Locoregional Failure In Patients Research Articles

Treatment outcomes and radiotherapy deintensification strategies in human papillomavirus-associated tonsil cancer

BackgroundHuman papillomavirus (HPV)-positive tonsil cancer has a better prognosis than HPV-negative tonsil cancer. Deintensification strategies to reduce or avoid radiotherapy (RT) for patients with HPV-associated tonsil cancer have been suggested. This study investigated the treatment outcomes of patients with HPV-associated tonsil cancer and suggested RT deintensification strategies.MethodsA cohort of 374 patients with HPV-associated tonsil cancer treated with primary surgery or RT between 2008 and 2020 was retrospectively evaluated. Survival and locoregional control rates after primary surgery or RT were analyzed, and propensity score matching was performed to adjust for clinical factors. Pearson's chi-square or Fisher's exact test was used to compare categorical variables, and Student's t-test was used to compare continuous variables. The Kaplan–Meier method and log-rank test were used to assess overall survival, progression-free survival, and locoregional failure (LRF).ResultsNo significant differences in survival or LRF were observed between the primary surgery and RT groups. Subgroup analysis was conducted for patients who underwent primary surgery. Advanced pathological N stage, negative contralateral nodes at diagnosis, abutting or positive surgical margins, and no adjuvant RT were independent risk factors for LRF. Advanced pathological T stage was an independent risk factor for LRF in patients who underwent primary surgery without subsequent adjuvant RT. None of the patients with pathological complete remission (CR) after induction chemotherapy died or experienced LRF.ConclusionsOur study revealed that the outcomes of primary surgery and primary RT in HPV-positive tonsil cancer were similar after adjusting for clinical factors. Primary RT might be considered instead of surgery in patients with advanced pathological T stage. In the case of pathological CR after induction chemotherapy, deintensification for adjuvant RT should be considered.

Radiation Dose and Volume De-Escalation for High-Risk HPV Positive Oropharyngeal Cancer

<h3>Purpose/Objective(s)</h3> Human papillomavirus (HPV) associated oropharyngeal cancers (HPV+OPC) have a favorable prognosis with standard of care treatment paradigms. Recently published and ongoing clinical trials are investigating therapy de-escalation for patients with HPV+OPC with low-risk features with promising results, but largely exclude high risk (HR) patients. This is a secondary pooled analysis reporting outcomes of patients with HR HPV+OPC treated on consecutive prospective response-adaptive de-escalation trials. <h3>Materials/Methods</h3> Patients meeting HR criteria treated on the prospective phase II trials (NCT02258659, NCT03107182) as well as on a prospective cohort registry were included for analysis. HR criteria were defined by the NRG-HN005 exclusion criteria (T4, N2c-N3 (AJCC 7th ed.), and/or > 10 pack year smoking history). Patients were treated with induction chemo- or chemoimmunotherapy followed by RECIST 1.1 response adapted volume and dose de-escalated definitive chemoradiation. Patients with ≥ 50% response to induction therapy were treated either to 45 Gy in 1.5 Gy BID fractions with 3 cycles of TFHX in a week on week off fashion or to 50 Gy in 2 Gy daily fractions delivered over 5 weeks with concurrent cisplatin. Those with < 50% response received standard dose chemoradiotherapy. Descriptive statistics were used to summarize patient characteristics. Survival was estimated using the Kaplan Meier method for progression free survival (PFS), locoregional PFS (LRPFS), and overall survival (OS). Log rank analysis was used to investigate association between the number of NRG risk factors (RF) (1 vs > 1 RF) and LRPFS. <h3>Results</h3> 80 patients met HR criteria and were evaluable (15 registry patients). Median follow up was 38.5 (IQR 27.25-61.25) months. 60% smoked > 10 pack years. 25% of patients had T4 and 45% had N2c-N3 disease. 72.5%, 25%, and 2.5% had 1, 2, and 3 NRG RF, respectively. 56 of 80 (70%) patients were de-escalated. 3-year PFS, OS, and LRPFS was 92.9%, 93.5%, and 94.7%, respectively. Locoregional failure (LRF) was 1.7% in patients with 1 NRG RF, and 13.6% LRF in patients with 2 or 3 NRG RF (p=0.0265). 3-year LRPFS was 100% for patients with N0-N2b disease and 88.6% for patients with N2c-N3 disease; all 4 locoregional failures were in-field and in patients with N2c-N3 disease who were de-escalated. Only 1 patient had an isolated distant failure. <h3>Conclusion</h3> This prospective experience demonstrates feasible dose and volume de-escalation of HPV+OPC patients with NRG HR factors. The results for the overall cohort compare favorably to prior published results. Importantly, the failure rate in de-escalated patients is in line with acceptability criteria on prior phase II de-escalation studies for low-risk patients. No patients experienced regional out-of-field failures and distant failure rates were low in a traditionally HR population. Our pooled results call for renewed cooperative group focus on trial design for radiation dose de-escalation for HPV+ patients with higher-risk disease features.

Radiotherapy Planning and Molecular Imaging in Lung Cancer.

IntroductionIn patients suitable for radical chemoradiotherapy for lung cancer, 18F-FDG-PET/CT is a proposed management to improve the accuracy of high dose radiotherapy. However, there is a high rate of locoregional failure in patients with locally advanced non-small cell lung cancer (NSCLC), probably due to the fact that standard dosing may not be effective in all patients. The aim of the present review was to address some criticisms associated with the radiotherapy image-guided in NSCLC.Materials and MethodsA systematic literature search was conducted. Only published articles that met the following criteria were included: articles, only original papers, radiopharmaceutical ([18F]FDG and any tracer other than [18F]FDG), target, only specific for lung cancer radiotherapy planning, and experimental design (eventually “in vitro” studies were excluded). Peer-reviewed indexed journals, regardless of publication status (published, ahead of print, in press, etc.) were included. Reviews, case reports, abstracts, editorials, poster presentations, and publications in languages other than English were excluded. The decision to include or exclude an article was made by consensus and any disagreement was resolved through discussion.ResultsHundred eligible full-text articles were assessed. Diverse information is now available in the literature about the role of FDG and new alternative radiopharmaceuticals for the planning of radiotherapy in NSCLC. In particular, the role of alternative technologies for the segmentation of FDG uptake is essential, although indeterminate for RT planning. The pros and cons of the available techniques have been extensively reported.ConclusionPET/CT has a central place in the planning of radiotherapy for lung cancer and, in particular, for NSCLC assuming a substantial role in the delineation of tumor volume. The development of new radiopharmaceuticals can help overcome the problems related to the disadvantage of FDG to accumulate also in activated inflammatory cells, thus improving tumor characterization and providing new prognostic biomarkers.

Radiomics Nomogram for Predicting Locoregional Failure in Locally Advanced Non-small Cell Lung Cancer Treated with Definitive Chemoradiotherapy

To develop and validate a radiomics nomogram for predicting locoregional failure (LRF) in patients with locally advanced non-small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy (CRT). 141 patients with locally advanced NSCLC treated with definitive CRT from Jan 2014 to Dec 2017 were included and divided into testing cohort (n = 100) and validation (n = 41) cohort. Radiomic features were extracted from portal venous-phase computed tomography (CT) before treatments using 3D Slicer. The least absolute shrinkage and selection operator (LASSO) logistic regression was processed to select predictive features from the testing cohort and constructed a radiomics signature. Clinical data and the radiomics signature were analyzed using univariable and multivariate Cox regression. The radiomics nomogram was established with the radiomics signature and independent clinical factors. Harrell's C-index, calibration curves and decision curves were used to assess the performance of the radiomics nomogram. The radiomics signature, which consisted of 8 selected features, was an independent factor of LRF. And the clinical predictor of LRF was the histologic type. The radiomics nomogram combined with the radiomics signature and the histologic type showed good performance with C-indexes of 0.828 (95% confidence interval [CI]:0.748-0.908) and 0.765 (95% CI:0.668-0.862) in the testing and validation cohorts respectively. The combined radiomics nomogram resulted in better performance (p<0.001) for the estimation of LRF than the nomograms with the radiomics signature (C-index: 0.776; 95%CI: 0.686-0.866) or the histologic type (C-index: 0.631; 95%CI: 0.536-0.726) alone. Decision curve analysis demonstrated the clinical usefulness of the radiomics nomogram. The radiomics signature is an independent predictor of LRF in patients with locally advanced NSCLC. The radiomics nomogram incorporated the radiomics signature and the histologic type showed good prognostic value of LRF and might be helpful for individual treatments.

Perineural invasion predicts for locoregional failure in patients with oesophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy

AimThe prognostic significance of perineural invasion (PNI) in oesophageal adenocarcinoma (EAC) is unclear. We examined the association of PNI with clinical outcomes in patients treated with neoadjuvant chemoradiotherapy (nCRT) and...

Prognostic factors and patterns of loco-regional failure in patients with R0 resected gallbladder cancer

BackgroundIn this study, risk factors for loco-regional recurrence in curative R0 resected gallbladder adenocarcinoma were investigated. MethodsPatients with gallbladder adenocarcinoma with curative R0 resections between 2000 and 2016 were retrospectively reviewed. Loco-regional failure-free survival (LRFFS) and overall survival (OS) were analyzed using the Kaplan–Meier method; prognostic factors were analyzed using the Cox proportional hazards model. Based on the identified risk factors, patients were grouped for further analysis. ResultsA total of 272 patients were included for analysis; overall, 5-year LRFFS and OS were 83% and 81%, respectively. On multivariate analysis, 3 risk factors for LRFFS were identified; lymphovascular invasion, T3, and N1, by which patients were grouped; group 1 for 0 factor, group 2 for 1 factor and group 3 for 2 to 3 factors. The 5-year LRFFS in groups 1, 2, and 3 were 94%, 73%, and 40%, and the 5-year OS in groups 1, 2, and 3 were 90%, 75%, and 47%, respectively. LRFFS and OS differed significantly among groups (p < 0.05). ConclusionIn patients with R0 resected gallbladder cancer, the presence of >1 risk factor increased the risk of loco-regional recurrence. Additional therapeutic strategy for these patients needs further consideration.

1070PD - Treatment outcomes and pattern of failure in primary gastric diffuse large B cell lymphoma with complete remission following R-CHOP chemotherapy

BackgroundThe optimal treatment for primary gastric diffuse large B cell lymphoma (DLBCL) is unclear. The treatment for primary gastric DLBCL is in accordance with the principle of treatment for general DLBCL. We aimed to evaluate the treatment outcomes and pattern of failure in primary gastric DLBCL. MethodsBetween April 2001 and November 2018, 120 patients with stage I–IV primary gastric DLBCL were retrospectively reviewed in this study. All patients had been in complete remission after receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ninety patients (75%) were treated with R-CHOP alone, and the other 30 patients (25%) underwent R-CHOP with local treatment for gastric lesions. Twelve patients (10%) underwent gastrectomy, and 18 patients (15%) received consolidation radiotherapy (RT). ResultsThe median follow-up time was 49 (range, 5 to 197) months. The 5-year locoregional failure-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates were 85.6%, 86.5%, 83.4%, and 90.3%, respectively. During the follow-up, 17 patients (14.2%) experienced disease recurrence. Only 3 patients developed distant metastasis without locoregional failure (LRF). All except two cases of LRF included gastric failure. There was no LRF in patients who received R-CHOP with local treatment. On multivariate analysis, poor performance status was an independent prognostic factor for LRFS, and multiple gastric lesions influenced LRFS, DMFS, DFS, and OS. ConclusionsThe main pattern of initial failure is LRF, especially in the stomach in patients with primary gastric DLBCL. Gastric local treatment such as consolidation RT can effectively prevent gastric failure. Therefore, gastric local treatment should be considered for patients at high risk of LRF, such as multiple gastric lesions. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Risk factors associated with locoregional failure and estimation of survival after curative resection for patients with distal bile duct cancer

Our aim was to identify the risk factors associated with locoregional recurrence in resected distal bile duct cancer (DBDC), and to determine the subgroup that may benefit from adjuvant radiotherapy. Between 2001 and 2013, we retrospectively analyzed 93 patients with DBDC who had undergone curative resection. Patients who received adjuvant radiotherapy were excluded. The 3-year locoregional failure-free survival (LRFFS) and overall survival (OS) rates for all patients were 50.7%, and 53.2%, respectively. On multivariate analysis, the preoperative carcinoembryonic antigen (CEA) level, resection margin, histologic grade, T stage, and N stage were significant prognostic factors for LRFFS. Locoregional recurrence was observed in more than 78% of the patients who underwent R1 resection and were node-positive, and the 3-year LRFFS rate was 19.3%. The 3-year LRFFS rate was 46.9% in the patients who underwent R0 resection and were node-negative with more than 2 risk factors (preoperative CEA level ≥ 5 ng/mL, poorly differentiated histologic grade, and T3 stage). On multivariate analysis for OS, patients with more than 2 risk factors showed a 7-fold higher risk of death, compared with patients with 1 or no risk factor. The important risk factors of locoregional failure in patients with DBDC who underwent resection were R1 resection and positive lymph nodes. Adjuvant radiotherapy should be considered for these patients to improve the oncologic outcomes. Patients undergoing selective R0 resection and those with node-negative status and multiple locoregional failure risk factors may benefit from adjuvant radiotherapy.

Diffusion-weighted Magnetic Resonance Imaging for Predicting Response to Chemoradiation Therapy for Head and Neck Squamous Cell Carcinoma: A Systematic Review

To systematically review the evaluation of the diagnostic accuracy of pre-treatment apparent diffusion coefficient (ADC) and change in ADC during the intra- or post-treatment period, for the prediction of locoregional failure in patients with head and neck squamous cell carcinoma (HNSCC). Ovid-MEDLINE and Embase databases were searched up to September 8, 2018, for studies on the use of diffusion-weighted magnetic resonance imaging for the prediction of locoregional treatment response in patients with HNSCC treated with chemoradiation or radiation therapy. Risk of bias was assessed by using the Quality Assessment Tool for Diagnostic Accuracy Studies-2. Twelve studies were included in the systematic review, and diagnostic accuracy assessment was performed using seven studies. High pre-treatment ADC showed inconsistent results with the tendency for locoregional failure, whereas all studies evaluating changes in ADC showed consistent results of a lower rise in ADC in patients with locoregional failure compared to those with locoregional control. The sensitivities and specificities of pre-treatment ADC and change in ADC for predicting locoregional failure were relatively high (range: 50-100% and 79-96%, 75-100% and 69-95%, respectively). Meta-analytic pooling was not performed due to the apparent heterogeneity in these values. High pre-treatment ADC and low rise in early intra-treatment or post-treatment ADC with chemoradiation, could be indicators of locoregional failure in patients with HNSCC. However, as the studies are few, heterogeneous, and at high risk for bias, the sensitivity and specificity of these parameters for predicting the treatment response are yet to be determined.

Abstract 3681: A biologic basis for locoregional failure in patients with oral cavity cancers

Abstract BACKGROUND: The standard treatment for patients with oral cavity cancer (OCC) with intermediate risk pathologic variables after surgery is adjuvant radiotherapy. Despite this, one-third of patients experience locoregional failure (LRF). Clinicopathologic prognostic models have not been able to identify subsets of patients at higher risk of failure in whom treatment intensification with the addition of systemic chemotherapy should be considered. We posited that gene expression-derived tumor taxonomies can predict treatment failures and therefore guide more nuanced clinical decision making. Herein, we report on a score model based on OCC gene expression characteristics that can be incorporated into risk stratification and treatment decisions. METHODS: Formalin-fixed paraffin-embedded (FFPE) tissue samples from patients with intermediate risk OCC treated with surgery followed by radiation alone were subjected to quantitative nuclease protection and next-generation sequencing to measure gene expression (HTG Molecular EdgeSeq™). A subset of samples that had corresponding frozen tumor samples were profiled by RNAseq to validate the FFPE results. Patients were divided into two groups based on LRF. Differentially expressed genes were identified using the R limma package. 98 genes were selected on the basis of unadjusted P values and predicted biological impact, as measured by gene set enrichment results (GSEA) and resultant biological pathway scores. The Cancer Genome Atlas (TCGA) HNSCC dataset (n=521) was used to validate the prognostic performance of our gene set. RESULTS: Of the 78 patients included in the study, 35% of patients had LRF. GSEA of the 98 genes demonstrated a role for DNA repair, oxidative phosphorylation, hypoxia and p53 pathways, indicating radiobiologic plausibility for a significant subset of the genes that constitute the score. The mean composite score was 0.42 for patients with LRF, and -0.19 for patients without LRF (P = 0.0002). The Kaplan-Meier estimates of progression free survival at 3 years for the 1st (high risk) and 4th quartile (low risk) groups were 0.65 (0.47 to 0.89; 95% CI) and 0.93 (0.82 to 1; 95% CI), respectively. On multivariate analysis, the composite score was the strongest predictor of LRF (P = 0.0073). Composite scores also strongly predicted for overall survival in the TCGA HNSCC dataset (P &amp;lt; 0.01) and the Kaplan-Meier estimates of overall survival at 2 years for the 1st and 4th quartile groups were 0.55 (0.45 to 0.68; 95% CI) and 0.73 (0.63 to 1; 84% CI), respectively. Composite scores performed the best in patients with OCC (P = 0.033). CONCLUSIONS: We developed a gene signature that predicts LRF in patients with intermediate risk OCC treated with surgery and adjuvant radiotherapy. Further validation on larger datasets are needed. This biomarker can potentially identify higher risk patients who should be considered for intensification strategies with the addition of systemic therapy. Citation Format: Elif I. Sarihan, Brian B. Burkey, Joseph Scharpf, Robert Lorenz, Eric D. Lamarre, Brandon Prendes, Jessica L. Geiger, David J. Adelstein, Shlomo A. Koyfman, Mohamed E. Abazeed. A biologic basis for locoregional failure in patients with oral cavity cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3681.

EP-1096: Using DIR to study patterns of loco-regional failure in patients with head and neck cancer

EP-1096: Using DIR to study patterns of loco-regional failure in patients with head and neck cancer

Preoperative Chemoradiation Therapy With Capecitabine/Oxaliplatin and Cetuximab in Rectal Cancer: Long-Term Results of a Prospective Phase 1/2 Study

We have previously shown that the addition of cetuximab to chemoradiation therapy failed to improve complete response rates (pCR) in rectal cancer. Here we report the long-term results of the cetuximab added to preoperative radiation therapy with capecitabine and oxaliplatin (CET-CAPOX-RT) phase 1/2 study that evaluated preoperative chemoradiation with cetuximab, capecitabine, and oxaliplatin in patients with rectal cancer. The median follow-up was 63 months (range, 5-73 months). Sixty patients were enrolled; 3 patients were excluded due to protocol violation, and 4 died before surgery. Total mesorectal excision was performed in 53 patients, in 85% (n=45) with curative intention (M0-status). Secondary end points including overall survival (OS) disease-free survival (DFS) and cancer-specific survival (CSS) were calculated. The prognostic value of KRAS mutation status was also assessed. Histopathological examination confirmed ypUICC stages 0 (n=4; pCR), I (n=17), II (n=10), III (n=14), and IV (n=8). For patients who underwent surgery (n=53), OS at 1, 3, and 5 years was 88.7%, 83%, and 75.5%, respectively, whereas CSS rates were 94.1%, 88.1%, and 78.1%, respectively. In the 45 patients who were treated with curative intent (M0), the OS rates at 1, 3, and 5 years were 91.1%, 88.9%, and 86.7%, respectively; whereas CSS rates were 97.6%, 95.2%, and 90.3%, respectively; and DFS rates were 90.7%, 88.3%, and 88.3%, respectively. We did not find any locoregional failure in patients with M0-status (n=45). Chronic toxicity was rare. KRAS mutations, as detected in 33.3%, showed no correlation with the clinicopathological parameters nor significance for either OS (P=.112), CSS (P=.264), or DFS (P=.565). Taken together, chemoradiation therapy combined with cetuximab is safe, feasible, and offers excellent survival rates. KRAS mutation status was not a predictive factor. Importantly, lack of improvement in pCR rate did not translate to poor survival in our clinical trial.

Locoregional Failure in Early-Stage Breast Cancer Patients Treated With Breast-Conserving Therapy: Which Patients Benefit From Supraclavicular Nodal Irradiation?

To assess the locoregional failure in patients with Stage I-II breast cancer treated with breast conserving surgery followed by adjuvant whole breast radiation therapy (RT), and to evaluate whether potential risk factors might identify patients that are at sufficiently high risk of regional recurrence (RR) to benefit from supraclavicular nodal irradiation. The records of all patients with stage I-II breast cancer treated with breast conserving-surgery and adjuvant whole breast RT were retrospectively reviewed. Loco-regional recurrence (LRR) was defined as clinical or radiographic recurrence in the ipsilateral breast or in the regional lymphatics (axilla, infra/supraclavicular nodes). Kaplan-Meier analysis was used to calculate rates of regional recurrence (RR), LRR, disease-free survival (DFS) and overall survival (OS). Cox proportional hazards methods were used to evaluate potential risk factors. The study was conducted on 492 patients, and the median follow-up was of 95 months (range, 3-309 months). Median patient age was 54 years. One hundred eighty-five (37%) patients were premenopausal; 443 (90%) were affected by invasive ductal carcinoma and 49 (10%) by invasive lobular carcinoma. Four hundred six (83%) women were T1, and 86 (17%) were T2; 324 (66%) were pN0, 47 (10%) pN1a mic, 113 (23%) pN1a, and 8 (2%) were Nx. Two hundred fifteen (44%) tumors were grade 3; 423 (86%) patients were estrogen receptor positive; lymphovascular invasion (LVI) was present in 158 (32%) cases; positive pathologic margin was present in 12 2%) cases. Two hundred twenty-two (45%) patients underwent sentinel node biopsy. One hundred ninety-eight (40%) patients received adjuvant chemotherapy, 246 (50%) received hormonal therapy alone, and 48 (10%) received no adjuvant systemic therapy. The actuarial rates of RR at 5 and 10 years were 2.2% and 3.5%, respectively. The actuarial rates of LRR at 5 and 10 years were 5.5% and 18%, respectively. The actuarial rates of DFS and OS at 10 years were 80.5% and 96.3%, respectively. Statistically significant factors associated with increased risk of RR at the univariate analysis were node positive disease (HR = 3.6, p = 0.003) and the presence of LVI (HR = 3.5, p = 0.03). Patients with Stage I and II breast cancer treated with breast conserving surgery followed by whole breast RT are at a low overall risk of regional and locoregional relapse. However, patients with 1-3 positive lymph nodes and with LVI are higher risk of regional recurrence, and supraclavicular nodal irradiation should be considered.

Risk Factors for Locoregional Failure in Patients With Inflammatory Breast Cancer Treated With Trimodality Therapy

PurposeTo compare patterns of local and regional failure between patients with inflammatory breast cancer (IBC) and non-IBC in patients treated with trimodality therapy. Materials and MethodsWe reviewed records of 463 patients with stage II/III breast cancer, including IBC, who completed trimodality therapy from January 1999 to December 2009. ResultsThe median follow-up was 46.3 months (range, 4-152 months). Clinical stage was 29.4% (n = 136) II, 56.4% (n = 261) non-IBC III, 14.2% (n = 66) IBC, 30.5% (n = 141) cN0/Nx, and 69.5% (n = 322) N1-N3c. All the patients received neoadjuvant therapy and mastectomy (98%, n = 456 with axillary dissection), and all had postmastectomy radiation therapy to the chest wall with or without supraclavicular nodes (82.5%, n = 382) with or without axilla (6%, n = 28). The median chest wall dose was 60.4 Gy. Patients with IBC presented with larger tumors (P < .001) and exhibited a poorer response to neoadjuvant therapy: after surgery, fewer patients with IBC were ypN0 (P = .003) and more had ≥ 4 positive nodes (P < .001). Four-year cumulative incidence of locoregional recurrence was 5.9%, with 25 locoregional events, 9 of which had a regional component. On multivariate analysis, triple-negative disease (hazard ratio [HR] 7.75, P < .0001) and residual pathologic nodes (HR 7.10, P < .001) were associated with an increased risk of locoregional recurrence, but IBC was not. However, on multivariate analysis, the 4-year cumulative incidence of regional recurrence specifically was significantly higher in IBC (HR 9.87, P = .005). ConclusionIn this cohort of patients who completed trimodality therapy, the patients with IBC were more likely to have residual disease in the axilla after neoadjuvant therapy and were at greater risk of regional recurrence. Future study should focus on optimizing regional nodal management in IBC.

Long‐term regional control and survival in patients with “low‐risk,” early stage oral tongue cancer managed by partial glossectomy and neck dissection without postoperative radiation

The objectives of this study were to determine the incidence of locoregional failure in patients with low-risk, early stage oral tongue squamous cell cancer (OTSCC) who undergo partial glossectomy and ipsilateral elective neck dissection without receiving postoperative radiation. A combined database of patients with OTSCC who received treatment at Memorial Sloan-Kettering Cancer Center and Princess Margaret Cancer Center from 1985 to 2005 was established. In total, 164 patients with pathologic T1-T2N0 OTSCC who underwent partial glossectomy and ipsilateral elective neck dissection without postoperative radiation were identified. Patient-related, tumor-related, and treatment-related characteristics were recorded. Local recurrence-free survival, regional recurrence-free survival, and disease-specific survival were calculated by the Kaplan-Meier method. Predictors of outcome were analyzed by univariate and multivariate analysis. At a median follow-up of 66 months (range 1-171 months), the 5-year rates of local recurrence-free survival, regional recurrence-free survival, and disease-specific survival were 89%, 79.9%, and 85.6%, respectively. Regional recurrence was ipsilateral in 61% of patients and contralateral in 39% of patients. The regional recurrence rate was 5.7% for tumors <4 mm and 24% for tumors ≥ 4 mm. Multivariate analysis indicated that tumor thickness was the only independent predictor of neck failure (regional recurrence-free survival, 94% vs 72% [P = .02] for tumors <4 mm vs ≥ 4 mm, respectively). Patients who developed recurrence in the neck had a significantly poorer disease-specific survival compared with those who did not (33% vs 97%; P < .0001). Patients with low-risk, pathologic T1-T2N0 OTSCC had a greater than expected rate of neck failure, with contralateral recurrence accounting for close to 40% of recurrences. Failure occurred predominantly in patients who had primary tumors that were ≥ 4 mm thick.

Are there high-risk subgroups for isolated locoregional failure in patients who had T1/2 breast cancer with one to three positive lymph nodes and received mastectomy without radiotherapy?

To define the factors associated with increased risk of isolated locoregional failure that may justify postmastectomy radiotherapy in patients with T1/2 breast cancer and 1-3 positive lymph nodes. Between 1990 and 2002, 248 patients who had pT1-2 breast cancer and 1-3 positive lymph nodes were treated with mastectomy without radiotherapy (age 32-84, median 54). Median follow-up time was 82 months (range 2-189 months). For all patients, the 8-year isolated locoregional failure-free rate was 95 %. In univariate analysis, hormone receptor status and administration of hormone therapy were statistically significant factors, and vascular invasion was the borderline significant factor for isolated locoregional failure-free rates (P = 0.0377, 0.0181, and 0.0555, respectively). The 8-year isolated locoregional failure-free rates were 98 % for patients with positive hormone receptor status and 90 % for patients with negative hormone receptor status, 97 % for patients who received hormone therapy and 89 % for patients who did not receive hormone therapy, 92 % for patients with vascular invasion and 97 % for patients without vascular invasion. In multivariate analysis for hormone receptor status and vascular invasion, the former was statistically significant (P = 0.0491) and the latter was borderline significant (P = 0.0664). When patients had both negative hormone receptor and positive vascular invasion status, the 8-year isolated locoregional failure-free rates decreased to 83 %. With regard to patients who had pT1/2 breast cancer and 1-3 positive lymph nodes, isolated locoregional failure was not common in general; however, patients who had both negative hormone receptor status and vascular invasion were comparatively high-risk patients for isolated locoregional failure.

Locoregional Failure in Early-Stage Breast Cancer Patients Treated With Radical Mastectomy and Adjuvant Systemic Therapy: Which Patients Benefit From Postmastectomy Irradiation?

To assess the locoregional failure in patients with Stage I-II breast cancer treated with radical mastectomy and to evaluate whether a subset of these patients might be at sufficiently high risk of locoregional recurrence (LRR) to benefit from postmastectomy irradiation (PMRT). Stage I-II breast cancer patients (n = 150) treated with radical mastectomy without adjuvant irradiation between 1999 and 2005 were analyzed. The pattern of LRR was reported. Kaplan-Meier analysis was used to calculate rates of LRR, and Cox proportional hazards methods were used to evaluate potential risk factors. Median follow-up was 75 months. Mean patient age was 56 years. One-hundred forty-three (95%) patients received adjuvant systemic therapy: 85 (57%) hormonal therapy alone, 14 (9%) chemotherapy alone, and 44 (29%) both chemotherapy and hormonal therapy. Statistically significant factors associated with increased risk of LRR were premenopausal status (p = 0.004), estrogen receptor negative cancer (p = 0.02), pathologic grade 3 (p = 0.02), and lymphovascular invasion (p = 0.001). T and N stage were not associated with increased risk of regional recurrence. The 5-year LRR rate for patients with zero or one, two, three, and four risk factors was 1%, 10.3%, 24.2%, and 75%, respectively. A subset of patients with early-stage breast cancer is at high risk of LRR, and therefore PMRT might be beneficial.

Highlights of This Issue

Retinoid resistance is common in most solid tumors, including pancreatic adenocarcinoma. Gupta and colleagues show that the majority (∼80%) of pancreatic cancers are likely to be resistant to retinoic acid due to the tumorspecific overexpression of fatty acid–binding protein-5 (FABP5), which channels all-trans retinoic acid (ATRA) into survival and proliferation pathways. On the contrary, approximately 20% of cases that lack FABP5 expression but are characterized by high levels of cellular retinoic acid–binding protein-2 (CRABP2), retain retinoid sensitivity. A simple immunohistochemical assay can identify the subset of FABP5-negative tumors most likely to benefit from ATRA therapy in settings such as gemcitabine resistance.Immunosuppressive phenotype and infiltrative growth into the surrounding brain tissue are characteristic features of malignant gliomas. Such factors as TGF-β are relevant in both processes. Here, Lemke and colleagues show that 4IgB7H3, a member of the B7-family of costimulatory proteins, has similar properties that function in a TGF-β–independent manner. Clinically, expression of B7H3 in human glioma correlates with the grade of malignancy and is associated with worse clinical outcome. Mechanistically, the active immunosuppressive and proinvasive form of 4IgB7H3 is released into the supernatant in glioma, whereas in other tumors and dendritic cells the membrane-bound form has been found to be active. Thus, 4IgB7H3 has potential as a diagnostic and therapeutic target in malignant glioma.Follicular cystic lesions, keratoacanthomas, and squamous cell carcinomas, all seemingly originating from hair follicles, frequently occur in patients treated with sorafenib. More than 30% of these lesions harbor oncogenic, potentially UV-induced HRAS, TGFBR1, or TP53 mutations. Sorafenib, like other BRAF inhibitors, induces a paradoxical increase in keratinocyte proliferation and MAP kinase pathway activation due to BRAF/CRAF dimerization and CRAF activation. The findings reported by Arnault and colleagues have major implications because they suggest that other cells with wild-type BRAF carrying a somatic event like a RAS mutation could be transformed by sorafenib or other BRAF inhibitors in vivo.TP53 is the most commonly mutated gene in head and neck squamous cell carcinoma (HNSCC); however, its use as a prognostic marker is controversial. Skinner and colleagues found that a class of TP53 mutations (“disruptive”) was predictive for higher locoregional failure in patients treated with radiation, who showed increased in vitro radioresistance and decreased rates of senescence. They observed that HNSCC cells harboring disruptive TP53 could be selectively radiosensitized with metformin both in vitro and in vivo. Also, metformin use was associated with decreased locoregional failure in patients following radiation. These data suggest that TP53 is a promising biomarker to predict local failure and that metformin is a potential agent to target these tumors.

Need for a new trial to evaluate postoperative radiotherapy in renal cell carcinoma: a meta-analysis of randomized controlled trials

BackgroundA meta-analysis was conducted to assess the impact of postoperative radiotherapy (PORT) in renal cell carcinoma (RCC) on overall survival (OS), disease-free survival (DFS) and locoregional failure (LRF). Materials and methodsThe Medline, CANCERLIT, Cochrane library database and search engines were searched to identify randomized controlled studies comparing radical nephrectomy alone with radical nephrectomy followed by PORT for localized RCC. Further, radiotherapy techniques and associated side-effects were evaluated. ResultsSeven controlled trials with a total patient population of 735 were identified. Pooled results from these trials showed a significant reduction of LRF in patients treated with PORT (P ≤ 0.0001). However, there was no difference in OS (P = 0.29) and DFS (P = 0.14). The majority of patients was treated with larger field sizes with parallel-opposed anteroposterior fields. PORT was generally well tolerated; in total, six PORT-related deaths were seen. The resultant funnel plot was broader (Egger test P = 0.14) due to low number of patients. ConclusionsPORT significantly reduces LRF but has no effect on OS and DFS. However, due to poor patient accrual and older radiotherapy techniques in previous studies, there is a need for a new trial to evaluate PORT using conformal and intensity-modulated radiotherapy techniques.

Prognostic factors for loco-regional failure in early stage (I and II) squamous cell carcinoma of the gingivobuccal complex

The objective of the article is to study the prognostic indicators of loco-regional failure in patients with early stage cancers of the gingivobuccal complex (GBC) treated at a single institution. The study design is based on retrospective chart review. A review of 2,275 patients diagnosed with GBC was conducted from January 1997 to December 1999, wherein 207 patients who fulfilled our inclusion criteria were analyzed. Univariate analysis, multivariate analysis, and disease-free survival are reported. During a median follow-up of 2.85 years there were 85 (43%) loco-regional failures of which 64% could be salvaged. As much as 80% of all failures occurred within the first 24 months and the mean survival for patients with recurrences was 9.6 months. Two and five-year disease-free survival for the entire cohort was 65% and 52%, respectively. Nodal metastasis, soft tissue infiltration, and pathological bone involvement correlated with poor disease-free survival on multivariate analysis. Early stage tumors of the GBC as evaluated clinically are often upstaged pathologically due to a high rate of occult nodal metastasis and local failure as they tend to invade bone and infiltrate adjacent soft tissue. Consequently, we recommend aggressive surgical therapy as we would recommend for advanced stage cancers of the GBC which includes a wide three-dimensional resection to account for soft tissue and bony infiltrations and adjuvant therapy in the presence of adverse features since salvage rates for recurrent tumors are poor.