant difference in survival rate between chemoradiation therapy alone (CRT) and post-esophagectomy chemoradiation therapy (CRT-S) (P>0.005). Conclusion: Based on these data, we concluded that patients with tumors, especially of squamous cell carcinoma, that respond to initial chemoradiotherapy did not derive any survival benefit from subsequent surgery and three-month mortality was significantly higher in the surgery group. Surgery imposes a major emotional trauma and an excessive and unnecessary cost on the patient and the community health system. We conclude that it is better to use CRT for patients with non-advanced esophageal cancer.

O10.09 * REDUCTION IN NEUTROPHIL-LYMPHOCYTE RATIO DURING INITIAL CONCURRENT CHEMORADIOTHERAPY IS PROGNOSTIC FOR SURVIVAL OF GLIOBLASTOMA PATIENTS

INTRODUCTION: Elevated baseline neutrophil-lymphocyte ratio (NLR) has been associated with poorer outcome in multiple tumour sites. In the context of glioblastoma (GBM), elevated NLR prior to any initial therapy, including surgery or corticosteroids, or prior to second surgery for recurrent disease predicted worse outcome. The aim of this retrospective cohort study was to assess if change in NLR during initial focal radiotherapy (RT) and concurrent temozolomide (TMZ) predicted outcome in newly diagnosed GBM patients. METHODS: A retrospective chart review was performed for patients treated concurrently with TMZ and RT, at our tertiary referral centre between Jan 2004 and Sept 2010, for histologically confirmed GBM. Age, baseline ECOG performance status (ECOG-PS) and extent of surgery were recorded. Baseline NLR, change in NLR, and time-weighted mean dexamethasone dose (TWMdex) were collected between 2 weeks prior to commencing RT and 10 weeks following the start of RT. Overall survival (OS) was calculated using Kaplan Meier method. Univariate (UVA) and multivariable (MVA) analyses using cox proportional hazard models evaluated variables associated with OS, accounting for colinearity of variables. RESULTS: There were 394 patients who met eligibility and were included in the final analysis. Median age was 54 (range 18-73). With median follow up of 15.2 months (range 1.6-134.6), OS was 66.4% (CI 61.4-70.7) and 31.1% (CI 26.5-35.8) at 1 and 2 years respectively. Median baseline dexamethasone dose was 8 mg (0-30 mg) and median TWMdex dose was 4.94 mg (0.0 -27.4 mg). On UVA, older age (HR 1.034, p 2 (HR 1.076, p < 0.001) were associated with shorter survival whereas baseline NLR below the median of 7.5 (HR 0.628, p < 0.0001) and decrease in NLR during treatment (HR 0.644, p < 0.0001) were associated with better survival. On MVA, decrease in NLR remained significantly prognostic for OS (HR 0.763, p = 0.02; CI 0.603 - 0.964) in addition to age (HR 1.032, p < 0.001; CI 1.018-1.045), TWMdex (HR 1.039, p = 0.002; CI 1.014-1.065) and ECOG-PS (HR 0.593, p = 0.008; CI 0.430-0.873). Although, baseline NLR was no longer statistically significant (HR 0.814, p = 0.09; CI 0.641 - 1.032), patients with low baseline NLR and further reduction in NLR during treatment had significantly longer survival (p < 0.0001). The association between change in NLR and change in dexamethasone dose over time was weak (r = 0.22). CONCLUSION: In patients with newly diagnosed glioblastoma, any reduction in neutrophil-lymphocyte ratio during initial concurrent chemoradiotherapy was an independent prognostic factor for longer survival, accounting for other prognostic factors including dexamethasone dose. Patients with low baseline NLR and further reduction in NLR during treatment had the best prognosis.

Spin-echo echo-planar perfusion prior to chemoradiation is a strong independent predictor of progression-free and overall survival in newly diagnosed glioblastoma.

Spin-echo echo planar (EP) perfusion weighted imaging (SE-PWI) has been demonstrated to be more selective than gradient-echo EP PWI for blood volume in microvessels the size of glioma neocapillaries, but it has not been comprehensively studied in human clinical use. We assessed whether SE-PWI before and after initiating chemoradiation can stratify patients with respect to progression free survival (PFS) and overall survival (OS). Sixty-eight patients with newly diagnosed glioblastoma (mean age 58.3, 36 males) were included in analysis. SE EP cerebral blood volumes (SE-CBVs) in enhancing and nonenhancing tumor, normalized to contralateral normal appearing white matter (SE-nCBV), were assessed at baseline and after initial chemoradiation. SE-nCBV parameters predictive of PFS and OS were identified in univariate and multivariate Cox proportional hazards models. Multivariate analysis demonstrated that baseline tumor mean SE-nCBV was predictive of PFS (p = 0.038) and OS (p = 0.004). Within the patient sample, baseline tumor mean SE-nCBV <2.0 predicted longer patient PFS (median 47.0 weeks, p < 0.001) and OS (median 98.6 weeks, p = 0.003) compared with baseline mean SE-nCBV >2.0 (median PFS 25.3, median OS 56.0 weeks). Exploratory multi-group stratification demonstrated that very high (>4.0) tumor SE-nCBV was associated with worse patient OS than intermediate high (>2.0, <4.0) SE-nCBV (p = 0.025). Baseline mean SE-nCBV can stratify patients for PFS and OS prior to initiation of chemoradiation, which may help select patients who require closer surveillance. Our exploratory analysis indicates a magnitude-dependent relationship between baseline SE-nCBV and OS.

Phase I study of neoadjuvant chemoradiotherapy with S-1 plus biweekly cisplatin for advanced gastric cancer patients with lymph node metastasis: -KOGC04-

BackgroundIn patients with highly advanced gastric cancer, the recurrence rate remains high and the prognosis disappointing. We previously reported a phase I study of a neoadjuvant chemoradiotherapy of S-1 plus weekly cisplatin. Although adequate safety and efficacy were reported, myelosuppression was frequently observed, leading to treatment delay in several cases. To decrease toxicity and improve efficacy, we planned a phase I study with a modified chemotherapy regimen with biweekly cisplatin.MethodsPatients with advanced gastric cancer and lymph node metastasis who were treated by our institution between 2011 and 2012 were eligible for inclusion. The initial chemoradiotherapy schedule consisted of 6 weeks of S-1 orally administered on days 1–15 with an escalating dose of cisplatin administered on days 1 and 15. The starting dose (level 1) of cisplatin was 15 mg/m2, the second dose (level 2) was 20 mg/m2, and the third dose (level 3) was 25 mg/m2. Radiation of 40 Gy was administered in 20 fractions. After initial chemoradiotherapy, one cycle of combination chemotherapy with S-1 plus cisplatin was delivered. The second cycle was 42 days in duration and included S-1 administered on days 1–29 plus biweekly cisplatin administered on days 1, 15, and 29. After neoadjuvant treatment, a curative gastrectomy with extended (D2) lymph node dissection was planned.ResultsNine patients were enrolled. At level 3, one patient had dose-limiting grade 3 diarrhea. Another patient experienced grade 3 nausea and intended to discontinue the treatment. Overall, because 2 of 3 patients experienced dose-limiting toxicity at level 3, we confirmed level 3 (Cisplatin 25 mg/m2) as the maximum tolerated dose and level 2 (Cisplatin 20 mg/m2) as the recommended dose (RD). The response rate was 78%, and 8 patients underwent curative gastrectomy. Resected specimens showed a histological response in 6 patients (75%), including one with a pathological complete response.ConclusionsIn this phase I trial, RD of cisplatin was identified as 20 mg/m2. Generally, S-1 plus biweekly cisplatin can be given safely with concurrent radiation. We have initiated a multicenter phase II trial to further confirm the efficacy and safety of this approach.Trial registrationUMIN000008941

Neoadjuvant chemotherapy followed by chemoradiation in selected locally advanced squamous cervical cancer.

5603 Background: Although there has not been a direct comparison between neoadjuvant chemotherapy followed by chemoradiation with chemoradiation alone, neoadjuvant chemotherapy is active in squamous cervical cancer. Methods: In this one arm phase II trial we accrued 25 patients from 2007 to 2012 diagnosed with squamous cervical cancer deemed poor candidates to initial chemoradiation (decided by a multidisciplinary committee). Patients had &gt; 18 years of age, PS 0-1, adequate organ function an gave informed consent. They received neoadjuvant paclitaxel and cisplatin (80 and 33 mg/m2 respectively) on days 1,7, 15 of every 28 for two cycles and then external radiation in 1.8 Gy/ fraction with concurrent weekly cisplatin 40 mg/m2followed by brachytherapy in 5-6 applications. Dose intensity and toxicity was accrued, and both after neoadjuvant and chemoradiation patients were evaluated by RECIST 1.1 criteria for response with CT scan and pelvic MNR. Results: Baseline characteristics of the patients are listed in Table. 24 patients were evaluable for efficacy and safety. Response rate after neoadjuvant chemotherapy was 84 % (complete and partial responses in 24 and 60% of patients, respectively), without progression disease. Response rate after radiochemotherapy was 93 % (complete and partial responses in 52 and 41% of patients, respectively). After a mean of 29 months of follow up, 11 patients (45%) thus far have developed recurrent disease. Median progression-free survival and overall survival were 33 (23- 42) and 34+ m (29 – not reached). Treatment was well tolerated, without toxicities grade 3-4. Conclusions: Our weekly cisplatin-paclitaxel neoadjuvant regimen has been feasible and very effective in terms of dose delivery, tolerance and radiological responses without compromising definitive treatment with chemoradiation. If this approach is superior than the standard chemoradiation alone in this population should be explored in a randomized trial. [Table: see text]

Abstract SY27-03: Biomarker-guided development of novel multi-peptide cancer vaccines - from discovery to phase lll trials.

Abstract SY27-03: Biomarker-guided development of novel multi-peptide cancer vaccines - from discovery to phase lll trials.

Phase I study of neoadjuvant chemoradiotherapy as an outpatient setting for patients with resectable advanced gastric cancer.

84 Background: The prognosis for advanced gastric cancer remains poor because of a high rate of metastasis or recurrence. Therefore, treatment options that might improve the prognosis are needed. Radiation is expected to improve the rate of curable resection and local recurrence. To that end, neoadjuvant chemoradiotherapy with S-1 and cisplatin (CDDP) was investigated. Methods: Advanced gastric cancer patients with regional lymph nodes metastases enrolled in this study. The chemoradiotherapy consisted of S-1 on days 1–14 and CDDP on days 1 and 15. The dose range of CDDP in the study was 15 mg/m2 to 30 mg/m2. Radiation therapy was started concurrently with chemotherapy and repeated daily on days 1–5, 8–12, 15–19, and 22–26. After the initial chemoradiation therapy, the chemotherapy was repeated within 2 weeks after the termination of radiotherapy. Surgery was scheduled to take place within 6 weeks after completion of the second cycle of chemotherapy. Results: A total of 9 patients were recruited. There was no dose-limiting toxicity (DLT) in patients both 15 mg/m2 and 20 mg/m2. In the next three patients at 25 mg/m2, there were two cases with DLTs. Therefore, the recommended dose (RD) of CDDP was 20 mg/m2. Eight patients underwent surgery and all had an R0 resection. Postoperative complications occurred in two cases (pancreatic fistula and chylous ascites). However, there was no treatment-related death. The grades of histological therapeutic effect were Grade 1a in two patients, Grade 1b in one patient and Grade 2 in four patients. One patient had no viable cancer cells, which is classified as a Grade 3 histological therapeutic effect and represented a pathological CR. Conclusions: The recommended dose of CDDP is 20mg/m2 bi-weekly and its safety and feasibility as a preoperative therapy are supported in this study. Neoadjuvant chemoradiotherapy can provide remarkable shrinkage of tumors and increases in curability rate would be expected. Further clinical trials in a larger number of patients are recommended to evaluate the validation of neoadjuvant chemoradiotherapy with S-1 and CDDP as a standard treatment strategy for resectable advanced gastric cancer. Clinical trial information: UMIN000008941.

Initial Experience With the Use of Biological Implants for Soft Tissue and Chest Wall Reconstruction in Thoracic Surgery

Synthetic materials have traditionally been used for tissue reconstruction in thoracic surgery. New biomaterials have been tested in other areas of surgery with good results. The aim of our study is to evaluate our initial experience using prostheses in extended thoracic surgery. A review was performed of all patients who underwent extended surgical procedures requiring soft tissue reconstruction with bioprosthetic materials after thoracic surgery from August 2009 to August 2011. A total of 44 consecutive patients were included. Operations involved radical pleurectomy and decortication for mesothelioma (n = 29), extended operations for thoracic malignancies (n = 8), surgery for trauma or perforated organs or complications (n = 6), and for benign infectious causes (n = 1). A total of 76 patches were used in 44 patients (median of 2; range 1 to 3 per patient). Median hospital stay was 13 (range 5 to 149) days. Three patients died during the postoperative period (6.8%); pulmonary embolism 5 days after intrapericardial pneumonectomy with chest wall reconstruction, fatal pneumonia 26 days after radical pleurectomy and decortication for mesothelioma, and bronchopleural fistula 11 days after pneumonectomy with diaphragm and atrium excision for lung cancer after initial chemoradiotherapy. No other surgical exploration or removal of patches has been required for infection. Our initial experience of using bioprosthetic patches for soft tissue reconstruction in thoracic surgery has proven satisfactory with overall acceptable results. The infection rates are low even when a proportion of procedures were performed under contaminated environments. Biologic prosthesis should be part of the surgical options to reconstruct soft tissues in thoracic surgery.

1210 - Long-Term Efficacy and Safety of L-BLP25 Vaccine in a Multi-Centre Open-Label Study of Patients with Unresectable Stage III NSCLC

ABSTRACT Introduction L-BLP25 (Stimuvax®) is an antigen-specific cancer immunotherapeutic agent targeting the mucin 1 tumour-associated antigen. Phase IIb data suggest prolonged overall survival with L-BLP25 when administered after completion of chemoradiotherapy for locally advanced non-small-cell lung cancer (NSCLC; non-significant). This study was initiated in April 2005 to obtain safety data when modifications of the adjuvant component of the immunotherapeutic were performed. Here we report an updated analysis of long-term data based on the cut-off date 18 May 2011. Methods The primary objective of this open-label phase II study was to evaluate the safety of the new formulation of L-BLP25 in patients with unresectable stage IIIA/B NSCLC, with a secondary objective of assessment of survival time. Following completion of initial chemoradiotherapy, patients with stage III NSCLC received treatment with L-BLP25 starting with weekly injections over 8 weeks, followed by injections given every 6 weeks from week 13 onwards until disease progression. A single low dose of intravenous cyclophosphamide 300 mg/m2 (maximum 600 mg) was given 3 days before first vaccination. Results Twenty-two patients were enrolled. After a median follow-up of 70.3 months (median treatment duration 9.9 months [range, 1–73]), median survival time was 51.9 months (95%CI, 17.5, not estimable [NE]) and median progression-free survival was 31.4 months (95%CI, 5.7, NE). Five-year survival was 50% (95%CI, 29–71%); previously reported 1- and 2-year survival rates, 82% (95%CI, 66–98%) and 64% (95%CI, 44–84%), respectively. Four patients survived more than 72 months. Safety findings were consistent with previous reports; adverse events (AEs) consisted mainly of fatigue (59%), injection-site reactions (55%) and mild-to-moderate influenza-like illness. Two serious treatment-emergent AEs were assessed as being treatment-related: cholecystitis and pneumonia. Conclusions Long-term follow-up of this small patient population provides encouraging survival data for L-BLP25 maintenance therapy in stage III NSCLC. Long-term safety data were consistent with previous reports and did not reveal any new safety issues. Disclosure C. Butts: Charles Butts has provided consultancy and served on Speakers' Bureaux for Merck Serono. A. Maksymiuk: Andrew Maksymiuk has some stock shares in Merck Canada ( M. Falk: Martin Falk is a Merck Serono employee. A.H. Loos: Dr Loos is a Merck employee. All other authors have declared no conflicts of interest.

Salvage surgery for recurrent oropharyngeal cancer after chemoradiotherapy

The current study aimed to assess the role of salvage surgery for failure cases of oropharyngeal cancer (OPC) undergoing initial chemoradiotherapy (CRT). The data for 523 patients with previously untreated OPC were gathered from 12 institutions belonging to the Head and Neck Cancer Study Group in Japan Clinical Oncology Group (JCOG). Of the 170 patients who received CRT, 35 patients (21%) had local recurrence or residual disease. Only 11 patients underwent further salvage surgery, and 24 patients received nonsurgical treatment. There were statistically significant differences between the two groups in terms of patient age and the presence of a simultaneous regional recurrence. The 5-year overall survival rates for the patients who underwent salvage surgery were 49.1%, whereas those for the patients who received nonsurgical treatment were 16.3%. The initial treatment method for OPC should be decided carefully and the limitations of salvage surgery should be fully considered.