Publications by authors named "Athanassios Argiris"

106 Publications

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19805 patients, on behalf of MACH-NC group.

Radiother Oncol 2021 Jan 27. Epub 2021 Jan 27.

Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Oncostat U1018 INSERM, labeled Ligue Contre le Cancer, Université Paris-Saclay, Villejuif, France; Groupe d'Oncologie Radiothérapie Tête Et Cou, Tours, France.

Background And Purpose: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.

Materials And Methods: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.

Results: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p<0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend=0.03). OS was not increased by the addition of induction (HR=0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend=0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR=0.84 [0.74; 0.95], p=0.005).

Conclusion: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.
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http://dx.doi.org/10.1016/j.radonc.2021.01.013DOI Listing
January 2021

Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect.

Front Oncol 2020 2;10:566315. Epub 2020 Dec 2.

Department of Otolaryngology - Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA, United States.

PD-1 blockade represents a promising treatment in patients with head and neck squamous cell carcinoma (HNSCC). We analyzed results of a neoadjuvant randomized window-of-opportunity trial of nivolumab plus/minus tadalafil to investigate whether immunotherapy-mediated treatment effects vary by site of involvement (primary tumor, lymph nodes) and determine how radiographic tumor shrinkage correlates with pathologic treatment effect.

Patients And Methods: Forty-four patients enrolled in trial NCT03238365 were treated with nivolumab 240 mg intravenously on days 1 and 15 with or without oral tadalafil, as determined by random assignment, followed by surgery on day 31. Radiographic volumetric response (RVR) was defined as percent change in tumor volume from pretreatment to posttreatment CT scan. Responders were defined as those with a 10% reduction in the volume of the primary tumor or lymph nodes (LN). Pathologic treatment effect (PTE) was defined as the area showing fibrosis or lymphohistiocytic inflammation divided by total tumor area.

Results: Sixteen of 32 patients (50%) with pathologic evidence of LN involvement exhibited discordant PTE between primary sites and LN. In four patients with widely discordant adjacent LN, increased PTE was associated with increased infiltration of tumor CD8 T cells and CD163 macrophages, whereas stromal regulatory T cells were associated with low nodal PTE. RVR correlated with PTE at both primary tumor (slope = 0.55, < 0.001) and in LN (slope = 0.62, < 0.05). 89% (16/18) of radiographic non-responders with T1-T3 primary sites had no (n = 7) or minimal PTE (n = 9), whereas 15/17 (88%) of radiographic responders had moderate (n = 12) or complete (n = 3) PTE.

Conclusion: Nivolumab often induces discordant treatment effects between primary tumor sites and metastatic lymph nodes within subjects. This treatment discordance was also demonstrated in adjacent lymph nodes, which may correlate with local immune cell makeup. Finally, although these data were generated by a relatively small population size, our data support the use of early radiographic response to assess immunotherapy treatment effect in HNSCC.
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http://dx.doi.org/10.3389/fonc.2020.566315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738605PMC
December 2020

Validation of brief symptom indexes among patients with recurrent or metastatic squamous cell carcinoma of the head and neck: A trial of the ECOG-ACRIN Cancer Research Group (E1302).

Cancer Med 2020 Dec 10;9(23):8884-8894. Epub 2020 Oct 10.

Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Patients with advanced head and neck cancer have identified pain, fatigue, and difficulties swallowing, breathing, and communicating as high-priority disease-related symptoms. The Functional Assessment of Cancer Therapy-Head and Neck Symptom Index-10 (FHNSI-10) assesses these symptoms. We sought to validate the FHNSI-10, another brief symptom index (FHNSI-7), and individual symptom endpoints representing these high-rated priority disease symptoms among patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).

Methods: Patients (N = 239) were enrolled in a phase III randomized clinical trial (E1302) and completed the FHNSI-10 at multiple time points. We assessed the internal consistencies and test-retest reliabilities of the FHNSI-10 and FHNSI-7 scores, and the known-groups validity, predictive criterion validity, and responsiveness-to-change of the symptom indexes and individual symptom endpoint scores.

Results: The FHNSI-10 and FHNSI-7 indexes showed satisfactory internal consistencies (Cronbach's alpha coefficient range 0.60-0.75) and acceptable test-retest reliabilities (intraclass correlation coefficients = 0.75 and 0.74, respectively). The FHNSI-10, FHNSI-7, and the pain, fatigue, swallowing, and breathing symptom scores showed evidence of known-groups validity by performance status at baseline. The FHNSI-10, FHNSI-7, and the pain, fatigue, and breathing symptom scores at baseline showed evidence of predictive criterion validity for overall survival, but not time-to-progression (TTP). Changes in the symptom indexes and individual symptom scores were not associated with changes in performance status over 4 weeks, though most patients had stable performance status.

Conclusions: There is initial evidence of validity for the FHNSI-10 and FHNSI-7 indexes and selected individual symptom endpoints as brief disease-related symptom assessments for patients with recurrent or metastatic SCCHN.
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http://dx.doi.org/10.1002/cam4.3506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724483PMC
December 2020

An update on angiogenesis targeting in head and neck squamous cell carcinoma.

Cancers Head Neck 2020 6;5. Epub 2020 Apr 6.

Department of Medical Oncology, Thomas Jefferson University, 1025 Walnut Street, Suite 700, Philadelphia, PA USA.

Angiogenesis is an integral aspect of the growth and proliferation of solid tumors, including head and neck squamous cell carcinoma (HNSCC), and has potential implications in prognosis and treatment of both localized and recurrent/metastatic HNSCC. Therefore, there has been a significant interest in utilizing anti-angiogenic agents either alone or in combination with currently approved and emerging therapies. A phase III randomized trial (E1305) of chemotherapy with or without bevacizumab in the first-line treatment of recurrent/metastatic HNSCC showed an increased response rate and longer progression-free survival but fell short in demonstrating a statistically significant improved survival with bevacizumab. Moreover, toxicity, especially bleeding, was increased. Nevertheless, the study of other anti-angiogenic agents and novel combinations with other therapies, including immunotherapy, remains of interest. Several clinical trials are currently underway.
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http://dx.doi.org/10.1186/s41199-020-00051-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132887PMC
April 2020

Editorial: Advances in the Systemic Therapy and Combined Modality Approaches for Head and Neck Cancer.

Front Oncol 2019 13;9:1190. Epub 2019 Nov 13.

Istituto Nazionale Tumori, Milan, Italy.

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http://dx.doi.org/10.3389/fonc.2019.01190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874120PMC
November 2019

Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer.

J Clin Oncol 2019 12 16;37(34):3266-3274. Epub 2019 Oct 16.

Yale University School of Medicine, New Haven, CT.

Purpose: We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).

Patients And Methods: Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved.

Results: The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; = .22). At 2, 3, and 4 years, the OS rates were 25.2% 18.1%, 16.4% 10.0%, and 11.8% 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; = .10), with a median OS of 14.2 months on BC 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months 4.3 months with chemotherapy ( = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy ( = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% 0.5%; < .001) and treatment-related deaths (9.3% 3.5%; = .022) with BC versus chemotherapy.

Conclusion: The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN.
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http://dx.doi.org/10.1200/JCO.19.00555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980834PMC
December 2019

Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies.

Cancer Chemother Pharmacol 2019 12 23;84(6):1289-1301. Epub 2019 Sep 23.

Winship Cancer Institute, Emory University, Atlanta, GA, USA.

Purpose: Veliparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and -2. PARP-1 expression may be increased in cancer, and this increase confers resistance to cytotoxic agents. We aimed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib combined with paclitaxel and carboplatin.

Methods: Eligibility criteria included patients with advanced solid tumors treated with ≤ 3 prior regimens. Paclitaxel and carboplatin were administered on day 3 of a 21-day cycle. Veliparib was given PO BID days 1-7, except for cycle 1 in the first 46 patients to serve as control for toxicity and PK. A standard "3 + 3" design started veliparib at 10 mg BID, paclitaxel at 150 mg/m, and carboplatin AUC 6. The pharmacokinetic (PK) disposition of veliparib, paclitaxel, and carboplatin was determined by LC-MS/MS and AAS during cycles 1 and 2.

Results: Seventy-three patients were enrolled. Toxicities were as expected with carboplatin/paclitaxel chemotherapy, including neutropenia, thrombocytopenia, and peripheral neuropathy. DLTs were seen in two of seven evaluable patients at the maximum administered dose (MAD): veliparib 120 mg BID, paclitaxel 200 mg/m, and carboplatin AUC 6 (febrile neutropenia, hyponatremia). The MTD and RP2D were determined to be veliparib 100 mg BID, paclitaxel 200 mg/m, and carboplatin AUC 6. Median number of cycles of the three-agent combination was 4 (1-16). We observed 22 partial and 5 complete responses. Veliparib did not affect paclitaxel or carboplatin PK disposition.

Conclusion: Veliparib, paclitaxel, and carboplatin were well tolerated and demonstrated promising antitumor activity.
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http://dx.doi.org/10.1007/s00280-019-03960-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825275PMC
December 2019

Laryngeal Preservation Strategies in Locally Advanced Laryngeal and Hypopharyngeal Cancers.

Front Oncol 2019 31;9:419. Epub 2019 May 31.

Centre Oscar Lambret, Lille, France.

For long, the treatment of locoregionally advanced laryngeal and hypopharyngeal squamous cell cancers (SCC) consisted of either total laryngectomy (TL) or definitive radiotherapy (RT). The development of induction cisplatin plus 5-fluorouracil (PF) and the correlation between chemosensitivity and radiosensitivity in previously untreated patients opened a new era of treatment aiming at laryngeal preservation (LP). The fundamental concept was to employ induction PF in order to select patients for subsequent treatment with either TL or RT according to tumor response to PF. The first two trials (VALGSG for laryngeal SCC and EORTC 24891 for hypopharyngeal SCC) concluded that such an approach could preserve nearly 60% of larynx without deleterious impact on survival. The EORTC 24954 trial compared 4 cycles of induction PF followed by RT in good responders vs. alternating PF-RT in laryngeal and hypopharyngeal SCC. There was no significant difference in 5-year overall survival with a functional larynx between the two arms (31 vs. 35%). The GORTEC 2000-01 trial compared induction PF to induction PF plus docetaxel (TPF) both followed by RT in good responders in larynx and hypopharynx SCC. The 5-year LP was significantly higher in the TPF arm (60 vs. 39%) but without a difference in survival. The RTOG 91-11 trial compared induction PF followed by RT in good responders vs. concurrent chemoradiotherapy (chemo-RT) vs. RT alone in laryngeal SCC. There was no significant difference in 5-year laryngectomy-free survival between the patients treated with induction chemotherapy (44%) vs. those treated with chemo-RT (47%), both being superior to RT alone (34%). At 5 years, LP was superior with chemo-RT: 84 vs. 71% with induction PF. Two phase II trials explored the role of cetuximab (E) in LP in laryngeal and hypopharyngeal SCC. The TREMPLIN trial compared RT+E or chemo-RT (RT + P) after TPF. The DeLOS-II trial compared TPE followed by RT+E vs. TP followed by RT. However, these trials failed to indicate an advantage for the incorporation of E in the treatment paradigm. To date, two approaches for LP have been validated: induction TPF followed by RT for laryngeal and hypopharyngeal SCC and concurrent chemo-RT for laryngeal SCC. An ongoing trial (SALTORL) is comparing these two approaches, induction TPF and chemo-RT, in laryngeal/ hypopharyngeal SCC.
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http://dx.doi.org/10.3389/fonc.2019.00419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554412PMC
May 2019

Combining Radiation and Immune Checkpoint Blockade in the Treatment of Head and Neck Squamous Cell Carcinoma.

Front Oncol 2019 6;9:122. Epub 2019 Mar 6.

Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United States.

Head and neck squamous cell carcinoma (HNSCC) is a significant cause of morbidity and mortality worldwide. Current treatment options, even though potentially curative, have many limitations including a high rate of complications. Over the past few years immune checkpoint inhibitors (ICI) targeting cytotoxic lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have changed treatment paradigms in many malignancies and are currently under investigation in HNSCC as well. Despite improvements in treatment outcomes and the implementation of combined modality approaches long-term survival rates in patients with locally advanced HNSCC remain suboptimal. Accumulating evidence suggests that under certain conditions, radiation may be delivered in conjunction with ICI to augment efficacy. In this review, we will discuss the immune modulating mechanisms of ICI and radiation, how changing the dose, fractionation, and field of radiation may alter the tumor microenvironment (TME), and how these two treatment modalities may work in concert to generate durable treatment responses against HNSCC.
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http://dx.doi.org/10.3389/fonc.2019.00122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414812PMC
March 2019

Phase 1 study of EGFR-antisense DNA, cetuximab, and radiotherapy in head and neck cancer with preclinical correlatives.

Cancer 2018 10 6;124(19):3881-3889. Epub 2018 Oct 6.

Department of Medical Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Background: Cetuximab combined with radiation therapy (RT) is an evidence-based treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, locoregional failure remains the primary cause of cancer-related death in this disease. Intratumoral injection of epidermal growth factor receptor (EGFR)-antisense plasmid DNA (EGFR-AS) is safe and has been associated with promising lesional responses in patients who have recurrent/metastatic HNSCC. For the current study, the authors investigated the antitumor effects of cetuximab and EGFR-AS in preclinical HNSCC models and reported their phase 1 experience adding intratumoral EGFR-AS to cetuximab RT.

Methods: Antitumor mechanisms were investigated in cell line and xenograft models. Phase 1 trial eligibility required stage IVA through IVC HNSCC and a measurable lesion accessible for repeat injections. Patients received standard cetuximab was for 9 weeks. EGFR-AS was injected weekly until they achieved a lesional complete response. RT was delivered by conventional fractionation for 7 weeks, starting at week 3. Research biopsies were obtained at baseline and week 2.

Results: When added to cetuximab, EGFR-AS decreased cell viability and xenograft growth compared with EGFR-sense control, partially mediated by reduced EGFR expression. Six patients were enrolled in the phase 1 cohort. No grade 2 or greater EGFR-AS-related adverse events occurred. The best lesional response was a complete response (4 patients), and 1 patient each had a partial response and disease progression. EGFR expression decreased in 4 patients who had available paired specimens.

Conclusions: In preclinical models, dual EGFR inhibition with cetuximab and EGFR-AS enhanced antitumor effects. In a phase 1 cohort, intratumoral EGFR-AS injections, cetuximab, and RT were well tolerated. A phase 2 trial is needed to conduct an extended evaluation of safety and to establish efficacy.
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http://dx.doi.org/10.1002/cncr.31651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521720PMC
October 2018

Induced Bias Due to Crossover Within Randomized Controlled Trials in Surgical Oncology: A Meta-regression Analysis of Minimally Invasive versus Open Surgery for the Treatment of Gastrointestinal Cancer.

Ann Surg Oncol 2018 Jan 6;25(1):221-230. Epub 2017 Nov 6.

Surgical Epidemiology Unit, Department of Surgery and Cancer, Imperial College London, St. Mary's Hospital, London, UK.

Background: Randomized controlled trials (RCTs) inform clinical practice and have provided the evidence base for introducing minimally invasive surgery (MIS) in surgical oncology. Crossover (unplanned intraoperative conversion of MIS to open surgery) may affect clinical outcomes and the effect size generated from RCTs with homogenization of randomized groups.

Objectives: Our aims were to identify modifiable factors associated with crossover and assess the impact of crossover on clinical endpoints.

Methods: A systematic review was performed to identify all RCTs comparing MIS with open surgery for gastrointestinal cancer (1990-2017). Meta-regression analysis was performed to analyze factors associated with crossover and the influence of crossover on endpoints, including 30-day mortality, anastomotic leak rate, and early complications.

Results: Forty RCTs were included, reporting on 11,625 patients from 320 centers. Crossover was shown to affect one in eight patients (mean 12.6%, range 0-45%) and increased with American Society of Anesthesiologists score (β = + 0.895; p = 0.050). Pretrial surgeon volume (β = - 2.344; p = 0.037), composite RCT quality score (β = - 7.594; p = 0.014), and site of tumor (β = - 12.031; p = 0.021, favoring lower over upper gastrointestinal tumors) showed an inverse relationship with crossover. Importantly, multivariate weighted linear regression revealed a statistically significant positive correlation between crossover and 30-day mortality (β = + 0.125; p = 0.033), anastomotic leak rate (β = + 0.550; p = 0.004), and early complications (β = + 1.255; p = 0.001), based on intention-to-treat analysis.

Conclusions: Crossover in trials was associated with an increase in 30-day mortality, anastomotic leak rate, and early complications within the MIS group based on intention-to-treat analysis, although our analysis did not assess causation. Credentialing surgeons by procedural volume and excluding high comorbidity patients from initial trials are important in minimizing crossover and optimizing RCT validity.
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http://dx.doi.org/10.1245/s10434-017-6210-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740197PMC
January 2018

Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck.

Front Oncol 2017 9;7:72. Epub 2017 May 9.

Department of Head and Neck Cancer Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, University of Milan, Milan, Italy.

The major development of the past decade in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy (CT), followed by maintenance cetuximab (the "EXTREME" regimen). This regimen is supported by a phase 3 randomized trial and subsequent observational studies, and it confers well-documented survival benefits, with median survival ranging between approximately 10 and 14 months, overall response rates between 36 and 44%, and disease control rates of over 80%. Furthermore, as indicated by patient-reported outcome measures, the addition of cetuximab to platinum-based CT leads to a significant reduction in pain and problems with social eating and speech. Conversely, until very recently, there has been a lack of evidence-based second-line treatment options, and the therapies that have been available have shown low response rates and poor survival outcomes. Presently, a promising new treatment option in R/M SCCHN has emerged: immune checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials. Nivolumab and pembrolizumab are the first two ICIs that were approved by the US Food and Drug Administration. We note that the trials that showed benefit with ICIs included not only patients who previously received ≥1 platinum-based regimens for R/M SCCHN but also patients who experienced recurrence within 6 months after combined modality therapy with a platinum agent for locally advanced disease. In this review, we outline the available clinical and observational evidence for the EXTREME regimen and the initial results from clinical trials for ICIs in patients with R/M SCCHN. We propose that these treatment options can be integrated into a new continuum of care paradigm, with first-line EXTREME regimen followed by second-line ICIs. A number of ongoing clinical trials are comparing regimens with ICIs, alone and in combination with other ICIs or CT, with the EXTREME regimen for first-line treatment of R/M SCCHN. As we eagerly await the results of these trials, the EXTREME regimen remains the standard of care for the first-line treatment of R/M SCCHN.
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http://dx.doi.org/10.3389/fonc.2017.00072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422557PMC
May 2017

Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non-small cell lung cancer.

Cancer 2017 Aug 4;123(15):2936-2944. Epub 2017 May 4.

Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota.

Background: Activation of the mesenchymal-epidermal transition factor (MET) tyrosine kinase and its ligand, hepatocyte growth factor (HGF), is implicated in resistance to epidermal growth factor receptor (EGFR) inhibitors. In this phase 1/2 trial, rilotumumab (an anti-HGF antibody) combined with erlotinib was evaluated in patients with metastatic, previously treated non-small cell lung cancer.

Methods: In phase 1, a dose de-escalation design was adopted with rilotumumab starting at 15 mg/kg intravenously every 3 weeks and oral erlotinib 150 mg daily. In phase 2, the disease control rate (DCR) (according to Response Evaluation Criteria in Solid Tumors) of the combination was evaluated using a Simon 2-stage design. The biomarkers examined included 10 plasma-circulating molecules associated with the EGFR and MET pathways.

Results: Without indications for de-escalation, the recommended phase 2 dose was dose level 0. Overall, 45 response-evaluable patients were enrolled (13 with squamous carcinoma, 32 with adenocarcinoma; 2 had confirmed EGFR mutations, 33 had confirmed wild-type [WT] EGFR, and 7 had KRAS mutations). The DCR for all patients was 60% (90% confidence interval [CI], 47.1%-71.3%). Median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 6.6 months (90% CI, 5.6-8.9 months). Among patients with WT EGFR, the DCR was 60.6% (90% CI, 46.3%-73.3%), median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 7.0 months (90% CI, 5.6-13.4 months). Elevated baseline levels of neuregulin 1 were associated with longer progression-free survival (hazard ratio, 0.41; 95% CI, 0.19-0.87), whereas elevated amphiregulin levels were associated with more rapid progression (hazard ratio, 2.14; 95% CI, 1.48-3.08).

Conclusions: Combined rilotumumab and erlotinib had an acceptable safety profile, and the DCR met the prespecified criteria for success. In the EGFR WT group, the DCR exceeded published reports for erlotinib alone. High circulating levels of neuregulin 1 may indicate sensitivity to this combination. Cancer 2017;123:2936-44. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517339PMC
August 2017

Increased PD-1 and TIM-3 TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients.

Cancer Immunol Res 2017 05 13;5(5):408-416. Epub 2017 Apr 13.

Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8 tumor-infiltrating lymphocytes (TIL) and compared them with those of peripheral blood T lymphocytes (PBL) in patients with head and neck cancer (HNSCC) during cetuximab therapy. The frequency of PD-1 and TIM-3 expression was significantly increased in CD8 TILs compared with CD8 PBLs ( = 0.008 and = 0.02, respectively). This increased CD8 TIL population coexpressed granzyme B/perforin and PD-1/TIM-3, which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8 TILs. Indeed, the increased frequency of PD-1 and TIM-3 CD8 TILs was inversely correlated with clinical outcome of cetuximab therapy. These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8 T cells in the tumor microenvironment during cetuximab therapy. Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8 TIL dysfunction, thus potentially improving clinical outcomes of HNSCC patients. .
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http://dx.doi.org/10.1158/2326-6066.CIR-16-0333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497750PMC
May 2017

Phase I Results from a Study of Crizotinib in Combination with Erlotinib in Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer.

J Thorac Oncol 2017 01 30;12(1):145-151. Epub 2016 Sep 30.

Birmingham Veterans Administration Hospital, Birmingham, Alabama; University of Alabama-Birmingham Comprehensive Cancer Center, Birmingham, Alabama.

Introduction: This phase I trial was conducted to determine the safety, maximum tolerated dose (MTD)/recommended phase II dose, and efficacy of crizotinib plus erlotinib in patients with advanced NSCLC.

Methods: Patients with NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 2 after failure of one or two prior chemotherapy regimens were eligible. Erlotinib, 100 mg, was given continuously once daily starting between day -14 and -7; crizotinib, 200 mg twice daily (dose level 1) or 150 mg twice daily (dose level -1), was added continuously beginning on day 1 of treatment cycle 1. Potential pharmacokinetic interactions between crizotinib and erlotinib were evaluated.

Results: Twenty-seven patients received treatment; 26 received crizotinib plus erlotinib. Frequent adverse events were diarrhea, rash, decreased appetite, and fatigue. Dose-limiting toxicities were dehydration, diarrhea, dry eye, dysphagia, dyspepsia, esophagitis and vomiting. The MTD was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily. Crizotinib increased the erlotinib area under the concentration-time curve 1.5-fold (dose level -1) and 1.8-fold (dose level 1). The plasma level of crizotinib appeared to be unaffected by coadministration of erlotinib. Two patients whose tumors harbored activating EGFR mutations achieved confirmed partial responses, one at each crizotinib dose level.

Conclusions: The MTD of the combination of crizotinib and erlotinib in patients with advanced NSCLC was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily, which is less than the approved dose of either agent. The phase II portion of the study was not initiated.
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http://dx.doi.org/10.1016/j.jtho.2016.09.131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249761PMC
January 2017

A phase 2 study of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

Cancer 2016 Dec 20;122(23):3641-3649. Epub 2016 Sep 20.

Department of Hematology and Oncology, University of North Carolina, Chapel Hill, North Carolina.

Background: Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor β superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM-SCCHN. The objective of the current study was to evaluate the activity of dalantercept in RM-SCCHN.

Methods: Forty-six patients received dalantercept at doses of 80 mg (n = 2), 0.6 mg/kg (n = 13), or 1.2 mg/kg (n = 31) subcutaneously every 3 weeks. The primary endpoint was the overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Secondary endpoints included progression-free survival and overall survival, safety and tolerability, and pharmacokinetic and pharmacodynamic assessments.

Results: Forty patients were evaluable for response (13 who received dalantercept 0.6 mg/kg and 27 who received dalantercept 1.2 mg/kg). The overall response rate was 5% (n = 2), and 35% of patients had stable disease; 44% of patients who received 1.2 mg/kg and 30.8% of those who received 0.6 mg/kg achieved disease control (partial response or stable disease). The median progression-fee survival was 1.4 months (95% confidence interval, 1.3-2.2 months), and the median overall survival was 7.1 months (95% confidence interval, 5.5-11.1 months). Drug-related adverse events (>15%) were anemia, fatigue, peripheral edema, headache, and hyponatremia.

Conclusions: In an unselected, heavily pretreated population of patients with RM-SCCHN, dalantercept monotherapy resulted in a favorable safety profile but only modest dose-dependent activity, and it did not meet the primary efficacy objective of the study. Cancer 2016;122:3641-9. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901028PMC
December 2016

Phase II trial of everolimus in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma.

Head Neck 2016 12 27;38(12):1759-1764. Epub 2016 May 27.

Department of Medicine, Division of Hematology/Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Background: Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) demonstrate aberrant activation of the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. We examined the efficacy of everolimus, an mTOR inhibitor, in patients with recurrent or metastatic HNSCC.

Methods: This single-arm phase II study enrolled biomarker-unselected patients with recurrent or metastatic HNSCC who failed at least 1 prior therapy. Everolimus was administered until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and evaluation of tissue and serum biomarkers related to the PIK3CA pathway.

Results: Seven of 9 patients treated in the first stage were evaluable. No objective responses were seen; CBR was 28%. Three patients discontinued everolimus because of toxicity. Median PFS and OS were 1.5 and 4.5 months, respectively. No activating PI3K mutations were identified in available tumor tissue.

Conclusion: Everolimus was not active as monotherapy in unselected patients with recurrent/metastatic HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1759-1764, 2016.
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http://dx.doi.org/10.1002/hed.24501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820341PMC
December 2016

Characterization of human papillomavirus antibodies in individuals with head and neck cancer.

Cancer Epidemiol 2016 06 21;42:46-52. Epub 2016 Mar 21.

German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. Electronic address:

Background: Human papillomavirus type 16 (HPV16) E6 antibodies are a promising biomarker of oropharyngeal cancer (OPC); however, seropositivity among non-OPC cases is not well characterized.

Methods: Pre-treatment sera from 260 (38 OPC, 222 non-OPC) incident head and neck cancers diagnosed at the University of Pittsburgh between 2003 and 2006 were tested for HPV16 (L1,E1,E2,E4,E6,E7) and non-HPV16 E6 (HPV6,11,18,33) antibodies. Sensitivity and specificity of HPV16 E6 antibodies for HPV-driven tumors was evaluated among tumors with known HPV status (n=25).

Results: 63.2% of OPC versus 27.5% of non-OPC cases were HPV16 seropositive; HPV16 E6 seroprevalence was 60.5% and 6.3% respectively, odds ratio 22.8 (95% confidence interval [CI] 9.8-53.1). Sensitivity and specificity of HPV16 E6 antibodies for HPV-driven OPC was 100% [95% CI: 50-100%; n=6] and 100% [95% CI: 60-100%, n=4] compared to 0% (n=2) and 0% (n=13) for non-OPC cases.

Conclusions: HPV16 antibodies were significantly more common in OPC versus non-OPC cases, particularly HPV16 E6 antibodies.
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http://dx.doi.org/10.1016/j.canep.2016.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910878PMC
June 2016

Emerging aspects of nanotoxicology in health and disease: From agriculture and food sector to cancer therapeutics.

Food Chem Toxicol 2016 May 8;91:42-57. Epub 2016 Mar 8.

Center of Toxicology Science & Research, Medical School, University of Crete, Heraklion, Crete, Greece; Scientific Educational Center of Nanotechnology, Far Eastern Federal University, Engineering School, Vladivostok, Russia. Electronic address:

Nanotechnology is an evolving scientific field that has allowed the manufacturing of materials with novel physicochemical and biological properties, offering a wide spectrum of potential applications. Properties of nanoparticles that contribute to their usefulness include their markedly increased surface area in relation to mass, surface reactivity and insolubility, ability to agglomerate or change size in different media and enhanced endurance over conventional-scale substance. Here, we review nanoparticle classification and their emerging applications in several fields; from active food packaging to drug delivery and cancer research. Nanotechnology has exciting therapeutic applications, including novel drug delivery for the treatment of cancer. Additionally, we discuss that exposure to nanostructures incorporated to polymer composites, may result in potential human health risks. Therefore, the knowledge of processes, including absorption, distribution, metabolism and excretion, as well as careful toxicological assessment is critical in order to determine the effects of nanomaterials in humans and other biological systems. Expanding the knowledge of nanoparticle toxicity will facilitate designing of safer nanocomposites and their application in a beneficial manner.
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http://dx.doi.org/10.1016/j.fct.2016.03.003DOI Listing
May 2016

p53-based strategy to reduce hematological toxicity of chemotherapy: A proof of principle study.

Mol Oncol 2016 Jan 18;10(1):148-56. Epub 2015 Sep 18.

Department of Radiation Oncology, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.

p53 activation is a primary mechanism underlying pathological responses to DNA damaging agents such as chemotherapy and radiotherapy. Our recent animal studies showed that low dose arsenic (LDA)-induced transient p53 inhibition selectively protected normal tissues from chemotherapy-induced toxicity. Study objectives were to: 1) define the lowest safe dose of arsenic trioxide that transiently blocks p53 activation in patients and 2) assess the potential of LDA to decrease hematological toxicity from chemotherapy. Patients scheduled to receive minimum 4 cycles of myelosuppressive chemotherapy were eligible. For objective 1, dose escalation of LDA started at 0.005 mg/kg/day for 3 days. This dose satisfied objective 1 and was administered before chemotherapy cycles 2, 4, and 6 for objective 2. p53 level in peripheral lymphocytes was measured on day 1 of each cycle by ELISA assay. Chemotherapy cycles 1, 3, and 5 served as the baseline for the subsequent cycles of 2, 4, and 6 respectively. If p53 level for the subsequent cycle was lower (or higher) than the baseline cycle, p53 was defined as "suppressed" (or "activated") for the pair of cycles. Repeated measures linear models of CBC in terms of day, cycle, p53 activity and interaction terms were used. Twenty-six patients treated with 3 week cycle regimens form the base of analyses. The mean white blood cell, hemoglobin and absolute neutrophil counts were significantly higher in the "suppressed" relative to the "activated" group. These data support the proof of principle that suppression of p53 could lead to protection of bone marrow in patients receiving chemotherapy. This trial is registered in ClinicalTrials.gov. Identifier: NCT01428128.
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http://dx.doi.org/10.1016/j.molonc.2015.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597306PMC
January 2016

EGFR inhibition for recurrent or metastatic HNSCC.

Lancet Oncol 2015 May 16;16(5):488-9. Epub 2015 Apr 16.

Hygeia Hospital, Athens, Greece; University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(15)70178-6DOI Listing
May 2015

CTLA-4⁺ Regulatory T Cells Increased in Cetuximab-Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis.

Cancer Res 2015 Jun 1;75(11):2200-10. Epub 2015 Apr 1.

Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

The EGFR-targeted antibody cetuximab is effective against head and neck cancer (HNSCC), but in only 15% to 20% of patients, and the variability and extent of cetuximab-mediated cellular immunity is not fully understood. We hypothesized that regulatory T cells (Treg) may exert a functional and clinical impact on antitumor immunity in cetuximab-treated individuals. The frequency, immunosuppressive phenotype, and activation status of Treg and natural killer (NK) cells were analyzed in the circulation and tumor microenvironment of cetuximab-treated patients with HNSCC enrolled in a novel neoadjuvant, single-agent cetuximab clinical trial. Notably, cetuximab treatment increased the frequency of CD4(+)FOXP3(+) intratumoral Treg expressing CTLA-4, CD39, and TGFβ. These Treg suppressed cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and their presence correlated with poor clinical outcome in two prospective clinical trial cohorts. Cetuximab expanded CTLA-4(+)FOXP3(+) Treg in vitro, in part, by inducing dendritic cell maturation, in combination with TGFβ and T-cell receptor triggering. Importantly, cetuximab-activated NK cells selectively eliminated intratumoral Treg but preserved effector T cells. In ex vivo assays, ipilimumab targeted CTLA-4(+) Treg and restored cytolytic functions of NK cells mediating ADCC. Taken together, our results argue that differences in Treg-mediated suppression contribute to the clinical response to cetuximab treatment, suggesting its improvement by adding ipilimumab or other strategies of Treg ablation to promote antitumor immunity.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-2788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452385PMC
June 2015

Targeting angiogenesis in head and neck cancer.

Oral Oncol 2015 May 10;51(5):409-15. Epub 2015 Feb 10.

Hygeia Hospital, Athens, Greece; University of Texas Health Science Center at San Antonio, TX, USA. Electronic address:

Angiogenesis is a crucial step in tumor growth and metastasis. Head and neck squamous cell carcinomas (HNSCC) highly express angiogenesis factors, such as vascular endothelial growth factor (VEGF), which are associated with patient prognosis. Antiangiogenesis agents can potentially modulate tumor microenvironment and induce radiosensitivity and chemosensitivity. In this review, we discuss the molecular mechanisms underlying angiogenesis involved in HNSCC, preclinical data with antiangiogenesis agents as well as potential predictive biomarkers. We also review novel therapies under investigation and summarize the results of clinical trials using antiangiogenesis agents alone or in combination with conventional therapies in HNSCC.
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http://dx.doi.org/10.1016/j.oraloncology.2015.01.006DOI Listing
May 2015

Phase II study of cetuximab in combination with cisplatin and radiation in unresectable, locally advanced head and neck squamous cell carcinoma: Eastern cooperative oncology group trial E3303.

Clin Cancer Res 2014 Oct 8;20(19):5041-51. Epub 2014 Aug 8.

Johns Hopkins University School of Medicine and Sydney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.

Purpose: Treatment with cisplatin or cetuximab combined with radiotherapy each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared with radiotherapy alone. Eastern Cooperative Oncology Group Trial E3303 evaluated the triple combination.

Experimental Design: Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400 mg/m(2)) followed by 250 mg/m(2)/week and cisplatin 75 mg/m(2) q 3 weeks ×3 cycles concurrent with standard fractionated radiotherapy. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6 to 12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival.

Results: A total of 69 patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal primaries constituted the majority (66.7%), stage T4 48.3% and N2-3 91.7%. Median radiotherapy dose delivered was 70 Gy, 71.6% received all three cycles of cisplatin, and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% [95% confidence interval (CI), 33%-61%]. Two-year overall survival (OS) was 66% (95% CI, 53%-77%); median OS was not reached. Response rate was 66.7%. Most common grade ≥3 toxicities included mucositis (55%), dysphagia (46%), and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all oropharyngeal) were HPV positive. HPV(+) patients had significantly longer OS and PFS (P = 0.004 and P = 0.036, respectively).

Conclusions: Concurrent cetuximab, cisplatin, and radiotherapy were well tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV(+) tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-0051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184913PMC
October 2014

Phase II study of bevacizumab in combination with docetaxel and radiation in locally advanced squamous cell carcinoma of the head and neck.

Head Neck 2015 Nov 29;37(11):1665-71. Epub 2014 Oct 29.

Department of Internal Medicine (Medical Oncology), University Hospitals Case Medical Center, Seidman Cancer Hospital, Cleveland, Ohio.

Background: The purpose of this study was to establish the efficacy and toxicities of concurrent bevacizumab and docetaxel with radiation for locally advanced head and neck squamous cell carcinoma (HNSCC).

Methods: Patients with previously untreated HNSCC received standard daily radiotherapy (RT) with concurrent weekly docetaxel (20 mg/m(2) ) and biweekly bevacizumab (5 mg/kg). Biweekly bevacizumab was then continued for up to 1 year after RT. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS), patterns of failure, and toxicities of treatment.

Results: Thirty patients were recruited. With median follow-up of 38 months, the 3-year PFS, OS, locoregional recurrence-free survival, and distant metastasis-free survival was 61.7%, 68.2%, 84.5%, and 80.5%, respectively. The most common local toxicities were mucositis and dermatitis. Two patients developed hemorrhage. There was no grade 5 toxicity.

Conclusion: The combination of bevacizumab, docetaxel, and RT is tolerable and effective in HNSCC. This regimen is worthy of further study in appropriate subset of patients receiving chemoradiation therapy.
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http://dx.doi.org/10.1002/hed.23813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272911PMC
November 2015

Posttraumatic stress disorder symptoms in newly diagnosed patients with head and neck cancer and their partners.

Head Neck 2015 Sep 17;37(9):1282-9. Epub 2014 Sep 17.

Biobehavioral Medicine in Oncology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

Background: Head and neck cancer is a life-threatening illness requiring aversive treatments. Despite clear potential for posttraumatic stress disorder (PTSD) symptoms in both patients and their partners, research is scant.

Methods: Newly diagnosed patients and partners (number of dyads = 42) completed questionnaires to assess symptoms of PTSD, anxiety, and depression, as well as demographic, medical, and attitudinal variables.

Results: Partners had higher average levels of PTSD symptoms than patients (p = .023). More partners (28.6%) met criteria for estimated PTSD caseness than did patients (11.9%). There were no significant differences in levels of other anxiety or depression symptoms. Perceived threat of disease appeared to be a stronger correlate of PTSD symptom levels than medical variables in patients and partners.

Conclusion: A diagnosis of head and neck cancer elicits significant levels of PTSD symptoms in patients, and even higher levels among partners. Identified correlates of distress, including perceived threat of disease, are potential intervention targets.
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http://dx.doi.org/10.1002/hed.23760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229455PMC
September 2015

Erlotinib, erlotinib-sulindac versus placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer.

Clin Cancer Res 2014 Jun 11;20(12):3289-98. Epub 2014 Apr 11.

Authors' Affiliations: Division of Head and Neck Surgery, Department of Otolaryngology, Oregon Health and Science University, Portland, Oregon; Division of Hematology/Oncology, Department of Internal Medicine; Department of Pharmacology and Chemical Biology;Biostatistics Facility, University of Pittsburgh, University of Pittsburgh Cancer Institute; Departments of Otolaryngology and Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas; Women's Health Integrated Research Center, Gynecologic Cancer Center of Excellence, Annandale, Virginia; Division of Hematology/Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota.

Purpose: The EGF receptor (EGFR) and COX2 pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic antitumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a nonselective COX inhibitor; versus placebo.

Experimental Design: Patients with untreated, operable stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after seven to 14 days of treatment. The primary endpoint was change in Ki67 proliferation index. We hypothesized an ordering effect in Ki67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX2 signaling intermediates.

Results: From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, P = 0.04). Wilcoxon pairwise contrasts confirmed greater Ki67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo, P = 0.043; erlotinib vs. placebo, P = 0.027). There was a significant trend in ordering of Ki67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, P = 0.0185). Low baseline pSrc correlated with greater Ki67 reduction (R(2) = 0.312, P = 0.024).

Conclusions: Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-3360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104657PMC
June 2014

Phase I dendritic cell p53 peptide vaccine for head and neck cancer.

Clin Cancer Res 2014 May 28;20(9):2433-44. Epub 2014 Feb 28.

Authors' Affiliations: Cancer Immunology Program; Biostatistics Facility, University of Pittsburgh Cancer Institute; Departments of Pathology and Otolaryngology, University of Pittsburgh School of Medicine; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Medicine, Hematology/Oncology, University of Texas-San Antonio Cancer Center, San Antonio, Texas; and Department of Otolaryngology, University of Ulm, Germany.

Background: p53 accumulation in head and neck squamous cell carcinoma (HNSCC) cells creates a targetable tumor antigen. Adjuvant dendritic cell (DC)-based vaccination against p53 was tested in a phase I clinical trial.

Experimental Methods: Monocyte-derived DC from 16 patients were loaded with two modified HLA-class I p53 peptides (Arm 1), additional Th tetanus toxoid peptide (Arm 2), or additional Th wild-type (wt) p53-specific peptide (Arm 3). Vaccine DCs (vDC) were delivered to inguinal lymph nodes at three time points. vDC phenotype, circulating p53-specific T cells, and regulatory T cells (Treg) were serially monitored by flow cytometry and cytokine production by Luminex. vDC properties were compared with those of DC1 generated with an alternative maturation regimen.

Results: No grade II-IV adverse events were observed. Two-year disease-free survival of 88% was favorable. p53-specific T-cell frequencies were increased postvaccination in 11 of 16 patients (69%), with IFN-γ secretion detected in four of 16 patients. Treg frequencies were consistently decreased (P = 0.006) relative to prevaccination values. The phenotype and function of DC1 were improved relative to vDC.

Conclusion: Adjuvant p53-specific vaccination of patients with HNSCC was safe and associated with promising clinical outcome, decreased Treg levels, and modest vaccine-specific immunity. HNSCC patients' DC required stronger maturation stimuli to reverse immune suppression and improve vaccine efficacy.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-2617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017234PMC
May 2014

Phase I trial of carboplatin and etoposide in combination with panobinostat in patients with lung cancer.

Anticancer Res 2013 Oct;33(10):4475-81

University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue (555), Pittsburgh, PA 15232, U.S.A.

Unlabelled: A phase I trial consisting of panobinostat (a HDAC inhibitor), carboplatin and etoposide was conducted in patients with lung cancer.

Patients And Methods: Patients received carboplatin AUC5 on day 1 and etoposide 100 mg/m(2) on days 1, 2 and 3, every 21 days. Concurrent oral panobinostat was given 3 times weekly on a 2-weeks-on and 1-week-off schedule during the 4-6 cycles of chemotherapy and then continued as maintenance therapy.

Results: Six evaluable patients were treated at the first dose level of panobinostat (10 mg). Dose-limiting toxicity occurred in two patients (33%) during the first cycle. One patient developed grade 4 thrombocytopenia and another grade 4 febrile neutropenia. Therefore, the study was suspended based on the pre-specified study design. No recommended phase II starting dose was established.

Conclusion: The addition of panobinostat to carboplatin and etoposide was not tolerable at the lowest dose level tested in this trial. Further research and development into this combination is not recommended.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157617PMC
October 2013

Current status and future directions in induction chemotherapy for head and neck cancer.

Crit Rev Oncol Hematol 2013 Oct 27;88(1):57-74. Epub 2013 Mar 27.

Division of Hematology/Oncology, Department of Medicine, UT Health Science Center at San Antonio, Cancer Therapy & Research Center, 7979 Wurzbach Road MC8232, Zeller Building - 4th Floor, Room Z418, San Antonio, TX 78229, United States. Electronic address:

As a component of multimodal therapy in locally advanced head and neck cancer, induction chemotherapy represents a strategy to reduce tumor burden and target distant metastases prior to definitive treatment. Although the addition of taxanes to the cisplatin and 5-fluorouracil induction regimen (TPF) has greatly benefitted outcomes in comparison with PF alone, recent phase III trials have not shown a survival advantage for TPF induction followed by chemoradiotherapy vs. chemoradiotherapy alone. While these trials may have been underpowered to demonstrate a survival benefit, additional phase III trials are ongoing, with highly anticipated results. "Next-generation" sequential regimens that include targeted agents such as cetuximab are emerging as an approach to increase activity while decreasing toxicity. In addition, patient selection based on individual disease characteristics may identify ideal candidates for induction therapy. These developments may result in personalized therapeutic regimens that improve clinical outcomes.
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http://dx.doi.org/10.1016/j.critrevonc.2013.03.001DOI Listing
October 2013