Shyam Rao

Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study

BACKGROUND Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma. METHODS We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov, numbers NCT02048020 and NCT01716195. FINDINGS Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54-67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26-37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77-97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 [39%]) and neutropenia (five [11%]), and during chemoradiotherapy were dysphagia (four [9%]) and mucositis (four [9%]). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment. INTERPRETATION Chemoradiotherapy with radiation doses reduced by 15-20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients. FUNDING University of California.

Long-term regional control in the observed neck following definitive chemoradiation for node-positive oropharyngeal squamous cell cancer

Traditionally, patients treated with chemoradiotherapy for node‐positive oropharyngeal squamous cell carcinoma (N+ OPSCC) have undergone a planned neck dissection (ND) after treatment. Recently, negative post‐treatment positron‐emission tomography (PET)/computed tomography (CT) imaging has been found to have a high negative predictive value for the presence of residual disease in the neck. Here, we present the first comprehensive analysis of a large, uniform cohort of N+ OPSCC patients achieving a PET/CT‐based complete response (CR) after chemoradiotherapy, and undergoing observation, rather than ND. From 2002 to 2009, 302 patients with N+ OPSCC treated with 70 Gy intensity‐modulated radiation therapy and concurrent chemotherapy underwent post‐treatment clinical assessment including PET/CT. CR was defined as no evidence of disease on clinical examination and post‐treatment PET/CT. ND was reserved for patients with

Age-specific periictal electroclinical features of generalized tonic-clonic seizures and potential risk of sudden unexpected death in epilepsy (SUDEP)

Generalized tonic-clonic seizure (GTCS) is the commonest seizure type associated with sudden unexpected death in epilepsy (SUDEP). This study examined the semiological and electroencephalographic differences (EEG) in the GTCSs of adults as compared with those of children. The rationale lies on epidemiological observations that have noted a tenfold higher incidence of SUDEP in adults. We analyzed the video-EEG data of 105 GTCS events in 61 consecutive patients (12 children, 23 seizure events and 49 adults, 82 seizure events) recruited from the Epilepsy Monitoring Unit. Semiological, EEG, and 3-channel EKG features were studied. Periictal seizure phase durations were analyzed including tonic, clonic, total seizure, postictal EEG suppression (PGES), and recovery phases. Heart rate variability (HRV) measures including RMSSD (root mean square successive difference of RR intervals), SDNN (standard deviation of NN intervals), and SDSD (standard deviation of differences) were analyzed (including low frequency/high frequency power ratios) during preictal baseline and ictal and postictal phases. Generalized estimating equations (GEEs) were used to find associations between electroclinical features. Separate subgroup analyses were carried out on adult and pediatric age groups as well as medication groups (no antiepileptic medication cessation versus unchanged or reduced medication) during admission. Major differences were seen in adult and pediatric seizures with total seizure duration, tonic phase, PGES, and recovery phases being significantly shorter in children (p<0.01). Generalized estimating equation analysis, using tonic phase duration as the dependent variable, found age to correlate significantly (p<0.001), and this remained significant during subgroup analysis (adults and children) such that each 0.12-second increase in tonic phase duration correlated with a 1-second increase in PGES duration. Postictal EEG suppression durations were on average 28s shorter in children. With cessation of medication, total seizure duration was significantly increased by a mean value of 8s in children and 11s in adults (p<0.05). Tonic phase duration also significantly increased with medication cessation, and although PGES durations increased, this was not significant. Root mean square successive difference was negatively correlated with PGES duration (longer PGES durations were associated with decreased vagally mediated heart rate variability; p<0.05) but not with tonic phase duration. This study clearly points out identifiable electroclinical differences between adult and pediatric GTCSs that may be relevant in explaining lower SUDEP risk in children. The findings suggest that some prolonged seizure phases and prolonged PGES duration may be electroclinical markers of SUDEP risk and merit further study.

External beam radiotherapy with or without concurrent chemotherapy in advanced or recurrent non‐anaplastic non‐medullary thyroid cancer

To review clinical outcomes and toxicities in locally advanced differentiated thyroid cancer patients treated with external beam radiotherapy (EBRT) with or without concurrent chemotherapy (CCRT).

Axitinib sensitization of high Single Dose Radiotherapy

BACKGROUND AND PURPOSE Single Dose Radiation Therapy (SDRT) provides remarkably high rates of control even for tumors resistant to fractionated radiotherapy. SDRT tumor control depends on acute acid sphingomyelinase-mediated endothelial cell injury and monoclonal antibodies targeting Vascular Endothelial Cell Growth Factor (VEGF) signaling radiosensitized tumor endothelium when delivered immediately prior to irradiation. Here we evaluate the ability of the oral VEGF receptor inhibitor, axitinib, to sensitize tumor endothelium and increase tumor control with SDRT. METHODS AND MATERIALS Axitinib was added to primary cultured endothelial cells, or administered orally to Sv129/BL6 mice bearing radiosensitive MCA/129 sarcoma or radioresistant B16F1 melanoma flank tumors, followed by SDRT. Endothelial apoptosis was assessed by TUNEL assay or bis-benzamide staining. Mice with irradiated tumors were followed for 90days to evaluate the impact of axitinib on SDRT tumor control. RESULTS Pre-treatment with axitinib increased acute endothelial cell apoptosis following SDRT in vitro, and in vivo for both MCA/129 and B16F1 tumors. Axitinib correspondingly increased SDRT tumor growth delay and complete response rate (by 40%) for both tumors. Administration precisely 1h before SDRT was critical for radiosensitization. CONCLUSIONS Axitinib radiosensitizes tumor endothelial cells and enhances tumor cure with SDRT, which may permit dose de-escalation and significantly expand the range of clinical indications for SDRT.

Development and validation of nomograms predictive of overall and progression-free survival in patients with oropharyngeal cancer

Purpose Treatment of oropharyngeal squamous cell carcinoma (OPSCC) is evolving toward risk-based modification of therapeutic intensity, which requires patient-specific estimates of overall survival (OS) and progression-free survival (PFS). Methods To develop and validate nomograms for OS and PFS, we used a derivation cohort of 493 patients with OPSCC with known p16 tumor status (surrogate of human papillomavirus) and cigarette smoking history (pack-years) randomly assigned to clinical trials using platinum-based chemoradiotherapy (NRG Oncology Radiation Therapy Oncology Group [RTOG] 0129 and 0522). Nomograms were created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index. Nomograms were externally validated in a cohort of 153 patients with OPSCC randomly assigned to a third trial, NRG Oncology RTOG 9003. Results Both models included age, Zubrod performance status, pack-years, education, p16 status, and T and N stage; the OS model also included anemia and age × pack-years interaction; and the PFS model also included marital status, weight loss, and p16 × Zubrod interaction. Predictions correlated well with observed 2-year and 5-year outcomes. The uncorrected concordance index was 0.76 (95% CI, 0.72 to 0.80) for OS and 0.70 (95% CI, 0.66 to 0.74) for PFS, and bias-corrected indices were similar. In the validation set, OS and PFS models were well calibrated, and OS and PFS were significantly different across tertiles of nomogram scores (log-rank P = .003;< .001). Conclusion The validated nomograms provided useful prediction of OS and PFS for patients with OPSCC treated with primary radiation-based therapy.

In Regard to Brown et al

To the Editor: With the increasing use of radiosurgery and stereotactic body radiation therapy (SBRT) in radiation oncology, there has been a growing need to understand the radiobiology contributing to the remarkably high tumor control rates seen with the large fraction sizes used. We therefore read with great interest the recent editorial by Brown et al regarding whether “New Biology” was needed to understand SBRT dose response in lung cancer (1), and their more recent paper revisiting the analysis with the same conclusions (2). The authors presented a fitted tumor control probability (TCP) curve based on a wide range of local control rates from published series, including conventional fractionation (3-dimensional conformal radiation therapy [3DCRT]; >10 fractions), hypofractionation (SBRT; 3-8 fractions), and single-dose radiation (SBRT; 1 fraction), according to their linear quadratic (LQ)-based biologically effective doses (BEDs) (1, 3). The stated conclusion was that “there is no indication from these data that SBRT and 3DCRT produce different TCP probabilities when adjusted for BED” and “it follows there is no need to invoke a new biology” (1). We disagree, however, that the data presented can support this conclusion. For their analysis, the authors coalesced the included series into average data points, but ignored the actual statistical spread of the data (based on sample size). Figure 1 shows the data presented by Brown et al, but with the addition of 95% confidence interval bars associated with each published data point. Using a simple χ2 test, we can ask if the spread of the original reports is consistent with the hypothesis that all the data are drawn from a single LQ model in BED, assumed to be the best fit model for all of the data together. If not, there is no evidence that all of the data are consistently drawn from the same distribution. With this type of analysis, the null hypothesis is that the distribution of studies follows a fitted curve, and the hypothesis is typically rejected when its probability falls below .05. In fact, using each report as its own bin in a χ2 analysis yields a χ2 value of 66.9 with 44 degrees-of-freedom and an associated probability of observing variations at least this large, if the data really were drawn from the best fit LQ curve, of only 1.4% (P=.014). For this reason, we reject the curve fit as a good representation for all of the data, and therefore disagree with the authors’ claim that “there is no indication from these data that SBRT and 3DCRT produce different TCP probabilities when adjusted for [LQ derived] BED.” Fig. 1 Tumor control probability (TCP) versus biologically effective dose (BED) using the linear quadratic (LQ) model. Data are from Mehta et al (3). The fitted line was obtained using a logistic regression model. The vertical lines indicate the 95% confidence intervals ... We followed up this initial statistical analysis with a review of the original dataset. The details are given in the Supplemental Materials, including a discussion of the sources of heterogeneity of the dataset. Even when the data are filtered to improve homogeneity, according to our own judgments, we reach a similar conclusion: The data across fractionation regimens are not consistent with the hypothesis that they are drawn from the same BED-based function. To further clarify SBRT tumor response, higher quality data, that is, data gathered in a more consistent and comprehensive fashion, will need to be collected and analyzed.

Primary surgery for advanced-stage laryngeal cancer: A stage and subsite-specific survival analysis.

Treatment recommendations for advanced‐stage laryngeal squamous cell carcinoma (SCC) have evolved significantly over the last 2 decades.

Factors Associated with Recurrence and Regional Adenopathy for Head and Neck Cutaneous Squamous Cell Carcinoma

Objective Cutaneous squamous cell carcinoma (CSCC) is one of the most common malignancies worldwide. With advanced CSCC of the head and neck, there is conflicting evidence on what constitutes high-risk disease. Our objective is to evaluate which factors are predictive of recurrence and nodal spread and survival. Study Design Case series with chart review. Setting Tertiary academic institution. Subjects and Methods Patients with advanced head and neck CSCC treated with primary resection identified by chart review. Results A total of 212 patients met inclusion criteria, with a mean age of 70.4 years; 87.3% were men. Mean tumor diameter was 3.65 cm, with an average depth of invasion of 1.38 cm. The mean follow-up time was 35 months (median, 21.5), and over that period 67 recurrences were recorded, 49 of which were local. The 5-year Kaplan-Meier estimate of disease-free survival for the cohort was 53.2%. On Cox multivariate analysis, recurrent disease, perineural invasion (PNI), and poorly differentiated histology were independent predictors of recurrence. On multinomial logistic regression, patients with primary tumors on the ear, cheek, temple, or lip, as well as those with PNI, were more likely to present with nodal metastasis. Conclusion For advanced CSCCs of the head and neck, patients with recurrent disease, PNI, and poorly differentiated tumors are at highest risk for local recurrence. Patients with tumors or the ear, cheek, temple, or lip, as well as those with PNI, are at increased risk of harboring nodal disease.

Targeting acid sphingomyelinase with anti-angiogenic chemotherapy.

Despite great promise, combining anti-angiogenic and conventional anti-cancer drugs has produced limited therapeutic benefit in clinical trials, presumably because mechanisms of anti-angiogenic tissue response remain only partially understood. Here we define a new paradigm, in which anti-angiogenic drugs can be used to chemosensitize tumors by targeting the endothelial acid sphingomyelinase (ASMase) signal transduction pathway. We demonstrate that paclitaxel and etoposide, but not cisplatin, confer ASMase-mediated endothelial injury within minutes. This rapid reaction is required for human HCT-116 colon cancer xenograft complete response and growth delay. Whereas VEGF inhibits ASMase, anti-VEGFR2 antibodies de-repress ASMase, enhancing endothelial apoptosis and drug-induced tumor response in asmase+/+, but not in asmase-/-, hosts. Such chemosensitization occurs only if the anti-angiogenic drug is delivered 1-2h before chemotherapy, but at no other time prior to or post chemotherapy. Our studies suggest that precisely-timed administration of anti-angiogenic drugs in combination with ASMase-targeting anti-cancer drugs is likely to optimize anti-tumor effects of systemic chemotherapy. This strategy warrants evaluation in future clinical trials.