Concurrent Cisplatin-based Chemotherapy Research Articles

Abstract A12: Metformin treatment in LAHNSCC induces an antitumorigenic immune response

Abstract Epidemiologic studies and meta-analyses have indicated that metformin is associated with a lower incidence of tumorigenesis among type 2 diabetic patients, including those with head and neck squamous cell carcinoma (HNSCC). HNSCC patients are often treated with concurrent cisplatin-based chemotherapy and radiation (CRT). However, the cure rate remains low at 50% in HPV-negative smokers. Metformin has been shown to inhibit tumor growth and progression, both in vitro and in mouse models, in a wide variety of cancers including HNSCC. The mechanism through which this occurs is thought to be via the inhibition of the mammalian target of rapamycin (mTOR) pathway directly and indirectly through activation of AMPK. Recent studies indicate that increasing the activity of AMPK reduces the expression of PD-L1 found on the surface of cancer cells, thus allowing a greater influx of CD8+ T cells and further activity of NKT cells correlated with increased tumor cell killing. Given the potential antitumorigenic activity of metformin in HNSCC and that biguanide is generally well tolerated compared to other mTOR inhibitors, we hypothesized that the addition of metformin to CRT would be safe and would result in enhanced antitumor responses through activation of AMPK and the immune system. Therefore, in accordance with the phase I open-label, single-site, dose-escalation study combining metformin and CRT in LAHNSCC (NCT02325401), we investigated the effects of metformin on T cells, NK cells, and cytokines from patient PBMCs. Using flow cytometry and cytokine magnetic bead assays (Luminex), we evaluated the immune cell phenotypes and cytokine profiles of peripheral blood in patients before and after metformin treatment on trial. Cytokine profiles were further studied in coculture experiments combining PBMCs, HNSCC cell lines, and metformin. Following metformin treatment, patients developed an increase in activated NK cell populations, determined via NKG2D expression, as well as a shift in their CD8+ T-cell memory phenotypes. Patient serum ELISA examination revealed alterations in cytokine profiles, which were recapitulated in ex vivo experiments. Metformin treatment of HNSCC cell lines in vitro as well as HNSCC PBMCs ex vivo resulted in downregulation of STAT3 compared to healthy controls. Downregulation of STAT3 may be a potential mechanism in which metformin activates NK cells. Here we show evidence that metformin treatment has a direct effect on the innate immune system in patients with LAHNSCC, inducing an antitumorigenic immune response. Our study thus demonstrates that metformin continues to be a good candidate in combination with other therapeutic agents to yield improved clinical outcomes in patients with advanced-stage HNSCC. Citation Format: Sarah M. Palackdharry, Benyamin Yaniv, Melissa Orr-Asman, Nooshin Hashemi, Vinita Takiar, Trisha Wise-Draper. Metformin treatment in LAHNSCC induces an antitumorigenic immune response [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A12.

The long-term survival of patients with III-IVb stage nasopharyngeal carcinoma treated with IMRT with or without Nimotuzumab: a propensity score-matched analysis

BackgroundTo assess the efficacy of Nimotuzumab in combination with first-line chemoradiotherapy treatment in Chinese patients with primary III-IVb stage nasopharyngeal carcinoma.MethodsPatients with primary locoregionally advanced nasopharyngeal carcinoma who were treated with intensity-modulated radiotherapy (IMRT) and concurrent cisplatin-based chemotherapy between January 2008 and December 2013 at a single institution were retrospectively reviewed. Group A received at least 6 doses of Nimotuzumab, while Group B did not receive Nimotuzumab. A propensity score matching method was used to match patients from each group in a 1:3 ratio.ResultsIn total, 730 eligible patients were propensity matched, with 184 patients in Group A and 546 patients in Group B. Significant differences were not observed in the patient and tumor characteristics between Group A and Group B. At a median follow-up of 74.78 months (range 3.53–117.83 months), locoregional recurrence, distant failure and death were observed in 10.68, 11.10 and 16.03% of all patients, respectively. The estimated 5-year locoregional relapse–free survival, distant metastasis–free survival, progression-free survival and overall survival in the Group A versus Group B were 85.34% versus 89.79% (P = 0.156), 93.09% versus 85.61% (P = 0.012), 79.96% versus 77.99% (P = 0.117) and 88.91% versus 78.30% (P = 0.006), respectively.ConclusionsThis nimotuzumab-containing regimen resulted in improved long-term survival of III-IVb stage NPC patients and warrants further prospective evaluation.

Outcomes and prognostic factors for patients with cervical esophageal cancer undergoing definitive radiotherapy or chemoradiotherapy.

Cervical esophageal cancer (CEC) is uncommon, accounting for less than 5% of all esophageal cancers. The management of CEC is controversial. This study investigated treatment outcomes and prognostic factors of survival in CEC patients undergoing definitive radiotherapy or concurrent chemoradiotherapy (CCRT). Ninety-one CEC patients were treated by intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3DCRT) between July 2007 and September 2017. The mean prescription dose was 64 Gy (range 54-70 Gy) delivered as 1.8-2.2 Gy per fraction per day, 5 days a week. Out of 91 patients, 34 received concurrent cisplatin-based chemotherapy (CT) including 18 patients who also received neoadjuvant CT. Overall survival (OS), locoregional failure-free survival (LRFFS), and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Prognostic factors of survival were determined in univariate (log-rank test) and multivariate (Cox proportional hazard model) analysis. Treatment-related toxicity was also assessed. Median follow-up time for all patients was 19 months. Two-year OS, LRFFS and PFS of all patients were 58.2%, 52.5% and 48.1%, respectively. Clinical stage was an independent prognostic factor for OS (HR = 2.35, 95% CI: 1.03-5.37, p = 0.042), LRFFS (HR = 3.84, 95% CI: 1.38-10.69, p = 0.011), and PFS (HR = 2.68, 95% CI: 1.11-6.45, p = 0.028). Hoarseness was an independent prognostic factor for OS (HR = 2.10, 95% CI: 1.05-4.19, p = 0.036). CCRT was independently associated with better LRFFS (HR = 0.33, 95% CI: 0.14-0.79, p = 0.012). 3DCRT and IMRT with concurrent CT is well-tolerated and may improve local tumor control in CEC patients. Advanced clinical stage and hoarseness are adverse prognostic factors for OS, LRFFS, and PFS in CEC.

Clinical significance of lymph node size in locally advanced cervical cancer treated with concurrent chemoradiotherapy.

BackgroundThis study aimed to assess the in-field lymph node (LN) failure rate according to LN size and to investigate effect of LN size on the survival outcome of patients with locally advanced cervical carcinoma treated with concurrent chemoradiotherapy (CCRT).MethodsA total of 310 patients with locally advanced cervical carcinoma treated with CCRT were enrolled in retrospective study. LN status was evaluated by magnetic resonance imaging. All patients received conventional external beam irradiation and high-dose rate brachytherapy, and concurrent cisplatin-based chemotherapy. In-field LN failure rate according to LN size was analyzed.ResultsThe median follow-up period was 83 months (range, 3-201 months). In-field LN failure rate in patients with pelvic LN size more than 10 mm was significantly higher than that in patients with pelvic LN size less than 10 mm (p<0.001). A similar finding was observed in the in-field para-aortic LN (PALN) failure rate (p=0.024). The pelvic and PALN size (≥10 mm) was a significant prognostic factor of overall-survival (OS) and disease-free survival rate in univariate and multivariate analyses. The OS rate was significantly different between groups according to LN size (<10 mm vs. ≥10 mm).ConclusionA LN of less than 10 mm in size in an imaging study is controlled by CCRT. On the other hand, in LN of more than 10 mm in size, the in-field LN failure rate increase and the prognosis deteriorate. Therefore, a more aggressive treatment strategy is needed.

Concurrent chemoradiotherapy for muscle-invasive bladder carcinoma for organ preservation: A feasibility study from tertiary care center

Background: The primary goal of treatment in oncology is cure but efforts should be made to preserve quality of life. The gold standard for treatment of muscle-invasive bladder cancer is radical cystectomy. However, radical cystectomy cannot be performed without risk of complications and often the outcome for the patient is a mediocre quality of life as the patient has to live with an artificial bladder or ileal conduit. Even after radical cystectomy, 40–50% of patients will succumb to distant metastases within 5 years. As in the case of several other malignancies, increasing efforts have been made over the last few decades to adopt organ sparing treatment. Bladder-sparing monotherapies lead to disappointing results, local disease control may be maximized using a trimodal approach based on complete transurethral tumor resection of bladder (TURB), followed by concurrent chemoradiotherapy and cisplatin-based systemic chemotherapy. Objectives: The aim of our study is feasibility of concurrent cisplatin with radiation in bladder preservation in our hospital. Materials and Methods: Thirty-two previously untreated patients of histologically proven transitional cell carcinoma of urinary bladder received concurrent chemoradiation (60 Gy) with cisplatin. All patients received concurrent chemotherapy with cisplatin infusion in a dose of 20 mg/m2/day on consecutive 5 days from Day 1 to Day 5 in 1st and 5th week of radiotherapy. Detailed clinical examination along with cystoscopy, TURB along with biopsy, and computed tomography scan of abdomen pelvis were done before treatment and to assess response toxicity, and disease-free survival (DFS) during follow-up period. Results: Median follows up period was 36 months. Local disease control was seen in 71% patients. Five years DFS is 58%. Five years overall survival is 64%. Conclusions: Concurrent chemoradiation in carcinoma of urinary bladder is feasible in our hospital and results in good local control, survival with acceptable toxicity.

Extended-field intensity-modulated radiation therapy combined with concurrent chemotherapy for cervical cancer with para-aortic lymph nodes metastasis.

This study was conducted to evaluate the efficacy and toxicity of extended-field intensity-modulated radiation therapy combined with concurrent chemotherapy in patients with cervical cancer with positive para-aortic lymph nodes (PALN). From September 2007 to December 2014, a total of 59 patients who had cervical cancer with para-aortic lymph node metastasis were treated with concurrent chemoradiotherapy at our institution. A dose of 45-50.4 Gy in 25-28 fractions with extended-field intensity-modulated radiation therapy was prescribed to planning target volume, and a dose of 30-36 Gy in 5-6 fractions was prescribed to Point A with high-dose-rate brachytherapy. A concurrent first-line cisplatin-based chemotherapy regimen was used. The median duration of follow-up was 32.1 months (range, 3.2-103.7 months). The 2- and 3-year overall survival, disease-free survival and local control rates were 69.0 and 52.8%, 45.0 and 41.3% and 83.4 and 81.0%, respectively. Distant metastasis was the major pattern of treatment failure, which occurred in 26 patients (44.1%). The incidence of Grade 3 or greater acute hematologic, gastrointestinal and genitourinary toxicity was 50.9, 1.7 and 3.4%, respectively. Only one patient had both Grade 3 late gastrointestinal and genitourinary toxicity. The study found that extended-field intensity-modulated radiation therapy combined with concurrent chemotherapy was safe and effective in patients who had cervical cancer with positive PALN.

A comparison of weekly versus 3-weekly cisplatin during concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma using intensity modulated radiation therapy: a matched study

Purpose: To compare the long-term survival outcomes and acute toxicity between locoregionally advanced nasopharyngeal carcinoma (NPC) patients who received either weekly or 3-weekly cisplatin during concurrent chemoradiotherapy (CCRT).Methods: Between November 2008 and August 2011, 241 biopsy-proved NPC patients receiving concurrent cisplatin with intensity modulated radiotherapy (IMRT) were included. 90 patients treated with 4-7 weeks of 30-40 mg/m2 cisplatin weekly were matched with 90 patients who received two or three cycles of 80 mg/m2 cisplatin three-weekly by sex, age, T stage, N stage, Karnosky performance score (KPS). IMRT was presented to the nasopharyngeal gross target volume at 66-72 Gy/30-32 fractions and those involved neck area at 60-66 Gy/30-32 fractions.Results: The median follow-up time was 69 months (range, 2-91 months), and the 5-year overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) rates were 85.6% vs. 90.0% (P = 0.207), 85.6% vs. 92.6% (P = 0.152), 94.4% vs. 96.7% (P = 0.411), and 88.9% vs. 95.6% (P = 0.107) for the group treated weekly and 3-weekly cisplatin, respectively. No statistically significant survival differences were found between the two treatment groups in both univariate and multivariate analyses. The similar incidence of acute toxicities was observed between two groups.Conclusions: Concurrent cisplatin-based chemotherapy administered weekly or three-weekly in combination with IMRT leads to similar acute toxicities and long-term survival outcomes in locoregionally advanced NPC patients.

Comparison three-dimensional conformal radiotherapy versus intensity modulated radiation therapy in local control of head and neck cancer.

About 74% of head and neck cancer (HNC) patients need to undergo either definitive or postoperative radiation therapy because of aggressive nature of disease. The transition from two-dimensional conventional radiotherapy to three-dimensional conformal radiotherapy (3D-CRT) and further technological evolutions led to the successful clinical implementation of intensity modulated radiation therapy (IMRT), which constitutes an evolution of 3D-CRT. The IMRT technique gives the ability to create treatment fields with varying beam intensity using inverse planning and optimization algorithms to treat irregularly shaped target volumes with high precision. IMRT is in existence in clinical practice since 1995. Since then, presuming its clinical benefit a significant amount of patients has been treated by this technique. PARSPORT was the first multi-institutional prospective trial comparing IMRT with conventional RT in the treatment of HNC. It has shown a reduction in severe xerostomia but no difference in other toxicity and locoregional control after 24 months' follow or overall survival. Except for early T1, 2 N0 stages, the prognosis for patients with oral cavity cancer (OCC) is dismal than for carcinoma in other sites of the head and neck (HNC). The aim of this study was to assess the outcome of OCC following IMRT. Between January 2013 and January 2015, 40 patients of carcinoma buccal mucosa and carcinoma alveolus were treated by postoperative (19) or definitive (21) radiation therapy by IMRT technique. Of these, 28 patients (70%) presented with locally advanced T3/4 or recurrent tumor. Total radiation doses delivered was between 60 and 70 Gray at 2 Gray/fraction. Of these 31 patients (78%) has received concurrent cisplatin-based chemotherapy. Another group of 42 similar patients treated by 3D-CRT as definitive or postoperative adjuvant treatment over the same period has been selected. Comparisons were performed between these two groups. Data were entered into Excel spreadsheet and expressed as mean and standard deviation for deriving P value, and unpaired t-test was used to calculate 95% confidence interval. Local control (LC) was analyzed using Kaplan-Meier curve. Of all assessed treatment subgroups, LC rate was highest for patients treated with postoperative IMRT (89% LC at 2 years) followed by postoperative 3D-CRT patients (79% LC at 2 years); and finally, poorest LC rates (43% and 32% at 2 years) were seen in definitively irradiated patients with IMRT and 3D-CRT, respectively. LC rate for T1 stage (83%, n = 6) was significantly higher, than that for T2-4 (LC 55%, n = 76) as expected. Postoperative IMRT of carcinoma buccal mucosa and alveolus resulted in the highest LC rate of all the treatment subgroups assessed hence should be generously recommended in such cases especially ones with unfavorable features such as close resection margin, nodal involvement, locally advanced tumor (>T1N0), or recurrent disease, respectively. Despite definitive IMRT, locoregional control in carcinoma buccal mucosa and alveolus remain unsatisfactory, comparable to that following definitive 3D-CRT.

Oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma involving the cervical lymph nodes of unknown primary origin.

The purpose of this study was to present our findings on the use of limited-field, oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma of unknown primary origin. Between April 2011 and January 2016, 25 patients with a histological diagnosis of p16-positive squamous cell carcinoma were selectively irradiated to the ipsilateral oropharynx and cervical neck for tumors of unknown primary origin. The dose to the oropharynx ranged from 54-60 Gy (median 60 Gy) in 30-33 fractions. Concurrent cisplatin-based chemotherapy was administered to 8 patients (32%). The actuarial 2-year estimates of locoregional control, progression-free survival, and overall survival were 91%, 87%, and 92%, respectively. One patient failed in the contralateral neck. There was no grade 3 + toxicity in either the acute or late setting. Oropharynx-directed, ipsilateral radiation results in disease control that compares favorably with historical controls treated by comprehensive mucosal and bilateral neck radiation.

Cytomembranic PD-L1 expression in locoregionally advanced nasopharyngeal carcinoma

Background and objectiveThe aim of this study was to evaluate the expression of cytomembranic programmed death-ligand 1 (PD-L1) and its clinical significance in locoregionally advanced nasopharyngeal carcinoma (NPC).Patients and methodsFormalin-fixed, paraffin-embedded tissue biopsies from 85 patients with histological diagnosis of locoregionally advanced NPC treated with radical intensity-modulated radiotherapy and concurrent cisplatin-based chemotherapy were studied. By using immunohistochemistry staining, expressions of cytomembranic PD-L1 on tumor cells were detected.ResultsAfter a median follow-up duration of 65.8 months, 7 (8.2%), 5 (5.9%), and 5 (5.9%) patients suffered from local failure, regional failure, and distant metastases, respectively. The 5-year local failure-free survival, regional failure-free survival, distant failure-free survival, and overall survival (OS) rates were 90.9%, 94.8%, 94.0%, and 92.2%, respectively. Our results revealed that a high expression of cytomembranic PD-L1 was correlated with shorter OS (5y-OS: 82.5% vs 97.6%, P=0.022). In the multivariate analysis, only the cytomembranic PD-L1 was an independent prognostic factor for OS (hazard ratio: 6.176, 95% confidence interval, 1.166–32.710, P=0.032).ConclusionCytomembranic PD-L1 expression levels correlated with OS in locoregionally advanced NPC. Agreement between different methods is needed for further application of PD-L1 biomarker assays in NPC.

287O - Neoadjuvant chemotherapy followed by surgery (NACT-surgery) versus concurrent cisplatin and radiation therapy (CTRT) in patients with stage IB2 to IIB squamous carcinoma of cervix: A randomized controlled trial (RCT)

Background: The standard treatment for locally advanced cervical cancer is CTRT. We tested in a RCT whether outcomes could be improved by NACT-surgery. Methods: Patients with clinical stages IB2, IIA or IIB squamous cervical cancer were randomized (stratified on stage) to either NACT-surgery arm comprising 3 cycles of paclitaxel (175 mg/m2) and carboplatin (AUC 5-6) every 3 weeks followed by radical hysterectomy or CTRT arm comprising standard pelvic radiation with 5 cycles of cisplatin (40 mg/m2) once per week. Post-operative radiation was given as per protocol criteria. Primary end point was disease-free survival (DFS, relapse or cancer-related death whichever earlier) while secondary end points were overall survival (OS) and toxicity. The trial was designed to demonstrate 10% absolute increase in 5-year DFS in NACT-surgery arm, assuming 65% DFS in CTRT (control) arm (2-sided α = 0.05, power=80%) with planned sample size of 730. Results: Between September 2003 and February 2015, 635 patients were randomised of whom 633 (316 in neoadjuvant chemotherapy-surgery group and 317 in concurrent chemotherapy-radiotherapy group) are included in final analysis with a median follow-up of 58·5 months. The 5-year disease-free survival in neoadjuvant chemotherapy-surgery group was 69·3% compared with 76·7% (95% CI, 71·6 to 81·8) in concurrent chemotherapy-radiotherapy group while the corresponding 5-year overall survival rates were 75·4% and 74·7%, respectively (hazard ratio 1·025, 95% CI, 0·752 to 1·398, p = 0·87). Early and delayed toxicities were acceptable in both groups with some difference in pattern. Conclusions: Radiotherapy with concurrent cisplatin-based chemotherapy resulted in superior disease-free survival compared to neoadjuvant chemotherapy followed by radical surgery and should continue to be the standard of care in locally advanced cervical cancer. Clinical trial indentification: NCT00193739 Legal entity responsible for the study: Tata Memorial Centre Funding: Tata Memorial Centre - Government of India Disclosure: All authors have declared no conflicts of interest.

Induction Chemotherapy Plus Simultaneous Modulated Accelerated Radiation Therapy in Non-operative Hypopharyngeal and Supraglottic Laryngeal Squamous Cell Carcinoma: Preliminary Results of a Prospective Phase 2 Study

To evaluate the toxicities and short-term outcome of induction chemotherapy (ICT) plus high biological effective dose (BED) simultaneous modulated accelerated radiotherapy (SMART) in non-operative hypopharyngeal and supraglottic laryngeal squamous cell carcinoma (SCCH/L). Patients diagnosed SCCH/L, aged from 18 to 75, either staged retrospectively from III to IV B, in accordance with the AJCC 2010 criteria,or refused operation were eligible. The patients were treated with 2 cycles of docetaxel-cisplatin based ICT, and 2-3 cycles cisplatin-based concurrent chemotherapy combined SMART.The prescription dose of pGTV was 69 Gy, in 30 fractions, 2.30 Gy per fraction.The BED is equivalent to 70Gy, in 33 fractions, 2.12 Gy per fraction.This study began enrolling patients since February 2013,and was registered with number ChiCTR-ONRC-14004240. Between February 2013 and June 2015, 60 newly diagnosed SCCH/L patients were enrolled. Xerostomia > grade 2 was not noted. The incidences of grade 3 skin reaction, oral mucositis and pharyngo-esophagitis were low, 11.7%(7/60), 3.3% (2/60) and 11.7% (7/60),respectively.Two patients had tracheotomy due to severe larynx toxicity. The main adverse reaction was hoarseness or sore throat, the incidence was 30% (18/60).Biopsy confirmed radiation injury in 3 cases.The 1-and 2-year local control rates(LC), progression free survival (PFS) and overall survival (OS) was 90.0% and 70.5%,90.0% and 70.7%, 90.0% and 71.9%,respectively.Patients with severe pharyngo-esophagitis had poor prognosis,it was independent factor of OS(p=0.03,95%CI 1.104-7.202). The ICT plus SMART regimen of 69Gy/30f in the treatment of SCCH/L demonstrated minor severe toxicities and satisfied short-term outcome.But we should pay attention to choose the appropriate crowd with high BED radiotherapy.

Robust Correlation between Immediate Post Radio-Chemotherapy FDG PET Response and Clinical Outcome and Impact of Salvage Radiation for Partial Metabolic Responders in Locally Advanced Non–Small Cell Lung Cancer

Only living cells retain FDG. Thus, residual cancer after radiotherapy (RT) or radio-chemotherapy (RTCT) can be detected with FDG PET. Goal of this study was to investigate correlation between tumor metabolic response measured with immediate post radio-chemotherapy (RTCT) FDG PET and clinical outcome and importance of salvage radiation for partial metabolic responders. A cohort of patients who underwent FDG PET/CT 8 days post-RT or RTCT for locally advanced non-small cell lung cancer (LANSCLC) and their subsequent therapy including salvage RT for partial metabolic response were retrospectively analyzed. Tumor metabolic response was graded with a 3-level visual scale method with levels 1 and 2 being FDG uptake lower than or comparable to noncardiac mediastinal structures (NCMS) and considered complete metabolic response (CMR) and level 3 being higher than NCMS and regarded as partial metabolic response (PMR). RTCT comprised a median total dose of 63 Gy in 35 fractions (F) over a 6-wk period and 2-4 cycles of cisplatin-based concurrent chemotherapy. Salvage RT administered a median dose of 12.5 Gy/5 F to only residual FDG avid tumor volume. A total of 41 patients treated between 2010 and 2016 were available for the data analysis. Patient demographics comprised median age 67 years (47-86) and gender ratio 23 men and 18 women. Tumor extent by AJCC included stage IIB (n=6), IIIA (n=14), IIIB (n=19) and IV (n=2) via a resected oligo metastasis in the brain. All patients had biopsy confirmed NSCLC. According to the visual score for metabolic response, 14 and 27 patients attained CMR (Group A) and PMR respectively. Among the 27 with PMR, 14 patients received salvage RT to residual FDG avid tumor volume (Group B) and the remaining 13 patients elected to receive consolidation chemotherapy (Group C) without additional RT. There was one grade 3 and no grade ≥ 4 toxicity among all patients.Abstract 3061; Table 1Group AGroup BGroup CNumber of patients141413Median progression free survival (month)27 (6-78)16 (4-68)7 (6-16)Median overall survival (month)38 (6-78)23 (8-82)11 (6-56)Local tumor control14/148/143/13The log-rank test comparing groups: A to B p=0.03; A to C p=0.002; and B to C p=0.2. Open table in a new tab The log-rank test comparing groups: A to B p=0.03; A to C p=0.002; and B to C p=0.2. The results suggest that immediate post-therapy FDG PET may help separate patients with CMR from PMR. While patients with PMR may benefit from salvage RT, CMR patients may be saved from escalated radiation dose, its toxicities and cost. Clinical trials are needed for validation of immediate post-therapy FDG PET/CT for its potential in guiding individualized therapy.

Outcomes and Tolerability of Selective Bladder Preservation by Combined Modality Therapy for Invasive Bladder Cancer in Elderly Patients

The median age of patients diagnosed with muscle invasive bladder cancer (MIBC) in the United States is 73 years old, and only about half of those over 70 receive potentially curative therapy (radical cystectomy, chemoradiation, definitive radiation), suggesting a large proportion of the elderly are undertreated. To address this unmet clinical need, we examined the outcomes and tolerability of bladder-sparing trimodality therapy (TMT) in elderly patients 75 years or older. We retrospectively analyzed 475 patients with cT2-T4a disease treated at our institution between 1986 and 2013 on or per protocol. Patients underwent induction chemoradiation (CRT) after maximal transurethral resection of bladder tumor (TURBT), in most cases with cisplatin-based concurrent chemotherapy. Patients achieving a complete response (CR) received consolidation CRT. Those with less than a CR or an invasive recurrence were recommended to undergo salvage cystectomy. For comparison of elderly patients (defined as 75 years or older) with younger patients, propensity score matching was performed based on T-stage, presence of hydronephrosis, completion of TURBT, and use of neoadjuvant chemotherapy. Disease-specific survival (DSS) was evaluated using Kaplan-Meier method. Multivariate analyses were performed using a Cox proportional hazards regression model. Median age was 67 years (range 27-94), and 112 patients (23.6%) were 75 years or older. Median follow-up was 7.2 years for surviving patients. In a propensity score matching analysis of 101 elderly and 101 younger patients, DSS at 5 and 10 years for the elderly was 61.2% and 47.3%, compared to 68.6% and 61.0% for younger patients (P = 0.20). CR to induction CRT was 72.3% in the elderly, compared to 80.2% in the younger cohort (P = 0.25). 23.8% of elderly and 29.7% of younger patients underwent a salvage radical cystectomy (P = 0.43). Elderly patients, in comparison to younger patients, had similar rates of ED visits during treatment (8.9% vs 6.9%, P = 0.80) and unplanned treatment breaks for any cause (20.8% vs. 17.8%, P = 0.72), but had a nonsignificant increase in hospital admissions for any cause (16.8% vs. 9.9%, P = 0.21) and early discontinuation of therapy due to toxicities (6.9% vs. 3.0%, P = 0.33). On multivariate analysis, T3/T4 disease, incomplete response to CRT, ED visits during treatment, and early treatment discontinuation were significantly associated with worse DSS in elderly patients. In elderly patients with MIBC, outcomes and tolerability of bladder-sparing TMT using cisplatin-based CRT are comparable to that of younger patients. Clinicians should not deny patients potentially curative therapies based on age alone, although further investigation is warranted.

SDF-1/CXCR4 expression in head and neck cancer and outcome after postoperative radiochemotherapy

IntroductionOutcome after postoperative radiochemotherapy (RT-CT) for patients with advanced head and neck squamous cell carcinomas (HNSCC) remains unsatisfactory, especially among those with HPV negative tumours. Therefore, new biomarkers are needed to further define subgroups for individualised therapeutic approaches. Preclinical and first clinical observations showed that the chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12) play an important role in tumour cell proliferation, survival, cancer progression, metastasis and treatment resistance. However, the data on the prognostic value of SDF-1/CXCR4 expression for HNSCC are conflicting. The aim of our hypothesis-generating study was to retrospectively explore the prognostic potential of SDF-1/CXCR4 in a well-defined cohort of HNSCC patients collected within the multicenter biomarker study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). Material and methodsPatients with stage III and IVA HNSCC of the oral cavity, oropharynx and hypopharynx were treated with resection and adjuvant radiotherapy (RT) with ≥60Gy and concurrent cisplatin-based chemotherapy (CT). Tissue micro-arrays (TMAs) from a total of 221 patients were generated from surgical specimens, 201 evaluated for the SDF-1 and CXCR4 expression by immunofluorescence and correlated with clinico-pathological and outcome data. ResultsIn univariate and multivariate analyses intracellular SDF-1 expression was associated with lower loco-regional control (LRC) in the entire patient group as well as in the HPV16 DNA negative subgroup. CXCR4 expression showed a trend for lower LRC in the univariate analysis which was not confirmed in the multivariate analysis. Neither for SDF-1 nor CXCR4 expression associations with distant metastasis free or overall survival were found. ConclusionsOur exploratory data support the hypothesis that overexpression of intracellular SDF-1 is an independent negative prognostic biomarker for LRC after postoperative RT-CT in high-risk HNSCC. Prospective validation is warranted and further exploration of SDF-1/CXCR4 as a potential therapeutic target to overcome treatment resistance in HNSCC appears promising.

Bladder-Preserving Therapy Patterns of Care: A Survey of US Radiation Oncologists

Clinical trials have demonstrated the efficacy of bladder-preserving chemoradiation therapy (BPT) in muscle-invasive bladder cancer but have differed in the radiation therapy dose/fractionations, radiation therapy targets, and concurrent chemotherapy regimens used. No data exist on the technical and practical approaches actually used in clinical practice throughout the United States when delivering BPT. We performed a survey to explore radiation oncologists' practice patterns. We conducted an electronic survey of US radiation oncologists regarding the management of patients with cT2-3N0M0 transitional cell muscle-invasive bladder cancer.The instrument included questions regarding the types of patients treated with BPT, as well as several aspects of treatment delivery. Descriptive statistics were reported for all responses. Pearson χ2 tests were used for univariate analysis. In total, 277 physicians completed our survey. Most respondents (58%) stated that they only treated 1 to 3 patients in the prior year. Seventy-four percent of respondents primarily treated patients deemed unfit for cystectomy, while only 28% saw patients prior to cystectomy for consultation to discuss BPT. The majority of radiation oncologists used conventional fractionation (91%) instead of hypofractionation (7.6%), but more variability existed for radiation therapy targets. Sixty percent used a small pelvis field, 29% used a whole-pelvis field, and 12% treated the bladder only. There was increased use of hypofractionation (29%) and bladder-only radiation therapy (34%) in patients who were not candidates for cystectomy or chemotherapy (P<.001). Cisplatin-based concurrent chemotherapy was most commonly preferred (89%). In non-cisplatin candidates, most respondents preferred 5-fluorouracil plus mitomycin C (32%) or carboplatin (32%).Intensity modulated radiation therapy use and midtreatment cystoscopic re-evaluation were variable, while hyperfractionation use was low. Our study describes radiation oncologists' practice patterns for patients undergoing BPT. Although there are areas of consistency, variability exists in many technical and practical aspects of treatment delivery. Further research and education are needed to determine the optimal radiation therapy target, dose/fractionation, and concurrent chemotherapy regimen.

Salvage radiotherapy with or without concurrent chemotherapy for pelvic recurrence after hysterectomy alone for early-stage uterine cervical cancer.

Treatment outcomes of patients with pelvic recurrence after hysterectomy alone for uterine cervical cancer who received salvage radiotherapy (RT) with or without concurrent chemotherapy were investigated. Salvage RT for recurrent cervical cancer confined to the pelvic cavity after hysterectomy alone was received by 33patients. The median interval between initial hysterectomy and recurrence was 26months. Whole-pelvic irradiation was delivered to median dose of 45 Gy, followed by aboost with amedian dose of 16 Gy to the gross tumor volume. Cisplatin-based concurrent chemotherapy was administered to 29patients. The median follow-up period was 53months for surviving patients. Most patients (97.0%) completed salvage RT of ≥45 Gy. Complete response (CR) was achieved in 23patients (69.7%). Pelvic sidewall involvement and evaluation with positron-emission tomography-computed tomography were significantly associated with CR. The 5‑year progression-free survival (PFS), local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) rates were 62.7, 79.5, 72.5, and 60.1%, respectively. Initial International Federation of Gynecology and Obstetrics stage, pelvic sidewall involvement, and CR status were significant factors for PFS and OS rates in multivariate analysis. The incidence of severe acute and late toxicities (≥grade3) was 12.1 and 3.0%, respectively. Aggressive salvage RT with or without concurrent chemotherapy for recurrent cervical cancer confined to the pelvic cavity was feasible, with promising treatment outcomes and acceptable toxicities. However, even more intensive novel treatment strategies should be investigated for patients with unfavorable prognostic factors.

Locally advanced paranasal sinus carcinoma: A study of 30 patients.

Sinonasal carcinomas (SNcs) are rare neoplasms arising from the paranasal sinuses and nasal cavity. Although these tumours have a heterogeneous histology, they are commonly diagnosed as a locally advanced disease and are associated with a poor prognosis. The present retrospective study reviewed 30 patients with locally advanced SNc, who were treated with surgery followed by chemoradiotherapy or radiotherapy, or radiotherapy with or without concomitant chemotherapy between January 1999 and January 2013 at the Department of Radiation Therapy, University of Naples 'Federico II' (Naples, Italy). A total of 19 patients were treated with upfront surgery followed by adjuvant radio- or chemoradiotherapy (group A), while the remaining 11 patients received exclusive radiotherapy with or without concomitant chemotherapy (group B). Concurrent cisplatin-based chemotherapy (100 mg/m2, days 1, 22 and 43 for 3 cycles) was administered to 34% of patients in group A and 55% of patients in group B. At a median follow-up of 31 months, 33.3% of patients were alive. Cause-specific survival (CSS) and progression-free survival (PFS) times were 32 and 12 months, respectively. No difference in CSS rate was observed between the two treatment groups. Univariate analysis determined that disease stage was the only factor that significantly affected CSS (P=0.002) and PFS (P=0.0001) rates. Acute and chronic toxicities were mild, with only 23.3% of patients reporting G1-2 side effects and no treatment-related blindness. The present study reported moderate activity and efficacy of surgery followed by adjuvant radio- or chemoradiotherapy, and exclusive radiotherapy with or without chemotherapy in this poor prognosis category of patients.

Feasibility study of toxicity outcomes using GEC-ESTRO contouring guidelines on CT based instead of MRI-based planning in locally advanced cervical cancer patients

PurposeTo report late rectal and bladder toxicity outcomes of a CT-based image-guided brachytherapy (IGBT) technique for treatment of cervical cancer. Methods and MaterialsBetween 2008 and 2014, 95 women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical carcinoma treated with definitive concurrent cisplatin-based chemotherapy and external beam radiation therapy 50.4 Gy in 28 fractions followed by planned prescription dose of 7 Gy × 4 fractions of high-dose-rate IGBT was retrospectively reviewed. At each implantation, all patients had a urinary catheter in situ and received bowel enema before undergoing planning CT simulation. A high-risk clinical target volume (HRCTV) as per GEC-ESTRO guidelines and the entire cervix, rectum, and bladder was contoured on the simulation CT according to Radiation Therapy Oncology Group Gynaecology Contouring Atlas. Reported doses to HRCTV and organs at risk were recorded. Toxicities were recorded using National Cancer Institute Common Terminology Criteria for Adverse Events version 3. ResultsThe median followup time was 29 months. The mean HRCTV equivalent dose in 2 Gy fractions (EQD2) of external beam radiation therapy combined with brachytherapy was 80 Gy (standard deviation [SD], 11), and the rectal doses to 2 cm3 (D2cc) EQD2 and bladder D2cc EQD2 were 74 Gy (SD, 6) and 79 Gy (SD, 15), respectively. Twenty-two patients (23%) had grade 2 proctitis and 10 patients (11%) had grade 3 proctitis. Four patients (4%) had grade 2 cystitis and two patients (2%) had grade 3 cystitis. No patients had ≥ grade 4 toxicity. ConclusionsDespite CT-based brachytherapy planning, reported organ at risk toxicity was still significant compared with reported MRI-based planning series. Coimplementation of interstitial IGBT using the European Study on MRI-guided Brachytherapy in Locally Advanced Cervical Cancer (EMBRACE) protocol or using intensity-modulated radiation therapy during the external beam phase treatment might help to limit these late toxicities.

Early Change in Metabolic Tumor Heterogeneity during Chemoradiotherapy and Its Prognostic Value for Patients with Locally Advanced Non-Small Cell Lung Cancer.

IntroductionTo observe the early change of metabolic tumor heterogeneity during chemoradiotherapy and to determine its prognostic value for patients with locally advanced non-small cell lung cancer (NSCLC).MethodsFrom January 2007 to March 2010, 58 patients with NSCLC were included who were received 18F-fluorodeoxyglucose (18F-FDG) PET/CT before and following 40 Gy radiotherapy with the concurrent cisplatin-based chemotherapy (CCRT). Primary tumor FDG uptake heterogeneity was determined using global and local scale textural features extracted from standardized uptake value (SUV) histogram analysis (coefficient of variation [COV], skewness, kurtosis, area under the curve of the cumulative SUV histogram [AUC-CSH]) and normalized gray-level co-occurrence matrix (contrast, dissimilarity, entropy, homogeneity). SUVmax and metabolic tumor volume (MTV) were also evaluated. Correlations were analyzed between parameters on baseline or during treatments with tumor response, progression-free survival (PFS), and overall survival (OS).ResultsCompared with non-responders, responders showed significantly greater pre-treatment COV, contrast and MTV (AUC = 0.781, 0.804, 0.686, respectively). Receiver-operating-characteristic curve analysis showed that early change of tumor textural analysis serves as a response predictor with higher sensitivity (73.2%~92.1%) and specificity (80.0%~83.6%) than baseline parameters. Change in AUC-CSH and dissimilarity during CCRT could also predict response with optimal cut-off values (33.0% and 28.7%, respectively). The patients with greater changes in contrast and AUC-CSH had significantly higher 5-year OS (P = 0.008, P = 0.034) and PFS (P = 0.007, P = 0.039). In multivariate analysis, only change in contrast was found as the independent prognostic factor of PFS (HR 0.476, P = 0.021) and OS (HR 0.519, P = 0.015).ConclusionsThe metabolic tumor heterogeneity change during CCRT characterized by global and local scale textural features may be valuable for predicting treatment response and survival for patients with locally advanced NSCLC.