Tien Phan

PIK3CA mutational status and overall survival in patients with cervical cancer treated with radical chemoradiotherapy

OBJECTIVE Mutational activation of PIK3CA is associated with poor prognosis in patients with solid tumors, and may predict favorable response to PI3K/AKT/mTOR pathway inhibitors. However, PIK3CA mutational status has not previously been evaluated in patients with cervical carcinoma treated with radical chemoradiotherapy (CRT). The aims of this study were (1) to evaluate the frequency of PIK3CA mutations in patients with cervical cancer treated with radical CRT and (2) to examine the effect of tumor PIK3CA mutational status in pre-treatment biopsies on overall survival (OS) and progression-free survival (PFS). METHODS Patients with cervical cancer, treated at a single institution with radical CRT, from 1999 to 2008, were eligible for this retrospective study. Pre-treatment tumor biopsies (n=157) were retrieved. Genomic DNA was extracted from tumor blocks, and exons 9 and 20 of the PIK3CA gene were sequenced for mutations. RESULTS Eighty-two tumors were sequenced for both exon 9 and exon 20. 19/82 (23%) tumors were PIK3CA mutation positive; of these 84% were squamous cell carcinomas. 79% of mutations were in exon 9. PIK3CA mutation status was strongly associated with overall survival (OS) in FIGO stage IB/II patients, unadjusted HR 6.0 (95% CI 2.1-17.5), p=0.0002, but not stage III/IVA patients, unadjusted HR 1.0 (95% CI 0.32-3.1), p=0.98. CONCLUSIONS In cervical cancer patients treated with CRT, tumor PIK3CA mutation status was associated with overall survival in FIGO stage IB/II cervix cancers. Further evaluation with a larger dataset will be required to validate these findings to inform potential clinical trials designs involving PI3K/AKT/mTOR pathway inhibitors.

Absence of Planned Neck Dissection for the N2-N3 Neck After Chemoradiation for Locally Advanced Squamous Cell Carcinoma of the Head and Neck

OBJECTIVE To review our institutional experience of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) and N2-N3 neck disease with respect to neck recurrence after chemoradiation without planned neck dissection (ND). DESIGN Retrospective study. SETTING Tom Baker Cancer Centre, Calgary, Alberta, Canada. PATIENTS Fifty-four adults with locally advanced SCCHN and N2-N3 neck disease. INTERVENTIONS Eighty consecutive patients were treated with chemoradiation, 70 Gy given as 2 Gy daily for 7 weeks, with cisplatin, 20 mg/m(2), given on the first 4 days of weeks 1 and 5. Of the 80 patients, 54 were evaluable. MAIN OUTCOME MEASURES Primary outcomes were overall survival and absence or presence of neck disease after chemoradiation. Secondary outcomes included disease-specific survival and locoregional recurrence-free survival. RESULTS Median follow-up of living patients was 35 months. Patients with a complete response (CR) did not have any planned ND. Factors associated with the absence of recurrent neck disease included CR (P < .001), younger age (P = .02), and better Karnofsky Performance Status (P = .049). In patients achieving CR, 2-year overall, disease-specific, and locoregional recurrence-free survival was 92%, 95%, and 95%, respectively. Three of the 43 patients (7%) with N2 lesions obtaining CR subsequently experienced a neck recurrence at a median of 15 months (range, 7-24 months). CONCLUSIONS In these patients with locally advanced SCCHN and N2-N3 neck disease treated with chemoradiation and achieving CR, only a few patients with N2 neck disease experienced recurrence despite the absence of planned ND. Prospective trials are needed to identify patients with N2 neck disease who may still benefit from planned ND after chemoradiation. There were not enough patients with N3 neck disease to make any recommendations.

Assessment of ERCC1 and XPF Protein Expression Using Quantitative Immunohistochemistry in Nasopharyngeal Carcinoma Patients Undergoing Curative Intent Treatment

PURPOSE We sought to evaluate the prognostic/predictive value of ERCC1 and XPF in patients with nonmetastatic nasopharyngeal carcinoma (NPC) treated with curative intent. METHODS AND MATERIALS ERCC1 and XPF protein expression was evaluated by immunofluorescence combined with automated quantitative analysis (AQUA) using the FL297 and 3F2 antibodies, respectively. ERCC1 and XPF protein expression levels were correlated with clinical outcomes. RESULTS Patient characteristics were as follows: mean age 52 years (range, 18-85 years), 67% male, 72% Karnofsky performance status (KPS) ≥ 90%, World Health Organization (WHO) type 1/2/3 = 12%/28%/60%, stage III/IV 65%. With a median follow-up time of 50 months (range, 2.9 to 120 months), the 5-year overall survival (OS) was 70.8%. Median standardized nuclear AQUA scores were used as cutpoints for ERCC1 (n=138) and XPF (n=130) protein expression. Agreement between dichotomized ERCC1 and XPF scores was high at 79.4% (kappa = 0.587, P<.001). Neither biomarker predicted locoregional recurrence, DFS, or OS after adjustment for age and KPS, irrespective of stratification by stage, WHO type, or treatment. CONCLUSIONS Neither ERCC1 nor XPF, analyzed by quantitative immunohistochemistry using the FL297 and 3F2 antibodies, was prognostic or predictive in this cohort of NPC patients.

ATM, THMS, and RRM1 protein expression in nasopharyngeal carcinomas treated with curative intent

In advanced nasopharyngeal carcinoma (NPC), biomarkers may help predict survival.

Expression of PD-L1 and presence of CD8-positive T cells in pre-treatment specimens of locally advanced cervical cancer

Several of the cancer immunotherapies under investigation or in clinical use target the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling axis. PD-L1 expression in tumor samples has been used as a predictive marker for response to these therapeutics, and may also have independent prognostic utility when assessed along with immune cell markers. Our objectives were to assess the expression of PD-L1 in tumor specimens from a uniformly treated patient cohort with locally advanced cervical cancer, and to determine its prognostic significance along with the density of tumor-infiltrating T cells. We identified 120 patients with locally advanced cervical cancer treated with radical chemoradiotherapy, and built tissue microarrays from their formalin-fixed, paraffin-embedded pre-treatment biopsies. We used conventional brightfield and fluorescence immunohistochemistry to detect PD-L1, and quantified protein expression using both manual pathologist scoring and automated software analysis. We also evaluated the effect of PD-L1 expression in tumors, along with the presence and density of intra-tumoral CD8+ T cells, on patient survival outcomes. Approximately 96% of the tumor samples expressed PD-L1, as determined using quantitative software analysis. Neither expression of PD-L1 nor density of CD8+ T cells was associated with progression-free or overall survival. However, there was a trend towards worse progression-free survival in patients whose tumors expressed PD-L1 but lacked CD8+ T cells (hazard ratio=0.43 (0.18–1.01), P=0.053). Nevertheless, the high percentage of cervical cancer tumor samples expressing PD-L1 suggests that anti-PD-L1 or anti-PD-1 therapies are potential treatment options for this patient population.

Implementation and validation of a combined MRI-CT–based cervical cancer brachytherapy program using existing infrastructure

PURPOSE To describe the implementation of an MRI-CT-based cervical cancer brachytherapy (BT) program using existing infrastructure. To evaluate its impact on treatment planning. METHODS AND MATERIALS A step-wise method was used to design and implement three-dimensional-based planning. Prospective risk analysis was used to create a process map and planning protocol. To evaluate the program, charts of cervical cancer patients treated curatively between January 2013 and December 2014, with at least one MRI during BT planning, were reviewed. Dosimetric comparisons were made between prescription point used and that of the traditional Point A and between MRI-planned treatments and CT-planned treatments. They were evaluated for differences between plans as well as adherence to Groupe Européen de Curiethérapie-European Society for Radiotherapy & Oncology (GEC-ESTRO) recommendations for high-risk clinical target volume coverage and organs-at-risk constraints. RESULTS Implementation of the MRI-CT planning program occurred using existing infrastructure. Key to the implementation was communication between departments and the use of a process map to document the workflow. Eighty percent of treatments were prescribed to a point other than Point A, there were no major differences between the MRI-planned and CT-planned (with MRI guidance) treatments, and GEC-ESTRO recommendations were met for target coverage and organs at risk dose constraints. CONCLUSIONS It was feasible to implement an MRI-CT-based cervical cancer BT planning program using existing infrastructure and that resulting plans meet GEC-ESTRO recommendations.

Retrospective evaluation of visually monitored deep inspiration breath hold for breast cancer patients using edge detection

Purpose: Deep inspiration breath hold (DIBH) can reduce cardiac dose during left-sided breast cancer radiotherapy. This study uses cine imaging with edge detection to evaluate a visually-monitored DIBH technique (VM-DIBH)

Including internal mammary lymph nodes in radiation therapy for synchronous bilateral breast cancer: an international survey of treatment technique and clinical priorities

PurposeThe aim of this study was to understand the international standard practice for radiation therapy treatment techniques and clinical priorities for institutions including the internal mammary lymph nodes (IMLNs) in the target volume for patients with synchronous bilateral breast cancer.MethodsAn international survey was developed to include questions that would provide awareness of favored treatment techniques, treatment planning and delivery resource requirements, and the clinical priorities that may lead to the utilization of preferred treatment techniques.ResultsOf the 135 respondents, 82 indicated that IMLNs are regularly included in the target volume for radiation therapy (IMLN-inclusion) when the patient is otherwise generally indicated for regional nodal irradiation. Of the 82 respondents that regularly include IMLNs, five were removed as those respondents do not treat this population synchronously. Of the 77 respondents, institutional standard of care varied significantly, though VMAT (34%) and combined static photon and electron fields (21%) were the most commonly utilized techniques. Respondents did preferentially select target volume coverage (70%) as the most important clinical priority, followed by normal tissue sparing (25%).ConclusionThe results of the survey indicate that the IMLN-inclusion for radiation therapy has not yet been comprehensively adopted. As well, no consensus on best practice for radiation therapy treatment techniques has been reached.

Expression of DNA damage response proteins in cervical cancer patients treated with radical chemoradiotherapy

OBJECTIVE The management of locally advanced cervical cancer has improved significantly with the advent of cisplatin-based chemoradiotherapy (CRT) as the primary treatment regimen. Nevertheless, a significant proportion of patients fail to respond or relapse on this treatment and have a very poor prognosis. Our goal was to determine the prognostic value of a panel of proteins involved in detection and repair of DNA damage. METHODS We performed fluorescence immunohistochemistry, and used software analysis to assess expression of DNA damage response proteins ATM, DNA-PKcs, PARP-1, Ku70 and Ku86 in 117 pre-treatment specimens from patients with locally advanced cervical cancer. We compared expression to clinicopathologic correlates to determine prognostic significance. RESULTS Five-year progression-free survival was significantly lower in the low expressors than in high expressors of ATM (35% vs. 58%, p=0.044) and PARP-1 (24% vs. 61%, p=0.003), and showed a trend to significance for DNA-PKcs (30% vs. 60%, p=0.050). Low expression of the same proteins also correlated significantly with lower overall survival. In multivariable analysis, adjusted for FIGO stage and tumor size, low ATM and PARP-1 expression was significantly associated with both poorer progression-free and overall survival. Pairwise analyses indicated that expression levels of these proteins were correlated. CONCLUSIONS Expression of DNA damage response proteins in cervical cancer is associated with outcome in patients treated with CRT. Immunohistochemical analysis of these proteins may be useful in guiding treatment decisions in such patients.

Anemia, leukocytosis and thrombocytosis as prognostic factors in patients with cervical cancer treated with radical chemoradiotherapy: A retrospective cohort study

Introduction Anemia has long been associated with poor prognosis in patients with cervical cancer. Recently, additional hematologic parameters have emerged as potential indicators of worse outcome in this patient group. In a cohort of cervical cancer patients treated with chemoradiotherapy (CRT) and brachytherapy, we report on the prognostic significance of hematologic parameters including anemia, leukocytosis, neutrophil to lymphocyte ratio (NLR), and thrombocytosis, the effect of combining anemia with other hematologic parameters, and the effect of changes in hemoglobin levels during treatment. Materials and methods Two-hundred fifty-seven cervical cancer patients were retrospectively identified from a single cancer institution’s database. Hematologic parameters were categorized as: anemia (hemoglobin ≤115 g/L), leukocytosis (white blood cell count >10 × 109/L), thrombocytosis (platelets >400 × 109/L), and NLR (ratio >5). The association between clinical factors and hematologic parameters on progression-free survival (PFS) and overall survival (OS) were assessed at 5 years. Results At 5 years, both pre-treatment anemia (PFS: 60% vs 34%, p < 0.0001; OS: 68% vs 41%, p < 0.0001) and on-treatment anemia (PFS: 62% vs 40%, p < 0.0001; OS: 70% vs 48%, p < 0.0001) were significantly associated with worse survival. This adverse effect on 5-year PFS and OS was increased in patients with both pre-treatment anemia and leukocytosis (PFS: 72% vs 42%, p < 0.0001; OS: 68% vs 37%, p < 0.0001) and pre-treatment anemia and elevated NLR (PFS: 61% vs 30%, p < 0.0001; OS: 68% vs 37%, p < 0.0001). Five-year PFS (50% vs 31%) and OS (60% vs 36%) was better in patients whose pre-treatment anemia improved to normal hemoglobin levels on treatment vs those patients who were anemic both pre- and on-treatment. Conclusion Pre-treatment and on-treatment anemia were significant, independent predictors of worse PFS and OS. Anemia and other hematologic parameters remain prognostic markers for cervical cancer patients. Improvement in PFS and OS was seen in patients with normalization of hemoglobin.