Danielle N. Margalit

Tolerability of combined modality therapy for rectal cancer in elderly patients aged 75 years and older.

PURPOSE To determine the rate of treatment deviations during combined modality therapy for rectal cancer in elderly patients aged 75 years and older. METHODS AND MATERIALS We reviewed the records of consecutively treated patients with rectal cancer aged 75 years and older treated with combined modality therapy at Massachusetts General Hospital and Brigham & Womens Hospital from 2002 to 2007. The primary endpoint was the rate of treatment deviation, defined as a treatment break, dose reduction, early discontinuation of therapy, or hospitalization during combined modality therapy. Patient comorbidity was rated using the validated Adult Comorbidity Evaluation 27 Test (ACE-27) comorbidity index. Fishers exact test and the Mantel-Haenszel trend test were used to identify predictors of treatment tolerability. RESULTS Thirty-six eligible patients had a median age of 79.0 years (range, 75-87 years); 53% (19/36) had no or mild comorbidity and 47% (17/36) had moderate or severe comorbidity. In all, 58% of patients (21/36) were treated with preoperative chemoradiotherapy (CRT) and 33% (12/36) with postoperative CRT. Although 92% patients (33/36) completed the planned radiotherapy (RT) dose, 25% (9/36) required an RT-treatment break, 11% (4/36) were hospitalized, and 33% (12/36) had a dose reduction, break, or discontinuation of concurrent chemotherapy. In all, 39% of patients (14/36) completed≥4 months of adjuvant chemotherapy, and 17% (6/36) completed therapy without a treatment deviation. More patients with no to mild comorbidity completed treatment than did patients with moderate to severe comorbidity (21% vs. 12%, p=0.66). The rate of deviation did not differ between patients who had preoperative or postoperative CRT (19% vs. 17%, p=1.0). CONCLUSIONS The majority of elderly patients with rectal cancer in this series required early termination of treatment, treatment interruptions, or dose reductions. These data suggest that further intensification of combined modality therapy for rectal cancer should be performed with caution in elderly patients, who require aggressive supportive care to complete treatment.

Changing prognostic significance of tumor stage and nodal stage in patients with squamous cell carcinoma of the oropharynx in the human papillomavirus era

Although human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (OPSCC) tends to present at an advanced nodal stage (N stage), the prognosis is generally better than that for HPV‐negative OPSCC. Prior work has demonstrated the increasing incidence of HPV‐related OPSCC in the United States. This study was designed to determine whether the changing epidemiology of OPSCC is reflected in changes in the prognostic significance of the tumor stage (T stage) and the N stage in a population‐based cohort.

Technological Advancements and Error Rates in Radiation Therapy Delivery

PURPOSE Technological advances in radiation therapy (RT) delivery have the potential to reduce errors via increased automation and built-in quality assurance (QA) safeguards, yet may also introduce new types of errors. Intensity-modulated RT (IMRT) is an increasingly used technology that is more technically complex than three-dimensional (3D)-conformal RT and conventional RT. We determined the rate of reported errors in RT delivery among IMRT and 3D/conventional RT treatments and characterized the errors associated with the respective techniques to improve existing QA processes. METHODS AND MATERIALS All errors in external beam RT delivery were prospectively recorded via a nonpunitive error-reporting system at Brigham & Womens Hospital/Dana Farber Cancer Institute. Errors are defined as any unplanned deviation from the intended RT treatment and are reviewed during monthly departmental quality improvement meetings. We analyzed all reported errors since the routine use of IMRT in our department, from January 2004 to July 2009. Fishers exact test was used to determine the association between treatment technique (IMRT vs. 3D/conventional) and specific error types. Effect estimates were computed using logistic regression. RESULTS There were 155 errors in RT delivery among 241,546 fractions (0.06%), and none were clinically significant. IMRT was commonly associated with errors in machine parameters (nine of 19 errors) and data entry and interpretation (six of 19 errors). IMRT was associated with a lower rate of reported errors compared with 3D/conventional RT (0.03% vs. 0.07%, p = 0.001) and specifically fewer accessory errors (odds ratio, 0.11; 95% confidence interval, 0.01-0.78) and setup errors (odds ratio, 0.24; 95% confidence interval, 0.08-0.79). CONCLUSIONS The rate of errors in RT delivery is low. The types of errors differ significantly between IMRT and 3D/conventional RT, suggesting that QA processes must be uniquely adapted for each technique. There was a lower error rate with IMRT compared with 3D/conventional RT, highlighting the need for sustained vigilance against errors common to more traditional treatment techniques.

Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer

Background:Preclinical and clinical studies suggest potential synergy between high dose per fraction focal radiation and immunotherapy. However, conventionally fractionated radiation regimens in combination with concurrent chemotherapy are more commonly administered to patients as definitive treatment and may have both immune-stimulating and -suppressive effects.Methods:We prospectively collected longitudinal samples from head and neck squamous cell carcinoma patients receiving definitive radiation therapy. We quantified changes in populations of circulating immune cells and chemokines CXCL9, 10, and 16. Analyses of humoral and cellular immune responses were conducted in select patients via proteomic analysis and T-cell receptor sequencing.Results:Treatment not only increased circulating CD-8+ T-effector cells, but also myeloid-derived suppressor cells, regulatory T cells, and checkpoint receptor-expressing T cells, particularly PD-1+ T cells. Significant decreases in CXCL10 and increases in CXLC16 were noted. Treatment also increased the percentage of unique and dominant TCR clones, and increased humoral responses as measured by proteomic array.Conclusions:Our results suggest that fractionated chemoradiation leads to quantifiable effects in circulating immune mediators, including a balance of stimulatory and suppressive mechanisms. These results suggest future combinations with immune checkpoint blockade.

A Single Nucleotide Polymorphism in Inflammatory Gene RNASEL Predicts Outcome after Radiation Therapy for Localized Prostate Cancer

Purpose: To study associations between single nucleotide polymorphisms (SNP) in Ribonuclease L (RNASEL), a gene implicated in inflammation and prostate cancer risk, and outcomes after radiation therapy. Experimental Design: We followed participants in the prospective US Health Professionals Follow-Up Study treated with radiation therapy for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance. We used multivariable Cox proportional hazards models to assess per-allele associations with the primary outcome defined as time to a composite endpoint including development of lethal prostate cancer or biochemical recurrence. Results: We followed 434 patients treated with radiation therapy for a median of 9 years. On multivariate analysis, the rs12757998 variant allele was associated with significantly decreased risk of the composite endpoint [HR: 0.65; 95% confidence interval (CI), 0.45–0.94%; P = 0.02] driven by decreased biochemical recurrence (HR: 0.60; 95% CI, 0.40–0.89%; P = 0.01) and men treated with external beam (HR: 0.58; 95% CI, 0.36–0.93%; P = 0.02). In contrast, in 516 men from the same cohort treated with radical prostatectomy, we found no significant impact of this variant on outcome. Furthermore, the rs12757998 variant allele significantly modified the association between androgen deprivation therapy and outcomes after radiation therapy (p-interaction = 0.02). Conclusion: We show an association between RNASEL SNP rs12757998 and outcome after radiation therapy for prostate cancer. This SNP is associated with increased circulating C-reactive protein and interleukin-6, suggesting a potential role for inflammation in the response to radiation. If validated, genetic predictors of outcome may help inform prostate cancer management. Clin Cancer Res; 19(6); 1612–9. ©2013 AACR.

Incorporation of next-generation sequencing into routine clinical care to direct treatment of head and neck squamous cell carcinoma

Purpose: The clinical impact of next-generation sequencing (NGS) in patients with head and neck squamous cell carcinoma (HNSCC) has not been described. We aimed to evaluate the clinical impact of NGS in the routine care of patients with HNSCC and to correlate genomic alterations with clinical outcomes. Experimental Design: Single-center study examining targeted NGS platform used to sequence tumor DNA obtained from 213 HNSCC patients evaluated in outpatient head and neck oncology clinic between August 2011 and December 2014. We correlated tumor genomic profiling results with clinical outcomes. Results: PI3K/RTK pathway activation occurred frequently [activating PIK3CA mutation or amplification (13%), PTEN inactivation (3%), RAS activation (6%), EGFR or ERBB2 activation (9%)]. Alterations in pathways affecting cell-cycle regulation [CCND1 amplification (9%), CDKN2A inactivation (17%), BRCA2 inactivation (2%)] and squamous differentiation [NOTCH1 inactivation (8%) andEP300 inactivation (6%)] were identified. PIK3CA amplification (n = 43), not PIK3CA mutation, was associated with significantly poorer progression-free survival (P = 0.0006). Oncogenic RAS mutations (n = 13) were associated with significantly poorer progression-free survival (P = 0.0001) and lower overall survival (P = 0.003). Eight patients with advanced, treatment-refractory HNSCC enrolled on clinical trials matched to tumor profiling results, and 50% achieved a partial response. Conclusions: Incorporation of NGS clinical assays into the routine care of patients with HNSCC is feasible and may readily facilitate enrollment into clinical trials of targeted therapy with a higher likelihood of success. Data can be utilized for discovery of genomic biomarkers of outcome. PIK3CA amplification and RAS mutations were frequently identified and associated with poorer prognosis in this cohort. Clin Cancer Res; 22(12); 2939–49. ©2016 AACR.

Patterns of failure after reirradiation with intensity-modulated radiation therapy and the competing risk of out-of-field recurrences

PURPOSE To describe patterns of failure (POF) after reirradiation (reRT) with intensity modulated radiation therapy (IMRT) for recurrent/second primary squamous cell carcinoma of the head and neck. METHODS From 08/2004-02/2013, 75 consecutive patients received reRT with IMRT. Gross tumor was generally treated with a 5mm planning target volume (PTV) margin. For postoperative cases, a 5mm PTV was added to the clinical target volume which included the postoperative bed. Elective neck coverage was not standard. POF were characterized by correlating the recurrent tumor location on CT-imaging with the reRT IMRT plan. RESULTS Patients received definitive reRT (55%) or postoperative reRT (45%) to a median 60Gy (range, 59.4-70Gy). Most patients (88%) received concurrent chemotherapy including induction (16%). The median overall survival was 1.8years. Isolated local-regional recurrence (LRR) was the most common failure-type (2-year cumulative incidence [CI] 22.5% [95% C.I. 13.6-32.7%]), but concurrent LRR and distant-failure occurred frequently (2-year CI LRR+distant-failure 19.6% [95% C.I. 11.3-29.5%]); isolated distant-failure was rare (2-year CI 5.7% [95% C.I. 1.8-12.8%]). The 2-year in-field control was 65% (95% C.I. 52-81%) reflecting encouraging control within the irradiated target. Patients with gross disease were more likely to recur in-field (p=0.02), whereas postoperative patients were more likely to recur out-of-field/marginally than in-field (p=0.02). CONCLUSIONS POF after reRT differ when treating gross disease or postoperatively and should be considered when delineating reRT targets. Aggressive local therapy resulted in favorable in-field control, yet there remains a high competing risk of regional and distant micrometastatic disease. Better systemic agents are needed to control clinically occult local-regional and distant disease.

Effects of definitive chemoradiation on circulating immunologic angiogenic cytokines in head and neck cancer patients

BackgroundPreclinical studies suggest a synergistic effect between radiation, immunotherapy and anti-angiogenic therapy, although the mechanisms are unclear. Angiogenic cytokines are known to affect the immune system, and their levels may be associated with response to immunotherapy. Here, we assess changes in circulating VEGF, as well as angiogenic cytokines angiopoietin-1 and -2 (Ang1, Ang2), and placental growth factor (PLGF) that occur during definitive chemo-radiotherapy in HNSCC patients.MethodsWe prospectively collected blood samples from patients receiving definitive radiation with or without chemotherapy. Serum Ang1, Ang2, VEGF, and PLGF were measured via cytokine assays.ResultsThe majority of patients had advanced stage, node positive HPV-associated oropharyngeal cancer, and received radiation to a median dose of 70 Gy with concurrent cisplatin. Over the course of treatment, serum VEGF and Ang1 levels decreased in 20/24 (84 %, p < 0.0001) and 21/24 (88 %, p < 0.0001) patients, respectively, and Ang2 and PLGF levels increased in 20/24 (83 %, p < 0.0001) patients.ConclusionsWe find significant changes in angiogenic cytokines in the majority of HNSCC patients over the course of chemoradiation. Decreases in VEGF caused by radiation may represent one mechanism of potential synergy with immunotherapy. Increases in Ang2 and PLGF are interesting given their link to tumor associated angiogenesis and poor prognosis. Additional studies are needed to explore synergies between anti-angiogenic treatments, immunotherapy, and chemoradiation in HNSCC.

Salivary and serum HPV antibody levels before and after definitive treatment in patients with oropharyngeal squamous cell carcinoma

BACKGROUND HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence. Laboratory assays that identify virally-mediated disease and predict HPV clearance in OPSCC may have important prognostic implications. OBJECTIVE Here we investigated serum, salivary HPV16 early (E) antibodies before and after definitive chemoradiotherapy (CRT) in patients with locoregionally advanced OPSCC. METHODS We prospectively measured salivary, serum samples at the beginning of and 6-7 weeks following the completion of CRT in 44 patients. IgG antibodies targeting N- and C-terminal fragments of E2 (NE2, CE2), E6 and E7 were measured by programmable enzyme-linked immunosorbent assay. RESULTS We observed serum antibodies directed against HPV-associated E proteins in patients with HPV-associated OPSCC. E7 directed antibodies were detected in saliva in the majority of patients, and were associated with HPV status (p= 0.03). When analyzed longitudinally, median salivary E7 antibody levels decreased significantly post-treatment (p= 0.007). CONCLUSIONS Our results demonstrate the feasibility of measuring HPV16 E antibodies in saliva and serum. E7 antibodies, in particular, are more detectable in saliva as compared with other E protein antibodies. Measuring E7 salivary antibody levels at various time points may have utility in understanding HPV clearance and should be explored for their ability to predict the risk of recurrence.

Population-based validation of the recursive partitioning analysis-based staging system for oropharyngeal cancer.

The American Joint Committee on Cancer (AJCC) staging system does not adequately distinguish prognostic groups in the era of human papillomavirus (HPV)‐related oropharyngeal cancer. The purpose of this study was to validate a recursive partitioning analysis (RPA)‐based stage grouping on a population‐wide level.