bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression profiles can predict specific responses of capecitabine/docetaxel (C/D) based primary systemic therapy in breast cancer (BC) patients receiving neoadjuvant therapy
Authors: Perou C. , Moisa C. , Gulick S. , Tripathy D.
Published: March 2020

587

Background: The identification of efficacious neoadjuvant chemotherapy for BC is critical, especially if regimens with good activity and fewer side effects can be identified. Methods: This open-label, multicenter study of C 825 mg/m2 twice daily d1–14 plus D 75 mg/m2 every 21d for 4 cycles for HER2-neu negative (HER2-) patients (pts), and combined with trastuzumab (T) 4 mg/kg loading dose then 2 mg/kg qw for HER2-neu positive (HER2+) pts as preoperative therapy for newly diagnosed BC T2 N1 and T3 N1 (stages II and III), has enrolled 112 pts. The study aims to determine the activity of C+D±T as primary systemic neoadjuvant therapy for operable BC and to identify potential biomarkers of response. The primary endpoint is pathological complete response, with secondary endpoints including clinical response rates after 2 and 4 cycles. Ninety-nine HER2- and 38 HER2+ pts will be recruited and evaluated for gene expression patterns, p53 mutation status, and circulating tumor cells. Results: The interim analysis for the first 30 HER2- pts shows an overall clinical response rate of 83.3% (tumor size reduction 55.5%), and 84.5% for 13 HER2+ pts (tumor size reduction 61.8%). Characteristics of 38 HER2- pts: mean age 51.9y; white 73.7%, African American (AA) 10.5%; premenopausal 36.8%, post 60.5%; ductal 86.8%, lobular 7.9%; ER+ 63.2%, ER- 36.8%. For 16 HER2+ pts: mean age 56y; white 75.0%, AA 12.5%; premenopausal 25.0%, post 75.0%; ductal 93.8%, lobular 6.3%; ER+ 43.8%, ER- 56.3%. The gene expression data (n=50) identifies tumors of all “intrinsic subtypes” and shows a potentially statistically significant association between pathological and clinical response and the HER2+/ER- subtype. Conclusions: Four cycles of C+D+T is active for HER2+ and HER 2- pts prior to surgery. Confirmation of these early results will likely require the entire study sample set. Genomic analyses continue to be conducted on pretherapy tissue samples.

[Table: see text]
Dose-dense nab-paclitaxel (nanoparticle albumin-bound paclitaxel) in adjuvant chemotherapy for breast cancer: A feasibility study
Authors: Burstein H. J. , Mayer E. L. , Peppercorn J. , Parker L. M. , Hannagan K. , Moy B. , Younger J. , Schapira L. , Wulf G. , Gelman R. , Winer E. P.
Published: March 2020

594

Background: We sought to evaluate the feasibility of substituting nab-paclitaxel (ABI-007) for paclitaxel as part of “dose-dense” adjuvant sequential doxorubicin / cyclophosphamide (AC) followed by taxane chemotherapy. Patients and Methods: Eligible patients had stage I-III breast cancer receiving adjuvant/neoadjuvant chemotherapy, ANC > 1500, and LVEF > 50%. Patients received AC (60 mg/m2 and 600 mg/m2) every 2 weeks × 4 cycles with G-CSF support, followed by nab- paclitaxel 260 mg/m2 every 2 weeks × 4 cycles. The endpoint was incidence of treatment delay during nab-paclitaxel therapy. Results: 66 women (median age 48 years) were enrolled. Among the first 11 given nab-paclitaxel without G-CSF support, one developed febrile neutropenia, and 4 had nab-paclitaxel treatment delays related to neutropenia (ANC < 1,000). The protocol was amended to require G-CSF support (filgrastim or pegfilgrastim) during nab-paclitaxel. Among the next 55 patients, 3 had febrile neutropenia, none during nab- paclitaxel. In cycles 6–8, nab-paclitaxel was delayed only 6 times (1 neutropenia, 3 hepatic toxicity, 2 patient scheduling); 96% of these cycles were delivered on time. By comparison, 82% of such cycles were delivered on time in a prior institutional study using paclitaxel. In the full cohort, 8 patients had nab-paclitaxel dose reduction, 4 for neuropathy, while other neuropathy was moderate (grade 2, n = 6; grade 3, n=1; grade 4, n=0). Conclusions: Administration of nab-paclitaxel every 2 weeks is feasible but requires G-CSF support. Data comparing nab-paclitaxel dose-delivery, toxicities and quality of life to paclitaxel as seen in prior studies will be presented.

No significant financial relationships to disclose.
Functional (PET/CT) compared to conventional (mammography [M], sonography [US], MRI) imaging: Defining novel assessment modalities for inflammatory breast cancer (IBC)
Authors: Yang W. T. , Le-Petross H. T. , Gonzalez-Angulo A. , Macapinlac H. , Macapinlac H. , Dawood S. , Resetkova E. , Hortobagyi G. N. , Cristofanilli M.
Published: March 2020

600

Background: IBC is an aggressive frequently lethal form of breast cancer that is defined by sudden onset breast erythema often without an associated clinical or radiological breast mass. Tissue diagnosis remains problematic due to inability to define an area for biopsy. The aim of this study was to compare conventional [M, US, MRI] vs. functional imaging [PET/CT] in detecting a primary breast parenchymal lesion (BPL) at initial presentation of IBC. Methods: Patients (pts) with a new clinical diagnosis of IBC evaluated at the M. D. Anderson Cancer Center between January 2003 to December 2006 who had M, US, MRI, or PET/CT were included in this study. The visibility of a BPL and skin abnormality on each imaging modality was compared. Regional (axillary, supraclavicular, internal mammary) nodal disease confirmed by pathology was assessed at US and PET/CT. The presence of metastatic disease at diagnosis with PET/CT was documented. Results: Sixty-seven pts met eligibility criteria. Median age was 51 years, (range, 25 to 78). Of these, 61 (91%) had M, 62 (93%) had US, 21 (31%) had MRI, and 13 (19%) had PET/CT. By M, no BPL (mass or calcifications) was observed in 16% (10/61), skin-only abnormality (SOA) in 14% (9/61), and a BPL in 84% (51/61). By US, no BPL (mass or architectural distortion) and SOA were noted in 6% (4/62), and a PBL in 94% (58/62). By MRI, 21/21 (100%) showed malignant enhancing BPL and skin thickening. By PET/CT, 100% (13/13) showed hypermetabolic BPL and skin thickening. Pathologically confirmed regional nodal disease was diagnosed in 96% (59/62) by US and in 69% (9/13) by PET/CT. Distant metastases in the bone and lung were diagnosed in 15% (2/13) by PET/CT, one of which was visible on bone scan. Conclusions: MRI and PET/CT showed a primary BPL in all cases of IBC while conventional imaging (M and US) failed to reveal a BPL amenable to biopsy in up to 16%. US can diagnose regional nodal disease to facilitate loco-regional therapeutic planning. PET/CT provides additional information on distant metastasis and should be considered in the initial staging of IBC.

No significant financial relationships to disclose.
Incidence trends for human papillomavirus-related (HPV-R) and unrelated (HPV-U) head and neck squamous cell carcinomas (HNSCC) in the United States (US)
Authors: Chaturvedi A. , Engels E. , Anderson W. , Gillison M.
Published: March 2020

6001

Background: HNSCC are etiologically heterogeneous, with one subset primarily attributable to HPV and another to tobacco and alcohol. Methods: Data from SEER9 program registries were used to investigate the potential influence of HPV on incidence and survival of HNSCC in the US from 1973–2003. HNSCCs (N=58,158) were classified by anatomic site as potentially HPV-R (base of tongue; tonsil; oropharynx; N=16,712) or HPV-U (lip; tongue; gum; floor of mouth; palate; other mouth; hypopharynx; ill-defined sites of lip, oral cavity, and pharynx; N=41,446). Joinpoint regression was used to assess incidence trends and life-table methods were used to compare survival for HPV-R and HPV-U HNSCCs. Results: For HPV-R HNSCCs, age-adjusted incidence increased significantly from 1973–2003 (annual percent change [APC] = 0.65), particularly among males (APC=1.02), whites (APC=0.89), and younger ages (APCs for 30–39 = 1.46; 40- 49=1.92; 50–59=0.61, and =60= -0.66). By contrast, HPV-U HNSCC incidence was stable from 1973–1983 and then decreased significantly from 1983–2003 (APC= -2.42). Mean age at diagnosis was younger for HPV-R HNSCC than HPV-U (61.1 vs. 64.5 years; p<0.001), and from 1973- 2003, decreased significantly for HPV-R, but increased for HPV-U. Improvements in overall survival (OS) were observed for HPV-R (all stages) and HPV-U (regional and distant) HNSCC treated by radiotherapy (RT) from 1973–2003, but were more marked for HPV-R HNSCC, e.g. absolute increase in two-year OS for regional disease of 24.4% (vs. 5.8% for HPV-U). OS for HPV-R (local and regional) was significantly better than HPV-U HNSCC if treated by RT, but worse if not so treated. Conclusions: The proportion of HNSCC that is potentially HPV- R increased in the US from 1973–2003, particularly among recent birth cohorts, perhaps due to changing sexual and smoking behaviors. Recent improvements in locoregional control with RT-based therapy may be due in part to a gradual shift in the etiology of the underlying disease.

No significant financial relationships to disclose.
Potential advantage of studying preoperative sentinel node mapping with three-dimensional images by a hybrid single photon emission CT (SPECT)/CT system for breast cancer
Authors: Ibusuki M. , Yamamoto Y. , Kawasoe T. , Kai K. , Shiraishi S. , Tomiguchi S. , Iwase H.
Published: March 2020

601

Background: Lymph node status is one of the key factors in determining the stage, appropriate therapy and outcome in patients with breast cancer. Accurate identification of sentinel nodes (SNs) has clinical importance for each patients before surgery. The purpose of this study was to assess the role of Single-photon emission computed tomography (SPECT)/CT lymphoscintigraphy in SN identification for patients with breast cancer, and to analyze the impact of such information on estimating metastases to SNs. Methods: Two hundred and twenty-three clinically node-negative patients were underwent SN biopsy between July 2002 and November 2006. CT and SPECT images were obtained after injection of subcutaneal 1mCi (99m)Tc-nanocolloid, allowing identification of SN. Target and non-target structures, including lymph nodes identified by SPECT, were drawn by SPECT/CT combined system, which was comprised of a two-detector SPECT system and a multiple-detector CT at the same platform. We compared the anatomical location of SNs demonstrated on the 3D SPECT/CT images and correlation to SN positivity. Results: SPECT/CT uptake was detected in 221 cases (99.1%). 3D SPECT/CT images visualized accurate localization of SNs in each cases. Total number of biopsied SNs were 315 , and the most frequent locations of SN were trapezoid area in the upper side of axilla. We defined this area as ‘Pectoral area (PA)’. In SN negative (SN-) patients, 228 (98.3%) SNs were found in PA, and 4 (1.7%) SNs were out of this area such as parasternal area. In SN positive (SN+) patients, 65(78.3%) SNs were in the PA, and 18(21.7%)SNs were out of PA ,respectively. Significant differences (p<0.01 ,chi-square test) were found in SNs distribution whether in or out of PA between SN+ and SN- patients. Conclusions: SN biopsy navigated by 3D-SPECT/CT can clarify the preoperative anatomical localization of SNs in patients with breast cancer. Atypical distribution of SNs out of PA may suggest SN positivity as a reflection of the failure of lymphatic drainage systems.

No significant financial relationships to disclose.
Phase II study of combination cetuximab and weekly paclitaxel in patients with metastatic/recurrent squamous cell carcinoma of head and neck (SCCHN): Spanish Head and Neck Cancer Group (TTCC)
Authors: Hitt R. , Irigoyen A. , Nuñez J. , Grau J. , Garcia Saenz J. , Pastor M. , Jara C. , Garcia Giron C. , Hidalgo M. , Cruz Hernandez J.
Published: March 2020

6012

Background: Cetuximab and paclitaxel have shown to be active in SCCHN pts and preclinical data has demonstrated a possible synergy for the combination. In a variety of tumor types, weekly paclitaxel has demonstrated an improved safety profile and activity as compared to every 3 weeks paclitaxel, providing the rationale to study the combination of cetuximab and weekly paclitaxel in metastatic/recurrent SCCHN. Methods: Pts were required to have a y performance status (KPS) = 70%, measurable disease using RECIST criteria, and may have received one regimen of induction and/or concomitant chemotherapy, but not within the recurrent/metastatic setting. Treatment included weekly paclitaxel 80 mg/m2 and cetuximab (initial dose of 400 mg/m2, followed by a weekly infusion of 250 mg/m2). Biopsies of tumors and samples of blood are being analyzed for correlative markers including EGFR gene copy number -FISH-, polymorphisms of intron 1 of the EGFR, and downstream EGFR pathway markers and mutations. Results: 46 planned pts were enrolled from Ap-2006 to Sep-2006. Median age is 60 years (range 42–78). Median KPS is 80% (range 70–100%). 35 pts are evaluable for response. Complete responses have been observed in 7 pts, partial responses in 18 pts, and stable disease in 6 pts for an overall response rate of 71% and disease control rate of 88%. 44 pts are evaluable for safety. Main grade 3/4 toxicities(NCI): 8 pts had acne- like rash; 7 neutropenia but only 1 febrile neutropenia; 6 asthenia; 3 mucositis; 2 infusion related reactions to paclitaxel and 1 to cetuximab; 2 peripheral neuropathies; 1 diarrhea; 1 vomiting; and 1 conjunctivitis. Conclusions: This trial shows that the combination of cetuximab and weekly paclitaxel is well tolerated and provides very encouraging activity in advanced/recurrent SCCHN. The full data, including biomarker results, will be presented at the annual meeting.

No significant financial relationships to disclose.
Prognostic factors for clinical benefit after epidermal growth factor receptor (EGFR) directed therapy in squamous cell carcinomas of the head and neck (SCCHN)
Authors: Halpern A. B. , Kasza K. , Kocherginsky M. , Clark G. , Vokes E. E. , Williams R. , Cohen E. E.
Published: March 2020

6025

Background: Single agent EGFR tyrosine kinase inhibitors (TKI) have demonstrated reproducible response rates of 5–15% in treatment of SCCHN. The subset of patients that benefits most from these agents remains unknown. We undertook a review of data from 5 clinical trials administering EGFR TKI in order to determine if there are clinical characteristics that are associated with response or benefit. Methods: We reviewed individual patient data from 5 clinical trials of erlotinib, lapatinib, or gefitinib. The primary endpoint was association of clinical variables with clinical benefit, defined as response (CR or PR) and stable disease (SD) >4 months. Secondary correlative endpoints included progression-free survival (PFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used to conduct univariate and multivariate analysis. Results: 319 subjects were included in the analysis with a median age of 59 years, 79% male. Disease status at start of therapy was local only in 43%, metastatic only in 29%, and both in 27%. Performance status (PS) was 0 in 25%, 1 in 62%, and 2 in 13%. Observed responses were: 1% CR, 6% PR, 24% SD >4 mo, 18 % SD3 in 6%) and diarrhea (grade 1 in 30%, grade 2 in 10%, grade 3 in 5%). Lower PS (p=0.06, OR (0/2)=3.1), age 70+ (p=0.02, OR= 2.1), and development of rash (p<0.01, OR=3.6), and diarrhea (p=0.03, OR=1.8) were associated with higher response rates. These variables were also associated with longer OS and PFS. Conclusions: Clinical parameters that appear to predict response to EGFR TKI include PS and age. EGFR mechanistic toxicities that develop during therapy are highly associated with benefit and suggest a relationship between drug exposure and outcome.

No significant financial relationships to disclose.
Correlation of Src activation with epithelial-mesenchymal transformation and aggressive features of head and neck squamous carcinoma
Authors: El-Naggar A. K. , Lippman S. M. , Johnson F. M. , Mandal M. , Myers J. N. , Williams M. D. , Rosenthal D. I. , Weber R. S. , Gallick G.
Published: March 2020

6026

Background: The role of the epithelial-mesenchymal transition (EMT) is crucial to invasive and progression of several epithelial malignancies. The role of this process in head and neck squamous cell carcinoma (HNSCC) remains poorly defined. Methods: Eleven head and neck squamous cancer cell lines and 50 primary tumor specimens formed the materials for this study. We used Western blotting, immunohistochemistry, RT-PCR cell motility assay to determine the expression and the functional implications of several cell adhesions and singling molecular associated with EMT in these tumors. Results: Our results showed Src and E-Cadherin to be paradoxically overexpressed in the majority of cell lines and in primary tumor tissues relative to normal squamous mucosa. In both cell lines and tumor tissues elevation of activated Src was accompanied by down-regulation of E-Cadherin and vimentin detection. In-vitro inhibition of Src led to the increased E-Cadherin of expression and cell proliferation in squamous carcinoma cell lines. Immunophenotypic analysis of the protein products of these genes in primary tumor tissues demonstrated a spectrum of changes that correlated significantly with the differentiation, invasive patterns, sarcomatoid transformation and lymph node status. Our results show that high activated Src and low E-Cadherin expression were correlated with finger-like invasive pattern, poor differentiation, sarcomatoid transformation and lymph node metastasis in HNSC. Conclusions: Our study indicates that Src and E-Cadherin play a major role in EMT invasion and progression of head and neck squamous carcinoma. These proteins may be targeted in the therapeutic intervention of patients with HNSCC.

No significant financial relationships to disclose.
Phase I dose escalation study of fractionated stereotactic radiosurgery (fSRS) for recurrent squamous cell carcinoma of the head and neck (SCCHN)
Authors: Heron D. E. , Ferris R. L. , Burton S. , Lai S. , Karamouzis M. V. , Gooding W. , Johnson J. , Smith R. P. , Argiris A. , Grandis J.
Published: March 2020

6029

Background: Limited-field re-irradiation has been used as salvage and palliative therapy in recurrent previously irradiated SCCHN. Its primary limitation is the dose to critical structures, such as the spinal cord. With its greater degree of conformality, accuracy and limited number of fractions (fx), extracranial fSRS has become an attractive alternative. Prior reports have used 25 Gy in 5 fx in recurrent SCCHN. This phase I trial assessed the safety of fSRS and established a starting dose for a planned phase II trial with concurrent cetuximab. Methods: Eligibe patients (pts) had pathologically-confirmed SCCHN that recurred post standard therapies, ECOG performance status 0–2, and measurable disease. All pts were staged and planned with PET-CT and were treated with the CyberKnife Frameless Radiosurgery System (Accuray, Sunnyvale, CA). Prior therapies included: radiation therapy (all pts, dose range: 50.4–88 Gy), surgery (n=22), chemotherapy (n=14). fSRS was delivered in 5 fx, every other day in 2 weeks, and dose escalated in successive cohort of 4 pts at 5 dose levels: I: 5 Gy/fx (25 Gy), II: 6.4 Gy/fx (32 Gy), III: 7.2Gy/fx (36 Gy), IV: 8 Gy/fx (40 Gy), and V: 8.8 Gy/fx (44 Gy). Dose limiting toxicities (DLT) was assessed up to 4-week period post fSRS. Dose tiers 4 and 5 were expanded to include more patients when no DLT were observed in the earlier cohorts. Results: 25 pts were enrolled and 19 were evaluable for response (tier I:4, II:4 III:3 IV:7 V:7). Median age 62 years (range 35–86), Male/Female: 24/1, 7 ECOG Performance status 0 (n=7), PS 1 (n=11), PS 2 (n=7). There were no DLTs observed to date. Toxicities included: grade 2 dysphagia (n=1) and grade 1 mucositis (n=2). Best responses: CR=1, PR=5, SD=9, PD=4 with an overall response rate of 31% (95% CI 13%-56%). Additionally, in this cohort with inoperable recurrent SCCHN 15/19 pts (79%) had stable or responding disease at last follow-up. The median survival was 24 weeks. Conclusions: Re-irradiation with fSRS is feasible and well tolerated up to a total dose of 44 Gy (8.8 Gy/fx). A phase II trial incorporating concomitant cetuximab is currently approved.

No significant financial relationships to disclose.
Gefitinib plus concomitant boost accelerated radiation (AFX-CB) and concurrent weekly cisplatin for locally advanced unresectable squamous cell head and neck carcinomas (SCCHN): A phase II study
Authors: Rueda A. , Medina J. A. , Mesía R. , Galiana R. , Vega M. E. , Collado A. , Cobo M. , Contreras J. , Marguelí M. , Alba E.
Published: March 2020

6031

Background: Molecular inhibition of EGFR signaling represents one of the most promising current advances for the treatment of SCCHN. This study assesses the feasibility, toxicity and efficacy of gefitinib along with AFX-CB regimen and weekly cisplatin in treatment- naïve patients (pts) with locally advanced unresectable SCCHN. Methods: Eligible pts had stage III-IV SCCHN, exclusive of nasopharyngeal cancer. Tumors had to be considered unresectable by a multidisciplinary head/neck tumor board. AFX-CB dose was 72 Gy in 42 fractions over 6 weeks, delivered in 1 daily fraction of 1.8 Gy during the first 3.5 weeks and 2 fractions per day, 1.8 Gy and 1.5 Gy separated by a 6-hour interval, during the last 2.5 weeks. Cisplatin (40 mg/m2) was given weekly for the first 4 weeks. Gefitinib (250 mg PO OD) was started 1 day before radiochemotherapy (RCT) and continued 3 months after the end of AFX-CB. Response was evaluated 3 months after radiotherapy using RECIST criteria. Mucosal and skin toxicities were evaluated using the RTOG scale. Results: From Dec 2002 to Dec 2004, 46 pts with SCCHN, ECOG PS 0–1 and adequate hematologic and renal functions were included. Median age was 55 years (range, 39 to 75); T4, 73%; N2/3, 61%; stage IV disease, 93%. Four pts did not complete the concomitant treatment (1 PD/3 toxicity) and 8 pts did not complete the gefitinib monotherapy phase due to PD. Grade 3 and 4 toxicity was consistent with previous RCT or single agent gefitinib trials, and included mucositis (40% and 7%, respectively), radiation dermatitis (14% and 0%), skin rash (5% and 0%), and diarrhea (2% and 0%). Chemotherapy-associated toxicity was mild with only 2 cases of grade 3 neutropenia and 3 cases of grade 3 anaemia. Three months after AFX- CB, 24 pts (52%) achieved a complete remission, 5 pts (11%) a partial remission, and 17 pts (37%) were non-responders (SD, PD, and not evaluable). With a median follow-up of 23 months (range 1–43) 2-year PFS and OS are 47% and 56% respectively. Conclusions: The addition of gefitinib to radiochemotherapy appears tolerable and feasible. Efficacy is encouraging for this poor prognosis population, and further development of this targeted combined-modality paradigm is warranted.

No significant financial relationships to disclose.
Surrogate endpoints for overall survival (OS) in head and neck squamous cell carcinoma (HNSCC): Evaluation using individual data of 23,737 patients
Authors: Michiels S. , Le Maître A. , Buyse M. , Burzykowski T. , Bogaerts J. , Vermorken J. B. , Budach W. , Ang K. , Pajak T. , Pignon J. P.
Published: March 2020

6035

Background: The gold standard endpoint in randomized trials of HNSCC is OS. Our objective was to study if event-free survival (EFS) or loco-regional control (LRC) could be good surrogate endpoints to estimate the effect of radiotherapy (RT) and chemotherapy (CT) on OS. This would permit to decrease the duration and cost of the development of new treatments for HNSCC. Methods: EFS is the time from randomization to first event (loco-regional, distant recurrence or death), LRC the time from randomization to first loco-regional event. Individual patient data from two meta-analyses (MARCH; Bourhis, Lancet 2006, MACH-NC; Bourhis, ASCO 2004) were used. At the individual level, the rank correlation coefficient ρ between the surrogate endpoint (EFS or LRC) and OS was estimated from the bivariate distribution of these endpoints. At the trial level, the correlation coefficient R between treatment effects (estimated by log hazard ratios) on the surrogate endpoint and OS was estimated from a linear regression. EFS and LRC would be acceptable surrogates only if the correlation coefficients ρ and R were close to 1. Results: At the individual level, EFS was more strongly correlated with OS than LRC. For RT, treatment effects on both LRC and EFS were strongly correlated with those on OS. For CT, the correlation coefficients between treatment effects on EFS and OS were larger than those between LRC and OS. Conclusions: The preliminary analysis indicates that EFS can be used as a surrogate for OS to evaluate the treatment effect in randomized trials of patients with HNSCC. LRC is a possible alternative in RT alone trials. Unrestricted grants from ARC, LNCC, PHRC, Sanofi-Aventis.

[Table: see text]

[Table: see text]
Efficacy of neoadjuvant docetaxel and cisplatin followed by concurrent cisplatin-radiotherapy in locally advanced nasopharyngeal carcinoma (NPC): A randomized phase II study
Authors: Hui E. P. , Ma B. B. , Leung S. F. , King A. , Mo F. , Kam M. K. , Yu K. H. , Kwan W. H. , Zee B. C. , Chan A. T.
Published: March 2020

6037

Background: The current standard treatment for locally advanced NPC is chemoradiation (CRT) ± adjuvant chemotherapy. However, adjuvant chemotherapy is often poorly tolerated after intensive CRT. Our previous study of neoadjuvant chemotherapy followed by CRT showed encouraging toxicity profile and disease control in advanced NPC (JCO 2004: 22: 3053–60). The current study compared the safety and efficacy of neoadjuvant chemotherapy (neoadj) followed by CRT. Methods: Newly diagnosed patients (pts) with stage III to IVB NPC were randomized (stratified by stage III vs IV) to: (1) Neoadj-CRT: docetaxel 75 mg/m2 D1, cisplatin 75 mg/m2 D1, q3w × 2 cycles, followed by cisplatin 40 mg/m2 weekly × 6–8 cycles concurrent with RT (= 66 Gy in 2-Gy fractions), or (2) CRT: cisplatin-RT (same as arm 1) without neoadj. The primary endpoint was toxicity. Secondary endpoints included survival and quality of life. Planned accrual was 30 pts per arm to detect a 20% difference in toxicity on one side of a 95% confidence interval (CI). Results: From 11/2002 to 11/2004, 65 pts were recruited. Five pts were excluded after randomization but before treatment started (three pts were subsequently found ineligible, and two pts withdrew consent). There was a higher rate of G3–4 neutropenia (100% vs 16%, p<0.001), but not neutropenic fever (3% vs 4%) or other non-hematologic toxicity in the neoadj-CRT vs CRT arm. The proportion of pts progressing at 2-yrs by group was compared by Fisher’s Exact Test (p=0.158). At median follow-up of 2.74 yrs, there were 10 deaths and 13 progressions. The 2-yr progression free survival for neoadj-CRT vs CRT was 80% vs 71% (hazard ratio 0.42; CI 0.14− 1.27; p=0.11). The 2-yr overall survival was 93% vs 76% (hazard ratio 0.17; CI 0.037–0.82; p=0.013). Conclusions: Neoadjuvant docetaxel and cisplatin followed by CRT was well tolerated with a manageable toxicity profile and allowed subsequent delivery of full dose CRT. Preliminary result suggested improved survival. A phase 3 study to definitively test this strategy is warranted. Acknowledgement: Sanofi-Aventis Hong Kong Ltd supported this study in part.

No significant financial relationships to disclose.
A phase II trial of ZD 1869 for advanced cutaneous squamous cell carcinoma of the head and neck
Authors: Weber R. S. , Lustig R. , Glisson B. , Rosenthal D. , Kim E. , El-Naggar A. , Chalian A. , Hanna E.
Published: March 2020

6038

Background: Advanced HN CSSC carries a 30–40% risk of death by 2 years with standard therapies. A number of patients (pts) with clinically aggressive CSCC tend to have a poor prognosis when treated with standard approaches using surgery and radiation (RT), thus novel therapies are needed. CSSC over expresses the epidermal growth factor receptor (EGFR) and these compounds have activity in head and neck cancers. We are studying the use of gefitinib as an induction therapy in a high-risk patient group prior to definitive therapy to determine the overall efficacy, toxicity and feasibility. Methods: Eligible pts must have HN CSSC >2cm, regional nodal metastases, peri-neural invasion, or deep invasion into cartilage, muscle or bone and must be candidates for definitive local-regional therapy with surgery and/or radiation. Two 30-day cycles of gefitinib 250mg administered orally are given daily prior to definitive therapy. Pts are assessed clinically after the first 30-day cycle. If a response is noted, gefitinib is continued. For patients with stable disease, the dose is escalated to 500mg daily. Pts with progressive disease go off study. Biomarker evaluations including EGFR and Akt expression prior to and after induction are planned. Results: To date, 14 pts have been enrolled. 10 are evaluable for response and 13 for toxicity. A complete clinical response (CR) was noted in 3 pts (30%, one pathological CR), partial response in 2 patients (20%), stable disease in 2 (20%) and progressive disease in 3 (30%). Therapy was well tolerated with 2 patients having grade 3 toxicity (rash, diarrhea, or elevated liver enzymes). Conclusions: Standard definitive surgery and RT are inadequate for patients with advanced HN CSSC. The emergence of targeted therapies has given new hope for many patients with high-risk cancers. The preliminary results from our study suggest that gefitinib is an active agent for HN CSCC, and is well tolerated. Correlative studies may help identify patients most likely to respond to anti- EGFR therapy.

[Table: see text]
Impact of erythropoietin (EPO) on irradiation effect on the EPO receptor–positive head and neck cancer
Authors: Lo Nigro C. , Maffi M. , Fischel J. , Tonissi F. , Numico G. , Milano G. , Merlano M.
Published: March 2020

6058

Background: Anemia frequently occurs in Head and Neck Squamous Cell Carcinoma (HNSCC) and has been associated with decreased quality of life, impaired treatment outcomes and shortened survival. Furthermore, anemia is a causative factor of tumor hypoxia, which compromises the efficacy of radiotherapy (RT). In order to circumvent the negative effects of anemia, several attempts have been made including the use of EPO, particularly in HNSCC. However, recent clinical data suggest a detrimental effect of EPO on survival for HNSCC patients treated with RT plus EPO. Methods: The HNSCC CAL-166 cell line, which is wild type p53 and expresses the EPO receptor (EPOR), was investigated in the present study; a MTT test was used to examine the effects of EPO on the cellular response to RT. Extended preliminary experiments were performed to standardize the conditions (time of exposure to hypoxia and time to return of normal culture conditions) and the administration of radiation (fractionated or in single dose) to optimize the effects of hypoxia on radiation response. Cells were exposed to a X-rays source at escalating doses from 2–20 Gy and showed classical dose- response curves. Hypoxia was mimed using a ‘Bug-Box‘ anaerobic workstation for 24–48 hours. Results: After a single RT dose of 10 Gy, the data confirmed the negative effect of hypoxia, directly related to the duration of hypoxia (% surviving cells when irradiated in normoxia: 43.95 ± 4.24; when irradiated after 24 hours of hypoxia, 62.4 ± 8.3 or after 48 hours, % surviving cells 70.8 ± 7.4; p = 0.001 versus RT in normoxia). The addition of EPO, from 24 hours before RT to 72 hours after, until MTT test, did not modify the cytotoxic effect of RT in hypoxic, but also in oxic conditions. Conclusions: These preliminary data do not support a direct negative effect of EPO when treating EPOR positive tumor cells with irradiation. Additional data concern the molecular impact of EPO on tumor cell lines with examination of EPOR, HIF-1 alpha and EGFR.

No significant financial relationships to disclose.
Multi-center prospective study on sentinel node navigation surgery in early breast cancer
Authors: Imoto S. , Kitajima M. , Aikou T. , Kitagawa Y.
Published: March 2020

606

Background: Sentinel node navigation surgery (SNNS) is a standard technique to identify lymph node metastases in clinically node-negative breast cancer. However, the dye and radiopharmaceuticals for lymphatic mapping commonly used in Western countries are not available in Japan. Methods: To assess the optimal lymphatic mapping and the outcome after SNNS, the Japanese society for SNNS conducted a non-randomized multi-center prospective study on SNNS in early breast cancer. Primary endpoint is to evaluate the success rates and adverse events associated with various lymphatic mapping and SNNS, and secondary endpoint is to observe the outcome of patients who underwent SNNS during 5 years. After the protocol was approved by institutional review board, SNNS had been registered between July 2004 and October 2005. Results: Fourteen hundred and sixty-eight cases had pre-registration from 65 investigators at 23 institutions. As 46 cases were withdrawn for some reasons and 11 cases were diagnosed as benign disease, 1,411 cases were finally entered in this study. Dyes used for lymphatic mapping were indigocarmine, indocyanin green, patent blue, and isosulfun blue, and radiopharmaceuticals were 99m-technetium-labelled tin colloid, human serum albumin, and phytate. In 19 cases, superparamagnetic iron oxide was used for MRI- guided SNNS. As of December 2006, 98% of clinical report forms were analyzed. Dye-guided SNNS was performed in 240 cases, radio-guided SNNS in 56 cases, and combined method in 1,016 cases. Overall success rate was 99%. SNNS alone was treated in 1,138 cases (82%) and SNNS followed by axillary lymph node dissection in 258 cases (12%). Breast-conserving surgery was undergone in 1,175 cases (85%) and total mastectomy in 217 cases (15%). Dye-induced allergic adverse events were not reported. Postoperative adverse events of bleeding, wound infection and seroma were observed in about 1 % of cases, respectively. Conclusions: Dye-guided and/or radio-guided SNNS proved reliable for lymphatic mapping in breast cancer. The prognosis of all cases will be observed until 2010.

No significant financial relationships to disclose.
Retrospective analysis of the addition of cetuximab to induction chemotherapy (IC) with docetaxel, cisplatin, and 5-fluorouracil (TPF-C) for locally advanced squamous cell carcinoma of the head and neck (LA-HNSCC)
Authors: Kuperman D. I. , Nussenbaum B. , Thorstad W. , Haughey B. , Lewis J. , Adkins D.
Published: March 2020

6072

Background: Achievement of a partial (PR) or complete (CR) tumor response at the primary site to IC has been used to predict for tumor sensitivity to definitive radiation (RT)-based treatment approaches in patients with LA-HNSCC. Three randomized trials of IC showed that TPF resulted in superior tumor response rates at the primary site in comparison to PF (TAX 323, TAX 324, and GORTEC). Based on the improved tumor response rate with the addition of cetuximab to cisplatin in metastatic HNSCC, TPF-C is a rational approach to improving tumor response rate to IC in LA-HNSCC. Methods: Between 2/06–12/06, 23 consecutive patients with LA-HNSCC were treated with IC that included TPF + cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly dose) for 1–3 cycles, followed by a standardized clinical assessment of tumor response at the primary site and at the regional nodes. TPF (docetaxel and cisplatin both 75 mg/m2 on day 1; 5-FU 750 mg/m2/d for 3 days) was given at every 3 week intervals. PR was defined as = 50% decrease and CR as complete resolution of tumor at the primary site. This is a retrospective analysis of the efficacy and the adverse effects (AE) of TPF-C in these patients. Results: Of 23 patients, 21 were evaluable for tumor response rate (RR). During IC, there were no deaths and grade 3–4 AE included: neutropenic fever (4), sepsis (1), and infusion reactions (4). Patients with favorable (PR or CR) tumor response to IC were treated with definitive RT-based therapy; whereas others were treated with surgery first. Conclusions: In this population of patients with LA-HNSCC with mostly (74%) T3 and T4 primary tumors, the tumor RR at the primary site to TPF-C was 71%. The addition of cetuximab to TPF was feasible.

No significant financial relationships to disclose.

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Experience with cetuximab plus paclitaxel/carboplatinum in primary platinum-resistant recurrent head and neck cancer
Authors: Buentzel J. , de Vries A. , Micke O.
Published: March 2020

6077

Background: In patients with platinum-resistant recurrent head and neck cancer the Anti-EGF-receptor antibody cetuximab could be used as a treatment option. Little is known about results of this therapeutic option. The objective of this study was to evaluate therapeutic benefit of this indication. Methods: 23 patients with histological confirmed recurrent head and neck cancer (18 male, 3 female, median age was 57 years) were included in this exploratory study. All recurrences had occurred after chemotherapy with platinum- derivates. 19 patients received radiation therapy during primary treatment. No surgical or radiotherapeutic option in recurrent disease was possible. Two patients were diagnosed with lung metastasis. The 2nd-line therapy consisted of carboplatinum (200 mg/m2) + paclitaxel (200 mg/m2) every three weeks (week 1, 4, and 7) and additionally cetuximab, which was given with 400 mg/m2 as loading dose in week 1 and 250 mg/m2 in week 2–6. Results: A significant tumor response was observed in 13/23 patients (56%). 7 partial, 5 minor and one complete remission were registered. The median survival time was 8 month (range 3–10), 4 patients are still alive. Median time to progression was 5 month (range 2–8). Side effects were rash (16/22), fever (9/22) and typical chemotherapy induced toxicities as neuropathy (7/22) and cytopenia (4/22). All side effects were moderate and easy to handle. Conclusions: The described combined chemoimmuntherapy with cetuximab and paclitaxel + carboplatinum seems to offer new strategies in 2nd and 3rd line chemotherapy for patients with platinum-resistant head and neck cancer, potentially overcoming primary platinum resistance.

No significant financial relationships to disclose.
Phase III randomized trial of postoperative radiotherapy (RT) with or without carboplatin (Cb) in patients (pts) with head and neck squamous cell carcinoma (HNSCC)
Authors: Johnson J. T. , Agarwala S. S. , Karamouzis M. V. , Heron D. E. , Eibling D. E. , Cano E. , Urba S. , Gluckman J. , Wang Y. , Argiris A.
Published: March 2020

6078

Background: Postoperative RT plus cisplatin is a standard treatment in high-risk resected HNSCC. However, the role of Cb in the same setting has not been established. Methods: Eligible were pts with macroscopically resected stage III/IV HNSCC with high-risk pathologic features (=3 nodes, extracapsular extension, perineural or angiolymphatic invasion, or involved margins), ECOG performance status 0–2, and adequate laboratory parameters. Pts were randomized to receive RT 59.4 Gy (1.8 Gy/day) versus the same RT plus Cb 100 mg/m2 intravenously once weekly during RT. The primary endpoint was the 2-year disease-free survival (DFS); with a projected sample size 100 patients/arm, the power was 0.81 with alpha 0.1 to detect a 15% improvement (50% to 65%). Results: From 4/94 to 4/02, 76 pts were randomized, of whom 72 pts were eligible and analyzable (36/arm). The study was prematurely closed due to slow accrual. Median age 54 years (24–83); male/female: 60 pts/12 pts; primary sites: oral cavity (n=26), oropharynx (n=23), hypopharynx (n=8), larynx (n=15); stage III/IV: 6 pts/66 pts; ECOG performance status 0/1/2: 40 pts/30 pts/2 pts. Median follow-up was 5.3 years. The 2-, 3- and 5-year DFS with RT/Cb vs. RT was 70%, 60%, and 46% vs. 55% (p=0.21), 51% (p=0.48), and 43% (p=0.79) and the 2-, 3- and 5-year overall survival (OS) was 74%, 71%, and 47% vs. 51% (p=0.04), 51% (p=0.07) and 40% (p=0.59). There were no statistically significant differences in median DFS or OS. In the subset of pts with primary sites other than the oropharynx (n=49), RT/Cb resulted in better OS vs. RT (p=0.05, Wilcoxon; p=0.27, log-rank). RT/Cb was associated with infrequent grade III/IV toxicities, including leukopenia (RT/Cb 8% vs. RT 0%), stomatitis (11% vs. 3%), and dermatitis (6% vs. 3%). Gastrostomy tube was placed in 15 pts (RT/Cb 8 vs. RT 7). Conclusions: Our data do not show a statistically significant improvement in DFS with RT/Cb vs. RT but this may reflect insufficient sample size. The potential benefit of RT/Cb for a subset of pts merits further study.

No significant financial relationships to disclose.
Trends in head and neck squamous cell carcinoma (HNSCC) clinical research as reported in the ASCO Proceedings from 1996- 2006
Authors: David K. A. , Rademaker A. , Agulnik M.
Published: March 2020

6089

Background: The results of clinical research can be seen through the review of ASCO Proceedings abstracts. We aimed to identify treatment trends in HNSCC as reported at the ASCO annual meetings from 1996 to 2006 and to see if an improvement in patient survival occurred. Methods: All abstracts in the head and neck section of ASCO Proceedings from 1996 to 2006 were reviewed. Abstracts on locally advanced, recurrent or metastatic HNSCC were further explored. Descriptive summary information was recorded regarding number of authors, randomization, trial phase, presence of novel drug or combination therapies, timing of chemotherapy, and disease-free and overall survival. Results: From 1996 to 2006, there were a total of 1,043 Head and Neck Cancer abstracts. Out of 311 phase 2 and 3 abstracts, 207 were presented. Of these, 78 were presented in the first half of the study period (1996–2000) compared to 129 in the second half (2001–2006). The average number of authors over the 10-year period was 12.7. Randomized controlled study proportions fluctuated, ranging from 11.8% in 2005 to 47.1% in 2001. 60% of studies focused on locally advanced disease; 32% on metastatic or recurrent disease, and 7% on both. Induction chemotherapy accounted for 31% of presented abstracts, while only 4% presented adjuvant data. The majority of abstracts used concurrent chemoradiotherapy (57%); 36% studied drug therapy alone. Abstracts presenting new therapies or new therapy combinations decreased (75% in 1996 vs. 61% in 2006). 12 studies (6% of presented studies) showed a statistically significant survival benefit, with 9/12 presented since 2001. All 12 were of patients with locally advanced disease, with the majority (7/12) showing the survival benefit of radiation administered with chemotherapy or cetuximab. Two trials showed the survival benefit of induction docetaxel, cisplatin, and fluorouracil (TPF) compared to PF. Conclusions: Since 1996, the number of presented clinical trials of HNSCC has increased. Overall survival benefits have been shown in Phase III trials in locally advanced disease. The major therapeutic advance over the last decade has been the overall survival gain with the use of concurrent chemoradiotherapy in locally advanced HNSCC.

No significant financial relationships to disclose.
3-D MRI guided breast conserving surgery
Authors: Hisamatsu K.
Published: March 2020

610

Background: In breast cancer patients, accurate diagnosis of ductal spreading is of great importanace for deciding sugical procedure. The role of imaging diagnosis using 3D-MRI in deciding of ductal spreading was assessed histologically and efficacy of 3D-MRI guided surgery was evaluated. Methods: Preoperative 3D-MRI was underwent 374 cases of breast cancer patients. Images were obtained 371 cases (99%). These patients could be divided into four groups according to 3D-MRI images: pattern 1) localized type, 2) widely enhanced type A (enhanced area: less than Quadrant) and 3) widely enhanced type B (enhanced area: more than Quadrant) and 4) multifocal type. Diagnosis of ductal spreading was confirmed histologically and relation between 3D-MRI patterns and ductal spreading were assessed retrospectively. Local failure of 3D-MRI guided surgery was assessed by 3D-MRI image patterns Results: The rate of histological confirmed ductal spreading were seen in 59% (125/212cases), 86% (49/57 cases) and 83% (19/23cases) of patients with 3D-MRI pattern 1), 2), and 3), respectively. From April 2005, resected specimen was serially step cut and total specimens were evaluated. Tumor diameter from nipple side to lateral margin were measured by MRI and resected specimens, tumor size was correlated between MRI and resected specimens, significantly (n=80, r=0.790887, P < 0.001). Whole breast examination revealed that only 4 cases were multifocal cancer in 17 cases of multifocal image in 3D-MRI. Patient selection for breast conserving surgery was based by 3D-MRI images. The proportion of breast-conserved surgery were obtained 96% (203/212 cases), 86% (49/57 cases), 26% (6/23cases) and 89% (68/76 cases) of patients with 3D-MRI pattern 1), 2), 3), and 4), respectively. Local failures were seen 2cases in pattern 1), one case in 3) and one case in 4) (2–77 months, median follow up 39 months). Conclusions: These results suggest that MRI will be the useful breast imaging tool in diagnosing ductal spreading and tumor size in breast cancer patients. Safety breast conserving surgery was achieved by MRI guided surgery.

No significant financial relationships to disclose.
Therapeutic radiation for breast cancer in BRCA mutation carriers and contralateral breast cancer (CBC) risk
Authors: Moore H. C. , Wesolowski R. , Choueiri T. K. , Rybicki L. , Shealy A. G. , Casey G. , Weng D.
Published: March 2020

611

Background: BRCA mutation carriers diagnosed with breast cancer are at high risk for contralateral second primary breast cancers. Mutations in BRCA1 and BRCA2 lead to defects in DNA repair. Radiation treatment for breast cancer is felt to increase risk of CBC, but the interaction between BRCA status and local radiation therapy with respect to their effects on CBC is unclear. Methods: Through an IRB approved database registry at the Cleveland Clinic, breast cancer patients tested for BRCA1 and BRCA2 mutations were identified and evaluated for CBC events and radiation treatment history. Patients with inadequate clinical follow-up, those with bilateral synchronous breast cancer and those undergoing bilateral mastectomy within one year of the original breast cancer diagnosis were excluded from the analysis. Chi-square test was used to compare CBC rates with or without prior radiation separately in patients testing positive and those testing negative for BRCA mutations. Results: Of 115 identified breast cancer patients tested for BRCA mutations, 57 met the inclusion criteria. Twenty-one carried BRCA1 or BRCA2 mutations and 36 tested negative for these mutations. Median follow-up for the two groups was 69.5 months (92 months in BRCA positive group and 51.5 months in BRCA negative group). Median age at diagnosis was 45 years (41 years in BRCA positive group and 48.5 in BRCA negative group). Among the 21 carriers, 9 patients (43%) developed CBC while only 3 of 36 patients (8%) testing negative for BRCA mutations developed CBC. Thirteen of 21 mutation carriers (62%) had received radiation treatment for the original cancer: CBC occurred in 3 of 13 (23%) radiated patients and 6 of 8 (75%) patients who had not received radiation (p= 0.02). Among 36 patients with negative BRCA testing, 30 (83%) had received radiation: CBC occurred in 3 of 30 (10%) mutation negative patients who had received prior radiation and in 0 of the 6 patients who had not received radiation (p = 0.42). Conclusions: CBC incidence was higher among BRCA mutation carriers than a control group suspected of having hereditary breast cancer but testing negative for these mutations. The use of radiation in the presence of a BRCA mutation, however, does not appear to further increase the risk for CBC.

No significant financial relationships to disclose.