Improvement In Locoregional Control Research Articles

Anti‑epidermal growth factor receptor monoclonal antibody therapy in locally advanced head and neck cancer: A systematic review of phase III clinical trials.

The present systematic review evaluated the effectiveness of anti-EGFR therapy in combination with radiotherapy (RT) or with chemoradiation compared with the existing standard of care for the treatment of locally advanced head and neck squamous cell carcinoma (LAHNSCC). The PubMed, SCOPUS, EMBASE and COCHRANE databases were searched and 12 phase III randomized controlled trials were included. The effectiveness of the anti-EGFR monoclonal antibody cetuximab was evaluated in nine trials. Nimotuzumab (one trial), zalutumumab (one trial) and panitumumab (one trial) were the monoclonal antibodies evaluated in the remaining three trials. One study tested the effectiveness of adding cetuximab to radical RT and found that patients with LAHNSCC exhibited improvement in locoregional control (LRC), overall survival (OS) and progression-free survival (PFS) compared with those of patients treated with RT alone. A total of three studies tested the effectiveness of adding an anti-EGFR agent to chemoradiation. Of these, a single institution study in which patients received cisplatin at 30 mg/m2 weekly, instead of the standard doses of 100 mg/m2 every 3 weeks or 40 mg/m2 every week, reported significant improvement in PFS with the addition of nimotuzumab to chemoradiotherapy without an improvement in overall survival. However, the other two studies indicated that, when added to standard chemoradiation, the anti-EGFR monoclonal antibodies cetuximab or zalutumumab did not improve survival outcomes. Two phase III trials evaluated RT plus an anti-EGFR agent compared with chemoradiation alone. Of these, one study reported inferior outcomes with cetuximab-RT in terms of OS and LRC, whereas the other study with panitumumab plus RT failed to prove the non-inferiority. Two trials evaluated induction chemotherapy followed by cetuximab-RT compared with chemoradiotherapy and reported no benefits in terms of OS or PFS. Furthermore, one study evaluated induction chemotherapy followed by cetuximab-RT compared with induction chemotherapy followed by chemoradiotherapy and found no improvement in OS or PFS. Finally, three phase III trials tested the effectiveness of cetuximab plus RT in the treatment of human papillomavirus-positive oropharyngeal carcinoma, and found it to be inferior compared with cisplatin-RT in terms of OS, PFS and failure-free survival. Based on the aforementioned findings, it is difficult to conclude that anti-EGFR therapy in any form has an advantage over conventional chemoradiation in the treatment of LAHNSCC.

Combined Regional Approach of Talimogene laherparepvec and Radiotherapy in the Treatment of Advanced Melanoma.

Talimogene laherparepvec (TVEC) is a genetically modified oncolytic herpes simplex virus (HSV-1) that is used for the intralesional treatment of advanced or metastatic melanoma. Given that TVEC produces the granulocyte-macrophage colony-stimulating factor (GM-CSF), recent reports have suggested that radiation treatment (RT) given in conjunction with TVEC may provide synergistic immune activation at the site, and possibly systemically. However, studies on combining RT with TVEC remain limited. We conducted a retrospective review of melanoma patients from a single cancer center who received TVEC and RT in the same region of the body and compared them to patients who received TVEC with RT at another site (other than the site of TVEC injection). Between January 2015 and September 2022, we identified twenty patients who were treated with TVEC and RT; fourteen patients received TVEC and RT in the same region, and six had treatments in separate regions. Regions were determined at the time of analysis and were based on anatomic sites (such as arm, leg, torso, etc.). Kaplan-Meier analysis of progression-free survival (PFS), analyses of time to distant metastasis (DM), overall survival (OS), and locoregional control (LRC), and the corresponding log-rank test were performed. With a median follow-up of 10.5 months [mos] (range 1.0-58.7 mos), we found an improvement in PFS with TVEC and RT in the same region compared to different regions, which were 6.4 mos (95% CI, 2.4-NR mos) and 2.8 mos (95% CI, 0.7-4.4 mos), respectively; p = 0.005. There was also a significant improvement in DM when TVEC and RT were used in the same region compared to different regions: 13.8 mos (95% CI, 4.6-NR mos) and 2.8 mos (95% CI, 0.7-4.4 mos), respectively (p = 0.001). However, we found no difference in overall survival (OS) between patients who had TVEC and RT in the same region (19.0 mos, 95% confidence interval [CI], 4.1-not reached [NR] mos) and those who received treatments in different regions (18.5 mos, 95% CI, 1.0-NR mos); p = 0.366. There was no statistically significant improvement in locoregional control (LRC) in patients who had TVEC and RT in the same region was 26.0 mos (95% CI, 6.4-26.0 mos) compared to patients who received TVEC and RT in different regions (4.4 mos) (95% CI, 0.7-NR mos) (p = 0.115). No grade 3 or higher toxicities were documented in either group. Overall, there were improvements in PFS and DM when TVEC and RT were delivered to the same region of the body compared to when they were used in different regions. However, we did not find a significant difference in locoregional recurrence or OS. Future studies are needed to assess the sequence and timing of combining RT and TVEC to potentially enhance the immune response both locally and distantly.

Abstract 5424: Selection of RP3D of xevinapant in combination with CRT in patients with LA SCCHN

Abstract Xevinapant, an antagonist of Inhibitor of Apoptosis Proteins (IAPs) showed significant improvement in locoregional control at 18 months (LRC18; primary endpoint), overall survival (OS) and progression-free survival (PFS) at an oral dose of 200 mg/day given on days 1-14 every 3 weeks in combination with CRT versus CRT with placebo in a phase II trial in patients with high-risk LA SCCHN (NCT02022098). In the dose escalation (DE) part of NCT02022098, 200 mg/day was the maximum tolerated dose and a trend of dose-response for efficacy in the 100-300 mg/day dose range was observed. The phase III TrilynX study of xevinapant plus CRT in patients with LA SCCHN is currently enrolling (NCT04459715). Here we present the integrated rationale for the recommended phase III dose (RP3D) of xevinapant 200 mg/day based on all available clinical and preclinical data and modeling and simulation (M&S). At the RP3D, ~95% of the patients are projected to have free trough concentrations above in vitro IC50 for cIAP1 degradation (a pharmacodynamic [PD] marker), based on a population (pop) PK M&S. In patients, average free concentration over the dosing interval at RP3D is similar to that associated with maximal efficacy in preclinical SCCHN models. Pop PK/PD M&S suggests that maximal cIAP1 degradation is maintained in PBMCs with 100-200 mg/day doses during the 14-day dosing period, with a trend of dose-response for the partial cIAP1 degradation at the end of the 3-week cycle. Exposure response (E-R) analyses were conducted based on the pooled datasets of DE and randomized parts of study NCT02022098 (n=62 treated with xevinapant). Logistic regressions showed that probabilities of LRC18, overall response, complete response, and the composite safety endpoint of “mucositis and/or dysphagia” increase with increasing exposure (p<0.05). Statistically significant E-R relationships were not discernible for any other evaluated safety endpoints or for PFS, OS, or duration of LRC. However, patients in higher exposure subgroups showed a longer duration of LRC. In summary, integration of preclinical pharmacology, clinical efficacy and safety profiles, clinical PK/PD, popPK, and E-R analyses support the RP3D selection of xevinapant at 200 mg/day administered on days 1-14 every 3 weeks with concomitant CRT, allowing for successive dose reductions to 150 mg and 100 mg for management of toxicities. Citation Format: Yulia Vugmeyster, Abhigyan Ravula, Elisabeth Rouits, Paul M. Diderichsen, Huub J. Kleijn, Kosalaram Goteti, Andreas Schroeder, Karthik Venkatakrishnan. Selection of RP3D of xevinapant in combination with CRT in patients with LA SCCHN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5424.

Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial

BackgroundBC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer (MIBC), demonstrated improvement in locoregional control by adding fluorouracil and mitomycin C to radiotherapy (James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477–88). There are limited data on long-term recurrence risk. ObjectiveTo determine whether benefit of adding chemotherapy to radiotherapy for MIBC is maintained in the long term. Design, setting, and participantsA phase 3 randomised controlled 2 × 2 factorial trial was conducted. Between 2001 and 2008, 458 patients with T2-T4a N0M0 MIBC were enrolled; 360 were randomised to radiotherapy (178) or chemoradiotherapy (182), and 218 were randomised to standard whole-bladder radiotherapy (108) or reduced high-dose-volume radiotherapy (111). The median follow-up time was 9.9 yr. The trial is registered (ISRCTN68324339). InterventionRadiotherapy: 55 Gy in 20 fractions over 4 wk or 64 Gy in 32 fractions over 6.5 wk; concurrent chemotherapy: 5-fluorouracil and mitomycin C. Outcome measurements and statistical analysisLocoregional control (primary endpoint), invasive locoregional control, toxicity, rate of salvage cystectomy, disease-free survival (DFS), metastasis-free survival (MFS), bladder cancer–specific survival (BCSS), and overall survival. Cox regression was used. The analysis of efficacy outcomes was by intention to treat. Results and limitationsChemoradiotherapy improved locoregional control (hazard ratio [HR] 0.61 [95% confidence interval {CI} 0.43–0.86], p = 0.004) and invasive locoregional control (HR 0.55 [95% CI 0.36–0.84], p = 0.006). This benefit translated, albeit nonsignificantly, for disease-related outcomes: DFS (HR 0.78 [95% CI 0.60–1.02], p = 0.069), MFS (HR 0.78, [95% CI 0.58–1.05], p = 0.089), overall survival (HR = 0.88 [95% CI 0.69–1.13], p = 0.3), and BCSS (HR 0.79 [95% CI 0.59–1.06], p = 0.11). The 5-yr cystectomy rate was 14% (95% CI 9–21%) with chemoradiotherapy versus 22% (95% CI 16–31%) with radiotherapy alone (HR 0.54, [95% CI 0.31–0.95], p = 0.034). No differences were seen between standard and reduced high-dose-volume radiotherapy. ConclusionsLong-term findings confirm the benefit of adding concomitant 5-fluorouracil and mitomycin C to radiotherapy for MIBC. Patient summaryWe looked at long-term outcomes of a phase 3 clinical trial testing radiotherapy with or without chemotherapy for patients with invasive bladder cancer. We concluded that the benefit of adding chemotherapy to radiotherapy was maintained over 10 yr.

928TiP Induction versus adjuvant gemcitabine/cisplatin in locally advanced non-metastatic nasopharyngeal carcinoma: A randomised phase III trial

The standard of care for locally advanced nasopharyngeal carcinoma is radical chemoradiation (CRT). Recent advances in radiation techniques and supportive measures resulted in improvement of locoregional control and quality of life. However distant failure is still the main challenging reason of poor survival Addition of systemic therapy to concurrent CRT is widely used and accepted as an option to reduce these failures, however selection of chemotherapy regimen and timing in relation to CRT is controversial.

Distant Metastasis in Carcinoma Oral Cavity: Incidence and Prognostic Factors

Abstract Aim The predominant pattern of failure for oral carcinoma is locoregional failure. With improvement in locoregional control, incidence of distant metastasis has increased. Reported incidence of distant metastasis is 8 to 10%. With an aim to define incidence and predictive factors for distant metastasis posttreatment of oral cavity cancer, the present analysis was done. Materials and Methods This is a retrospective chart review of 531 patients who underwent surgery for oral cavity carcinoma from August 2013 to December 2017. All patients had undergone surgery followed by adjuvant treatment as per histopathology report. Results The median age of the cohort was 49 years. The median follow-up of alive patients was 21 months (range: 1–56 months). Locoregional recurrence seen in 61, distant metastasis in 23, and 72 patients had locoregional recurrence with distant metastasis. Total incidence of distant metastasis was 18% (95 patients) with median detection 7 months’ posttreatment. The sites of distant metastasis were: lung in 49 patients, bone in 9 patients, and multiple sites in 37 patients. Nodal stage (N2 and N3), differentiation, young age, and perineural invasion were associated with higher incidence of distant metastasis on multivariate analysis. Conclusion The incidence of distant metastasis was found to be higher as compared with published literature. Possibility of adjuvant systemic therapy may be explored in future studies.

COMPARATIVE STUDY BETWEEN LAPAROSCOPIC VERSUS OPEN RIGHT HEMICOLECTOMY

Background: Colorectal cancer (CRC) incidence and mortality rates vary markedly around the world. The right colon has a thin wall, a large caliber, and its contents are liquid; thus, obstruction is a late event in right colon cancer. Also, right colonic tumors grow large enough to be palpable through the abdominal wall before other symptoms appear. Objective: To compare between laparoscopic and open complete mesocolic excision with central vascular ligation in right colon cancer as regards technical feasibility, advantages and disadvantages of both procedures. Patients and Methods: This study was conducted on 30 patients admitted to Al-Azhar University Hospitals, and diagnosed as operable right sided colon cancer. It was prospectively conducted during the period from October 2019 to June 2020, and all the procedures were done on elective basis. Informed consents were obtained from all patients included in the study which approved by the local ethics committee of Al-Azhar University Hospitals. Patients were 7 (46.7%) males and 8(53.3%) females. Their ages ranged from 51 to 71 years with a mean age of 58.33±5.88 in laparoscopic technique, and ranged from 50 to 70 years with a mean age of 59.93±5.20 in open technique. Results: There was no statistical significant difference between the studied groups regarding the mean age, gender distribution, DM, hypertension and the tumor location. There was a statistical significant difference between the studied groups regarding the incision length as the incision of the open technique was longer than the laparoscopic technique, regarding the operative time and intraoperative blood loss as the laparoscopic technique take more time than the open technique and the intraoperative blood loss during the laparoscopic technique was less than the open technique. Conclusion: Complete mesocolic exicion(CME), with central vascular ligation is the novel key factor in the multimodal management of right colon cancer, determining a significant improvement in loco-regional control of tumors and improving the long-term oncological outcome, especially in intermediate stages of disease. it is a safe, valid, and feasible surgical method for right colon cancers, associated with smaller incisions, less operative blood loss, earlier recovery after operation, and shorter hospital stay compared with Open technique. The open technique is still superior in shorter operative time and more number of harvested lymph nodes.

Propensity score matching analysis of patients with inoperable stage III NSCLC treated with chemoradio- vs. chemoradioimmunotherapy.

e21087 Background: Chemoradiotherapy (CRT) followed by consolidation treatment with the PD-L1 Inhibitor durvalumab is the new standard of care for inoperable stage III NSCLC. The present study compares outcome of patients treated with CRT alone to those treated with additional concurrent and/or sequential immune check-point inhibition (CRT-IO) using propensity-score matching analysis (PSM). Methods: PSM was performed with retro- and prospectively collected data of patients treated with CRT or CRT-IO (consolidation with durvalumab/concurrent and consolidation with nivolumab). Overall survival (OS), progression free survival (PFS) and time to loco-regional recurrence (defined as progression in the mediastinum and ipsilateral lung) were calculated from last day of thoracic irradiation. Results: Sixty-two (37%) of 166 treated patients were successfully matched; 31 received CRT and 31 CRT-IO. 18F-FDG-PET/CT for treatment planning was performed in 97% and cranial contrast enhanced MRI in 81% of patients. PSM was based on age, gender, PTV volume, histology, T- and N-stage. 36 and 51% vs. 42 and 46% of patients had T4- and N3-disease in the CRT and CRT-IO cohorts, respectively. All patients were irradiated to a total dose of at least 60Gy (EQD2). 90% of patients received two cycles of concomitant platinum-based chemotherapy (CRT: 82%, CRT-IO 96%). The median follow-up for 62 patients was 17.3 (range: 1.7-96.0) months. Median PFS was 7.1 (95%CI 2.2-12.1) months in CRT vs. 13.8 (95%CI 13.1-14.5) in CRT-IO patients (p = 0.004). Twelve-month PFS rates were 30% and 55% in the CRT and the CRT-ICI cohort, respectively. Median time to loco-regional recurrence was 15.3 months for CRT vs. not reached for CRT-IO patients (p = 0.050). 12-month loco-regional recurrence rates were 43% vs. 22%; 6- and 12-month brain metastases rates after completion of radiotherapy in the CRT vs. CRT-ICI cohort were 8% and 26% vs. 0% and 20%, respectively. Median OS was 19.1 (8.4-29.8 95%CI) months for CRT and not reached for CRT-IO patients (p < 0.001). 12-month survival rates were 62% and 93% in the CRT and CRT-IO cohort, respectively. Conclusions: The addition of concurrent and/or sequential IO to CRT led to an impressive improvement of loco-regional control, PFS and OS in the matching cohorts.

Skeletal muscle deposits from primary oropharyngeal carcinoma: A home away from home

There have been significant improvements in loco-regional control of head and neck squamous cell carcinoma (HNSCC), but distant metastasis remains a clinically important challenge. The incidence of distant metastasis in HNSCC is quite uncommon, varying from 4% - 26%. The most often involved sites being lung, liver and bone. Several factors influencing the incidence of distant metastasis include primary tumour site, grading, nodal involvement, and status of locoregional disease. We report a case of a 59-year old gentleman with oropharyngeal carcinoma treated 6 months back presenting with swelling over the right infra-scapular region and the medial aspect of lower one third of right thigh resulting from metastasis to skeletal muscle. The results of histology and immunohistochemistry were consistent with a metastasis from a squamous cell carcinoma oropharynx. The disease was staged as stage III initially at the time of presentation. The patient received definitive concurrent chemoradiation therapy to the primary and nodal regions. There was no evidence of locoregional disease after 1 year. In the literature, there are reports of HNSCC metastasizing to different parts of the body. However, this is among the few case report of a metastasis to the skeletal muscle. Keywords: Chemoradiotherapy, Immunohistochemistry, Oropharyngeal neoplasm, Skeletal muscle.

Intensification of Radiation Therapy with Control of the Amount of Radiation Using MRI in Patients with Squamous Cell Carcinoma of the Anal Canal

Introduction. The increase in the number of cured patients with squamous cell anal carcinoma and the quality of life is directly related to the improvement of radiotherapy departments technical equipment in oncological clinics.Purpose. One of the main tasks of improving technics and technology is reducting duration of chemoradiation therapy, and also number and duration of interruptions, plus more accurate determination of the tumor volume by using modern diagnostic methods, such as MRI, and creating the possibility of maximum impact on the tumor and identified affected lymph nodes while limiting dose to organs at risk.Materials and methods. During the period from 2000 to 2015 year, 301 patients with squamous cell anal carcinoma, stage T1–4N 0–3M0–1, were treated by radiation therapy with 2D-RT, 3D-CRT, or IMRT in a total dose of 50–60 Gy, in combination with chemotherapy and local hyperthermia.Results. The use of IMRT with MRI in comparison with 3D-CRT resulted in an increase of frequency of complete tumor response (at the time of first diagnostic control) up to 67.5 % (p = 0.071); reduction of frequency of interruptions in the treatment course up to 48 % (p = 0.005); significantly increased the 3-year overall survival rate to 92.9 % (p = 0.050), distant metastases — free survival — 91.0 % (p = 0.049), with a trend of improvement in locoregional control — 89.9 % (p = 0.179).Conclusions. The use of radiation therapy in its modern version, modern methods of visualization of tumor lesions and critical structures has reduced the interruptions in the course of treatment, achieved high immediate and long-term oncological results.

Clinical Outcomes and Patterns of Failure after D2 Gastrectomy and Adjuvant Chemoradiotherapy in Patients with Locally Advanced Carcinoma Stomach: A Retrospective Review From A Tertiary Care Cancer Research Institute

Surgery is the primary curative approach for Gastric cancer. However, even after radical resection, overall prognosis remains dismal with increased locoregional and/or metastatic recurrences. Role of adjuvant chemoradiation after D2 gastrectomy has been widely investigated and has been found to have a modest survival advantage. The present study was conceived with the aim of reviewing gastric cancer data from our institute, in terms of clinical outcomes, patterns of failure and survival after D2 gastrectomy and adjuvant chemoradiation. This was a single institute retrospective study of all gastric adenocarcinoma patients who underwent D2-gastrectomy, along with either perioperative/adjuvant chemotherapy (CT) or adjuvant chemo-radiation (CTRT). All such patient records between January 2010 and December 2017 were included. Comparison was made between the two treatment arms in terms of patient and disease characteristics, clinical outcomes including overall and recurrence free survival (RFS) and pattern of failure. A total of 190 patient records were reviewed in the present study. There was an overall male preponderance, with median age at diagnosis of 56 years. Distal stomach was the commonest site of disease (65% cases in Antropyloric region). Histopathological examination revealed Stage III disease in majority of the patients (57%). Adjuvant treatment in the form of chemoradiation and chemotherapy was given to 57% (110/190) and 43% (80/190) patients respectively. Nearly one fourth of all patients [24%] developed subsequent recurrence following treatment; 73% of those who suffered recurrences (34/46) had local recurrences, 27% (12/46) failed distally. Lymph nodes were the most common sites of local failure accounting for 53% (23/46) and liver the most common site of isolated distal failure 7% (3/46) followed by lung and bone (4% each).Median follow up was 41 months (4-105 months). Local recurrence was significantly lower in CTRT group as compared to CT alone (15.4% vs. 36.2%; p =0.001). Distant metastasis was also significantly lower in CTRT than CT alone (6.3% vs. 20.0%; p = 0.001). The OS and RFS at 94 months was 75% and 88% respectively. Adjuvant chemo-radiation was associated with a statistically significant improvement in RFS 79% vs. 62% (p = 0.001) and showed a trend towards improved OS 77% vs. 65% (p = 0.07). Adjuvant chemoradiation after D2 gastrectomy has shown significant improvement in locoregional control with a modest trend towards improved OS. Our results are encouraging and comparable to published literature; It should be further evaluated in a prospective study.

Patterns of post-operative irradiation in breast cancer patients submitted to neoadjuvant chemotherapy.

Post-operative radiation therapy (PORT) is associated with improvement in loco-regional control and survival rates in early breast cancer. However, the evidence of benefit in patients after treatment with neoadjuvant chemotherapy (NAC) is poor. We aimed to assess the impact of the type of surgery in the PORT plan and the role of the PORT fields in clinical outcomes in breast cancer patients who had undergone NAC followed by surgery. We performed a retrospective analysis of all non-metastatic breast cancer patients treated between 2008 and 2014 at our institution who had received NAC and PORT. A total of 528 women were included of whom 396 were submitted to mastectomy or nipple-sparing/skin-sparing mastectomy. Most (92.8%) of the patients had locally advanced disease (clinical stage IIB to IIIC). All patients underwent irradiation for breast or chest wall. Most patients received PORT to the supraclavicular and axillary (levels II and III) nodes (87.1% and 86.4% for breast-conserving surgery and 95.1% and 93.8% for mastectomy and nipple-sparing/skin-sparing mastectomy, respectively). Irradiation of level I axillary and internal mammary nodes was uncommon. The disease-free survival and overall survival rates at 3 years were 72% and 85%, respectively. There were no statistically significant differences in clinical outcomes according to the use of nodal irradiation. After NAC, most patients received irradiation of the breast/chest wall and axillary and supraclavicular nodes. In this setting, PORT to breast/chest wall with or without regional nodal irradiation was safe and effective, with acceptable disease-free and overall survival rates reported in this high-risk population.

Speaker Presentations

Chemoradiotherapy, the standard of care for locally advanced non–small-cell lung cancer (NSCLC), often fails to eradicate all known disease. Despite advances in chemotherapeutic regimens, locally advanced NSCLC remains a difficult disease to treat, and locoregional failure remains common. Improved radiographic detection can identify patients at significant risk of locoregional failure after definitive treatment, and newer methods of escalating locoregional treatment may allow for improvements in locoregional control with acceptable toxicity. This review addresses critical issues in escalating local therapy, focusing on using serial positron emission tomography-computed tomography to select high-risk patients and employing stereotactic radiotherapy to intensify treatment. We further propose a clinical trial concept that incorporates the review's findings.

Dysregulation of the MiR-449b target TGFBI alters the TGF\u03b2 pathway to induce cisplatin resistance in nasopharyngeal carcinoma

Despite the improvement in locoregional control of nasopharyngeal carcinoma (NPC), distant metastasis (DM), and chemoresistance persist as major causes of mortality. This study identified a novel role for miR-449b, an overexpressed gene in a validated four-miRNA signature for NPC DM, leading to chemoresistance via the direct targeting of transforming growth factor beta-induced (TGFBI). In vitro shRNA-mediated downregulation of TGFBI induced phosphorylation of PTEN and AKT, increasing cisplatin resistance. Conversely, the overexpression of TGFBI sensitized the NPC cells to cisplatin. In NPC patients treated with concurrent chemoradiotherapy (CRT), the overall survival (OS) was significantly inversely correlated with miR-449b, and directly correlated with both TGFBI mRNA and protein expression, as assessed by RNA sequencing and immunohistochemistry (IHC). Mechanistically, co-immunoprecipitation demonstrated that TGFBI competes with pro-TGFβ1 for integrin receptor binding. Decreased TGFBI led to increased pro-TGFβ1 activation and TGFβ1 canonical/noncanonical pathway-induced cisplatin resistance. Thus, overexpression of miR-449b decreases TGFBI, thereby altering the balance between TGFBI and pro-TGFβ1, revealing a novel mechanism of chemoresistance in NPC.

Consolidative Radiotherapy After Autologous Stem Cell Transplantation for Relapsed or Refractory Diffuse Large B-cell Lymphoma.

We evaluated the role of consolidative radiotherapy (RT) for patients undergoing high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). We reviewed the medical records of 72 consecutive patients who had undergone ASCT for relapsed or refractory DLBCL at our institution from 2006 to 2014. Pretransplant conditioning consisted of HDC and total body irradiation. Of the 72 patients, 13 received post-transplant consolidative RT at the discretion of the consulted radiation oncologist. Consolidative RT was associated with significantly improved 2-year locoregional control (LRC) (92% vs. 68%; P= .04). However, no difference was seen in either the 2-year progression-free survival (PFS) (69% vs. 54%; P= .25) or overall survival (OS) (85% vs. 59%; P= .44). Analysis of the subgroup of 19 patients with persistent residual masses≥ 2 cm on post-transplant imaging demonstrated a significant improvement in LRC (100% vs. 36%; P< .01), PFS (88% vs. 27%; P= .01), and OS (100% vs. 45%; P=.02) with consolidative RT. The use of consolidative RT after HDC and ASCT for relapsed or refractory DLBCL appears to significantly improve LRC. For patients with masses≥ 2 cm after ASCT, improved 2-year PFS and OS were seen. Prospective trials are needed to further identify the patients who would derive the most benefit from consolidative RT in the ASCT setting.

Phase I/II trial of cetuximab with 5-fluorouracil and mitomycin C concurrent with radiotherapy in patients with muscle invasive bladder cancer.

4527 Background: This phase I/II trial assessed the safety, feasibility and efficacy of cetuximab (Cet) in combination with 5-fluorouracil (5FU) and mitomycin C (MMC) with concurrent radiotherapy (RT) for the treatment of muscle invasive bladder cancer (MIBC). BC2001 trial has previously reported significant improvement in locoregional control in patients (pts) with MIBC who were randomised to synchronous chemo-RT compared to RT alone (James, Hussain, Hall et al NEJM 2012). Results for phase I have been reported previously. This abstract reports the combined results of phases I/II. Methods: From September 2012 to October 2016, 33 pts were recruited (7 pts to phase I from 2 UK centres and 26 patients to phase II from 5 UK centres). Pts received loading dose of Cet 400 mg/m2 followed by weekly Cet 250 mg/m2 for 7 weeks, continuous infusion 5FU 500mg/m2/day during fractions 1-5 and 16-20 of RT and MMC 12mg/m2on day 1 in combination with radical RT 64 Gy in 32 fractions. Neoadjuvant chemotherapy was mandatory in phase I but optional in phase II. Primary outcomes in phase I were feasibility and toxicity. Primary outcome in phase II was 3 month pathological complete response (CR) rate, secondary outcomes included toxicity, progression free survival (PFS) and overall survival (OS). Results: Median age of pts was 70 (range 46.9-85.6). Treatment completion rates in phase I were RT 100%, 5FU 100 %, MMC 100%, Cet 96%. Of the 28 analysable pts, phase II primary outcome data was available for 25 pts at the time of analysis with a 3 month pathological CR rate of 88%. 5 local progressions and 4 deaths were reported. 12 pts suffered at least one SAE. Grade 4 toxicities observed were dyspnoea, atrial fibrillation, interstitial pneumonitis, sepsis, thromboembolism, neutropenia and palpitations. The commonest grade 3 toxicities were skin rash, diarrhoea, low platelet count, low white blood cell count, fever and haematuria. The most common grade 1 and 2 toxicities were diarrhoea and skin rash. Data on PFS and OS will be presented. Conclusions: It was feasible and safe to add cetuximab to full dose chemo-RT with 5FU/MMC. The CR rate is encouraging and further randomised studies with this combination are warranted. Clinical trial information: ISRCTN80733590.

Functional MRI for quantitative treatment response prediction in locally advanced rectal cancer.

Despite advances in multimodality treatment strategies for locally advanced rectal cancer and improvements in locoregional control, there is still a considerable variation in response to neoadjuvant chemoradiotherapy (CRT). Accurate prediction of response to neoadjuvant CRT would enable early stratification of management according to good responders and poor responders, in order to adapt treatment to improve therapeutic outcomes in rectal cancer. Clinical studies in diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) MRI have shown promising results for the prediction of therapeutic response in rectal cancer. DWI allows for assessment of tumour cellularity. DCE-MRI enables evaluation of factors of the tumour microvascular environment and changes in perfusion in response to treatment. Studies have demonstrated that predictors of good response to CRT include lower tumour pre-CRT apparent diffusion coefficient (ADC), greater percentage increase in ADC during and post CRT, and higher pre-CRT Ktrans. However, the mean ADC and Ktrans values do not adequately reflect tumour heterogeneity. Multiparametric MRI using quantitative DWI and DCE-MRI in combination, and a histogram analysis technique can assess tumour heterogeneity and its response to treatment. This strategy has the potential to improve the accuracy of therapeutic response prediction in rectal cancer and warrants further investigation.

BC2001 long-term outcomes: A phase III randomized trial of chemoradiotherapy versus radiotherapy (RT) alone and standard RT versus reduced high-dose volume RT in muscle-invasive bladder cancer.

280 Background: BC2001 showed that adding chemotherapy (5FU+MMC) to radiotherapy significantly improved rates of muscle invasive bladder cancer (MIBC) locoregional control (LRC) [James 2012] but that reduced high dose volume RT rather than standard RT did not significantly reduce late side effects [Huddart 2013]. Here we present an update of the time to event outcomes after a median 10 years follow up. Methods: Under the 2x2 partial factorial design, 458 pts were randomised to RT (178) or cRT (182) (CT comparison) and/or to stRT (108) or RHDVRT (111) (RT comparison). Primary endpoint was LRC, secondary endpoints included overall survival (OS), bladder-cancer specific survival (BCSS), metastasis free survival (MFS) and salvage cystectomy rates. Results: Median follow up was 118 months (95%CI: 112-122). LRC and invasive LRC (ILRC) were improved with cRT (Table 1). Though no statistically significant differences between groups were found in OS, cRT exhibited a trend towards improvement in BCSS, significant when adjusted by known prognostic factors. Similar trend was found for MFS. Salvage cystectomy rate was lower for cRT (2-year rate, cRT:11% vs RT:17%, p=0.03). No differences between stRT and RHDVRT were found for any trial endpoint. Conclusions: With extended follow-up, an improvement in LRC and a reduced salvage cystectomy rate is confirmed with cRT. After adjustment for known prognostic factors this results in an improvement in BCSS. This updated data supports the use of cRT with 5FU/MMC and confirms this should be a standard of care for this patient population. Clinical trial information: ISRCTN68324339. [Table: see text]

Advances in Radiotherapy for Head and Neck Cancer.

Over the last few decades, significant improvements have been made in the radiotherapy (RT) treatment of head and neck malignancies. The progressive introduction of intensity-modulated RT and the use of multimodality imaging for target volume and organs at risk delineation, together with the use of altered fractionation regimens and concomitant administration of chemotherapy or targeted agents, have accompanied efficacy improvements in RT. Altogether, such improvements have translated into improvement in locoregional control and overall survival probability, with a decrease in the long-term adverse effects of RT and an improvement in quality of life. Further progress in the treatment of head and neck malignancies may come from a better integration of molecular imaging to identify tumor subvolumes that may require additional radiation doses (ie, dose painting) and from treatment adaptation tracing changes in patient anatomy during treatment. Proton therapy generates even more exquisite dose distribution in some patients, thus potentially further improving patient outcomes. However, the clinical benefit of these approaches, although promising, for patients with head and neck cancer need to be demonstrated in prospective randomized studies. In this context, our article will review some of these advances, with special emphasis on target volume and organ-at-risk delineation, use of molecular imaging for tumor delineation, dose painting for dose escalation, dose adaptation throughout treatment, and potential benefit of proton therapy.

External beam radiotherapy in differentiated thyroid carcinoma: A systematic review.

External beam radiotherapy (EBRT) is not a first line treatment in differentiated thyroid carcinoma (DTC), but is recommended as an adjuvant treatment in certain cases. The evidence for EBRT in DTC is limited. A comprehensive literature search was performed. Data on patient demographics, disease stage, treatment characteristics, and outcomes were collected from included articles after quality appraisal. Sixteen articles met the inclusion criteria, with a pooled population of 5114. Only 1 study was prospective and there were no randomized controlled trials. Most of the evidence suggests that EBRT improves locoregional control in patients at high risk of locoregional recurrence. This was corroborated by analysis of pooled patient data. Available evidence suggests an improvement in locoregional control when EBRT is used in patients over the age of 45 at high risk for locoregional recurrence. However, there is a need for long-term prospective multicenter research on the subject. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2297-E2305, 2016.