bluuebunny/crossref_metadata_2025 huggingface dataset:
A concerted cell and serum proteomic approach for the identification of oral squamous cell carcinoma biomarkers
Authors: Mlynarek A. M. , Balys R. , Jie S. , Xu Y. , Hier M. P. , Black M. J. , Alaoui-Jamali M. A.
Published: March 2020

5512

Background: Head and neck squamous cell carcinoma is the sixth most common cause of cancer deaths in the world. Despite extensive research, the 5-year survival rates have not changed significantly over the last decade. Presently, the lack of serum biomarkers for head and neck carcinoma limits early diagnosis and treatment monitoring of advanced disease. In this study, we used a proteomic approach on serum from mice bearing human oral squamous cell carcinoma xenografts and from conditioned cell culture medium from matched cell lines. Methods: Oral squamous cell carcinomas, with distinct invasive phenotypes, and adjacent normal tissue were obtained from human patients, and were transplanted orthotopicaly into tongues of RAG-2/γ(c) mice. After a 20% weight loss, the mice were sacrificed by exsanguinations. Two distinct proteomic protocols were used to analyze the mouse serum. The first involved albumin depletion followed by two-dimensional gel electrophoresis and MALDI. The second arm utilized the same albumin depletion followed by multidimensional-protein-information-technology (ESI-LC and MS/MS). The top candidate proteins, which were differentially expressed in the cancer bearing mice compared to matched controls were then validated by Western blot, immunoprecipitation, immunofluorescence, and/or immunohistochemistry analyses using mouse serum and conditioned medium from matched cell lines. Results: Orthotopic implantation of human tumor tissues in mouse tongue was successful in 100% of the mice tested. The human origin of these tumors was confirmed pathologically. A correlation between disease stages and invasiveness was observed. We identified over one hundred proteins as being differentially expressed between control and cancer-bearing mice (p < 0.05), including proteins involved in cell cytoskeleton signaling. The expression of these proteins was then validated in mouse serum, tissue xenografts, and conditioned medium from oral cancer matched established cell lines. Conclusion: We report the first proteomic in-vivo model of oral cancer for the identification of low molecular weight serum biomarkers. We identified candidates that can be exploited as potential markers for diagnosis of human oral squamous cell carcinoma.

No significant financial relationships to disclose.
Induction chemotherapy (CT) with weekly paclitaxel, carboplatin, and cetuximab for squamous cell carcinoma of the head and neck (HN)
Authors: Kies M. S. , Garden A. S. , Holsinger C. , Papadimitrakopoulou V. , El-Naggar A. K. , Gillaspy K. , Lewin J. , Lu C. , Villalobos S. , Glisson B. S.
Published: March 2020

5520

Background: To further determine the potential efficacy of combining cetuximab with chemotherapy, we conducted a phase II trial with induction CT consisting of 6 weekly cycles of paclitaxel 135 mg/m2, carboplatin auc 2 and cetuximab 400 mg/m2 week 1 then 250 mg/m2 weekly. Methods: Patients (pts) were treatment-naïve with staging T0–4, N2b/c/3, M0; PS 0/1; with any HN primary site; and evaluated for clinico-radiographic complete response (CR). Pathway signaling biomarkers and genomic profiling are planned. Following CT, patients underwent “risk-based” local therapy. Choice of surgery ± postoperative radiotherapy (RT), RT, or concomitant chemoRT was based upon tumor stage and site at diagnosis. Results: Patient entry (2/05–11/05) has concluded with 47 patients (33 m, 14 f), median age 53 years and range 21–78. Two patients are too early for response analysis. Oropharynx was the dominant primary site, N = 42, with staging: Tx N2b - 4, Tx N3 - 1; T1 N2b - 5, T1 N2c - 6, T1 N3 - 3; T2 Nx - 1, T2 N2b - 10, T2 N3 - 3; T3 N2b - 5, T3 N2c - 3, T3 N3 - 1; T4 N2b - 2 and T4 N2c - 3. Toxicity was acceptable. Sixteen (34%) pts had grade 3/4 leukopenia; 22 (47%) grade 3 folliculitis (median 5 cycles of cetuximab administered); and 2 (4%) serious hypersensitivity. All 41 evaluable pts achieved a response in the primary site, 7 (17%) PR and 34 (83%) CR. Forty-three of 44 evaluable patients achieved a nodal response, 31 (70%) PR and 12 (27%) CR. Overall, 11 of 45 (24%) pts were disease-free after CT. At this early point, 3 pts have had 4 tumor recurrences, 2 local and 2 distant. Conclusions: CT administered over 6 wks, with cetuximab, was feasible and highly active with all patients achieving a tumor response. Severe skin rash affected nearly 50% of pts. Preliminary survival data, and correlation of surrogate biomarkers with tumor response are to be presented. Supported by: Bristol Myers Squibb Oncology and Imclone Systems Grant #CS 2004–00011435 WC.

[Table: see text]
Phase II study of combination cisplatin, docetaxel and erlotinib in patients with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC)
Authors: Kim E. S. , Kies M. S. , Glisson B. S. , Ginsberg L. E. , Holsinger F. C. , Burke B. J. , Truong M. , Tsao A. S. , Hong W. K. , Lippman S. M.
Published: March 2020

5521

Background: Interrupting the epidermal growth factor receptor (EGFR) signaling pathway has shown promise in a variety of cancers and preclinical data has demonstrated possible synergy with platinums and taxanes. Treatment options for advanced or recurrent HNSCC are limited. A study of cisplatin and docetaxel showed a response rate of 40% and 9.6 month median survival. Erlotinib, an EGFR tyrosine kinase inhibitor, had a 4.3% response rate in HNSCC. Because of the possible synergy and efficacy, we proposed to study the combination of cisplatin, docetaxel and erlotinib in advanced HNSCC. Methods: Patients (pts) were required to have adequate performance status, measurable disease, no prior EGFR therapy, and may have received one regimen of induction, concomitant or adjuvant chemotherapy, but not for recurrent/metastatic disease. Sites of disease included squamous cell head and neck sites excluding nasopharynx and sinus. Treatment included docetaxel 75mg/m2 and cisplatin 75mg/m2, intravenously every 3 weeks and erlotinib 150 mg by mouth daily. Patients were treated with growth factor support. Results: 37 pts have been enrolled thus far. Median age is 56 years (range 39–72). Median ECOG PS is 1 (range 0–2). 32 pts are evaluable for confirmed response using RECIST criteria. Complete responses have been in observed in 3 pts, partial responses in 18 pts and 8 pts have stable disease for an overall response rate of 66% and disease control rate of 91%. Only 2 pts progressed after 2 cycles of treatment. 5 pts had grade 3/4 neutropenia (2 febrile),1 pt had grade 4 diarrhea, and 2 pts had grade 3 rash. The most common grade 1–2 toxicities were diarrhea, nausea, and rash. Conclusion: The combination of cisplatin, docetaxel and erlotinib is well tolerated and has very encouraging activity in advanced HNSCC. Data collection for response rate, duration of response and survival is ongoing. Trial accrual continues up to 50 patients and biopsies are being collected for correlative markers including downstream EGFR pathway markers (p-akt, mek, k-ras). The full data set will be presented at the annual meeting.

[Table: see text]
Impact on quality of life (QoL) of the addition of docetaxel (T) to neoadjuvant cisplatin plus 5-fluorouracil treatment in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN): EORTC study 24971
Authors: Bernier J. , Coens C. , Remenar E. , Van Herpen C. , Germa Lluch J. , Stewart S. , Degardin M. , Spirlet C. , Vermorken J. B.
Published: March 2020

5522

Background: The EORTC 24971 trial compared the efficacy and safety of two neoadjuvant regimens in the treatment of stage III or IV, M0 SCCHN. Eligible patients (pts) with primary tumor sites in the oral cavity, oropharynx, hypopharynx, and larynx and WHO performance status (PS) ≤1) were randomized to 2–4 cycles of cisplatin (P) 100 mg/m2 day 1, followed by a continuous infusion of 5-fluorouracil (F) 1000 mg/m2/day from days 1- 5 (PF), or T 75 mg/m2 + P 75 mg/m2 day 1 then F 750 mg/m2/day from days 1 - 5 (TPF), followed by locoregional radiation therapy (RT). The impact of the two regimens on QoL was a secondary endpoint. Methods: QoL was assessed at baseline, at cycles 2 and 4, and 6 and 9 months after RT using the EORTC QLQ-C30 questionnaire to obtain the Global Health Status/Quality of Life (GHS/QoL) score, and the Head and Neck Performance Status Scale (PSS-HN) to assesses the normality of diet, eating in public, and understandability of speech on a scale of 0 to 100. The EORTC QLQ-HN35 questionnaire was also administered at those time-points. Results: 358 pts were randomized to PF (181 pts) or TPF (177 pts). Baseline (BL) characteristics of the pts were well balanced between groups. TPF was superior to PF in terms of response rate, progression-free survival (primary endpoint), overall survival, and tolerability. Compliance with the QLQ-C30 questionnaire was good ranging from 96% at BL to 41% at 9 months post RT, and was similar between the treatment arms. GHS/QoL scores were comparable at BL between the two arms (p = 0.54) and improved in both arms on starting treatment. Over time this score remained stable with TPF, but decreased after RT with PF (treatment-time interaction: p = 0.009). Evolution of the PSS-H&N score was better on TPF (normality of diet p= 0.0064; eating in public p = 0.0004; understandability of speech p = 0.0003). Moreover, TPF was associated with a 30% reduction in the risk of WHO PS deterioration (p = 0.0158) Conclusions: The use of docetaxel in neoadjuvant treatment of SCCHN improves efficacy without deleterious effects on QoL and functional outcomes.

[Table: see text]
Does positron emission tomography (PET) improve our ability to detect residual neck node (NN) disease in patients with squamous cell head and neck cancer (SCHNC) after definitive chemoradiotherapy?
Authors: Tan A. , Adelstein D. J. , Esclamado R. M. , Rybicki L. A. , Saxton J. P. , Wood B. G. , Lorenz R. R. , Strome M. , Carroll M. A.
Published: March 2020

5526

Background: Management of the neck in patients undergoing non-operative treatment for SCHNC is controversial. This study details our experience using the neck exam, computerized tomography (CT), and PET to clinically evaluate patients for residual NN disease after definitive chemoradiotherapy. Methods: We retrospectively reviewed all patients with SCHNC with NN involvement at presentation, who were treated with definitive concurrent chemoradiotherapy using fluorouracil and cisplatin. Clinical restaging by neck exam, CT, and PET was accomplished 8–12 weeks after completion of treatment. Residual palpable nodes on exam, residual nodes larger than 1 centimeter, or with central necrosis on CT, or any residual hypermetabolic lymph nodes on PET were considered to be clinical evidence of residual NN disease. Persistent NN disease was confirmed only if pathologic involvement was identified at the time of neck dissection, or if regional recurrence developed. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy (Acc) were calculated for all three clinical assessment tools. Results: The study included 43 patients with 64 positive necks at diagnosis, followed for a median of 11.5 (range 3.9–43.3) months. All but two patients are alive. Planned neck dissection was performed in 26 necks after chemoradiotherapy, and was positive in four. Recurrent primary site or NN disease prompted a delayed neck dissection in eight necks, which was positive in three. The utility of these clinical assessment tools and combinations thereof are detailed in the table . Conclusions: Residual NN disease after definitive chemoradiotherapy was infrequent and not well predicted by PET. A positive PET in this setting is of little utility. Although a negative PET was highly predictive for control of neck disease after chemoradiotherapy, it added little to the clinical neck exam and the CT.

[Table: see text]

No significant financial relationships to disclose.
Should early cancers of the oral tongue be kept under surveillance after wide excision alone? A prospective study
Authors: Gupta T. , Agarwal J. , D’Cruz A. , Ghosh-Laskar S. , Malde R. , Gupta M. , Shrivastava S. , Dinshaw K.
Published: March 2020

5541

Background: The treatment of the clinically N0 neck in early stage oral tongue cancer remains controversial. Several clinico-pathologic criteria that can reliably identify an increased risk of occult metastases in the neck have been proposed. Our aim was to assess the impact of elective neck dissection (END) on outcome and correlate it with clinico-pathologic criteria for patient selection for surveillance. Methods: Patients with early stage cancer of the oral tongue (T1–2, N0) after undergoing wide excision with or without END were prospectively kept under observation. Patients having adverse histological features necessitating adjuvant radiotherapy were excluded. All patients gave informed consent and were closely followed. Relapsers were offered appropriate salvage therapy. The primary end-point for our prospective phase II study was the impact of END on relapse-free survival (RFS) with an estimated sample size of 50 patients. Overall survival (OS) was a secondary endpoint. Results: Fifty three eligible patients were consecutively accrued on the trial after surgery. Forty eight patients underwent per oral wide excision, with only 5 requiring a neck approach. Twenty two patients underwent upfront END. Twenty four patients relapsed (23 of which had some loco-regional component). The risk of neck recurrence in patients whose necks were not dissected electively was significantly higher than in patients treated with END (55% vs 9% respectively, p = 0.0016). The 3-year RFS (69.1% vs 40.9%, p = 0.008) and OS (87.2% vs 42.6%, p = 0.0228) was significantly better for patients treated with END. Conclusions: Regional recurrences are the most important cause of failure after wide excision alone. END which achieves excellent disease control in the neck and significantly improves RFS and OS should be considered routine for early stage oral tongue cancer.

No significant financial relationships to disclose.
A phase II trial of BAY 43–9006 in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC): A Southwest Oncology Group (SWOG) trial
Authors: Williamson S. K. , Moon J. , Huang C. H. , Guaglianone P. , Wolf G. T. , Urba S. G.
Published: March 2020

5550

Background: Bay 43–9006 (Sorafenib) is a potent Raf-1 and B-Raf kinase inhibitor of the RAS/RAF/MEK/ERK pathway. The compound also inhibits protein tyrosine kinases associated with VEGFR-2 and 3 as well as PDGFR-B. We conducted a phase II trial to evaluate the efficacy of BAY 43–9006 in chemotherapy naive patients with metastatic or recurrent HNSCC. Methods: Chemotherapy naïve patients with histologically proven squamous cell carcinoma of the head and neck either metastatic, persisted or recurred following definitive surgery and/or radiation therapy, and not amenable to salvage surgical resection were eligible. Patients may have received only one induction or adjuvant chemotherapy regimen provided that at least 6 months have elapsed since the last course was administered. Patients must have adequate cardiac, hematologic, renal and hepatic function and a Zubrod Performance Status of ≤ 1. Specimens were obtained from either archival or fresh pre-treatment biopsies and at the time of progression of disease for molecular correlative studies. BAY 43–9006 was administered orally at 400 mg BID on a continuous basis, in 28-day cycles. Responses were evaluated every 8 weeks according to RECIST criteria. Initially 20 patients will be registered. If one or more confirmed responses are observed in the first 20 patients, an additional 20 patients will be registered. Results: Thirty-eight patients (31 males, 7 females, median age 64 years) have been enrolled to date. Twenty-seven patients are evaluable for toxicity. The drug was generally well tolerated. There have been 2 Grade 4 toxic events - one cerebral ischemia and an asymptomatic pulmonary embolus. Grade 3 toxicities include 2 patients with hand/foot syndrome, 4 with stomatitis or oral pain, and one episode each of anorexia, dysphagia, hypertension, and ulceration. The most common grade 2 toxic events were fatigue (8 pts.), anorexia (8 pts.), stomatitis (5 pts.), and hypertension (4 pts.). Complete accrual to 40 patients is anticipated by January 31, 2006. Conclusions: BAY 43–9006 is well tolerated. Updated toxicity data will be reported. Preliminary response, time to progression and survival data will be presented.

[Table: see text]
Association of serum level of YKL-40 in patients with squamous cell carcinoma of the head and neck with survival
Authors: Roslind A. , Johansen J. S. , Christensen I. J. , Bentzen J. , Nielsen D. L. , Price P. A. , Andersen E.
Published: March 2020

5551

Background: High serum YKL-40 is associated with poor prognosis in breast-, colorectal-, ovarian-, prostate-, small cell lung carcinoma and malignant melanoma. YKL-40 is secreted by cancer cells, macrophages and neutrophils. Its function in cancer is unknown. It may be a growth factor, play a role in angiogenesis or protect against apoptosis. The aim was to examine serum YKL-40 in patients with squamous cell carcinoma of the head and neck (SCCHN). Methods: YKL-40 was determined by ELISA (Quidel, Santa Clara, CA) in serum samples from 138 patients with SCCHN (median age 60, range 44–92 years) before surgery and/or fractionated radiotherapy (total dose of 60–68 Gy, 2-Gy fractions). 42 patients had stage 1, 28 stage 2, 22 stage 3, and 46 stage 4 disease. The median follow-up time was 4.0 years (range 15 days–8.5 years). 91 patients had died. Results: Serum YKL-40 was increased (p < 0.001) in patients with SCCHN (median 120 μg/l, range 25–1848 μg/l) compared to healthy controls (43 μg/l, 20–184 μg/l, n = 245). Serum YKL-40 was elevated in 52% of the patients. Patients with stage 1 disease had lower, but non-significant, serum YKL-40 compared to patients with stage 2–4 disease (median 113 μg/l, range 25–1000 μg/l vs. 139 μg/l, 29–1848 μg/l, p = 0.06). Patients with high serum YKL-40 had significantly shorter survival than patients with normal serum YKL-40 (33 months vs. 74 months, p = 0.01 logrank test). Univariate analysis of serum YKL-40 (log transformed and treated as a continuous covariate) showed significant association with overall survival after start of therapy (HR = 1.4, 95% CI: 1.2–1.7, p = 0.0004). Multivariate Cox analysis including age, stage and serum YKL-40 (log transformed and treated as a continuous variable) showed that stage (stage 3–4 vs. stage 1–2, HR = 3.0, 95% CI: 1.9–4.6, p < 0.0001) and serum YKL-40 (HR = 1.5, 95% CI: 1.2–1.8, p = 0.0003) were independent prognostic variables of overall survival. Conclusions: Serum YKL-40 is a prognostic biomarker of overall survival in SCCHN patients.

No significant financial relationships to disclose.
A phase II study of single agent depsipeptide (DEP) in patients (pts) with radioactive iodine (RAI)-refractory, metastatic, thyroid carcinoma: Preliminary toxicity and efficacy experience
Authors: Su Y. B. , Tuttle R. M. , Fury M. , Ghossein R. , Singh B. , Herman K. , Venkatraman E. S. , Stambuk H. , Robbins R. , Pfister D. G.
Published: March 2020

5554

Background: RAI-refractory thyroid cancer carries a poor prognosis, and no effective systemic therapy exists. DEP is a potent histone deacetylase inhibitor with broad in vitro and phase I anti-tumor activity, and has restored sodium-iodide symporter expression and RAI avidity in thyroid cancer cell lines. Methods: Eligible pts have confirmed papillary, follicular, or Hürthle cell carcinoma, progressive measurable disease, and adequate hepatic/renal function. All pts are RAI-refractory by diagnostic RAI whole body scan (WBS). Prior chemotherapy in the recurrent/metastatic setting, and history of significant cardiac disease are exclusions. DEP 13 mg/m2 IV is given on day 1, 8, and 15, every 28 days. A novel Simon 2-stage design specifies an initial accrual of 21 pts, with expansion to 41 total pts if 2 RECIST responses or 6 pts with PFS at 6 months are observed. Primary outcome is RECIST response rate. Change in RAI avidity (by diagnostic RAI WBS) is a secondary outcome. Results: To date, 14 pts have been enrolled: female 50%, median age 62 (42–78), median Karnofsky 90 (70–100), papillary/follicular/Hürthle histology (7/1/6). Grade 3–5 toxicities possibly related to drug: grade 5 sudden death (1); no grade 4 toxicity; grade 3 toxicity - fatigue (1), dysphagia (1), dyspnea (1). No grade 3 thrombocytopenia (phase I DLT) has been observed. Grade 1 (6) and grade 2 (4) fatigue have been common. As a result of the grade 5 event, protocol accrual and treatment were suspended temporarily. After NCI-CTEP review, more restrictive cardiac exclusions were added and protocol accrual was resumed. Response at 2 months: stable disease (4); progression (2); inevaluable (6, due to protocol suspension); withdrew consent (1); too early (1). In a proof-of-principle event, clinically significant restoration of RAI avidity was observed in a 78 year-old woman with papillary carcinoma. Per protocol, she was taken off study and given treatment-dose RAI; post-therapy WBS confirmed dramatic RAI avidity. Conclusions: Preliminary signs of in vivo reversal of RAI resistance have been observed. Accrual continues with more restrictive cardiac exclusions, and close surveillance for cardiac events.

No significant financial relationships to disclose.
Results of reduction of treatment intensity based on response to a novel induction therapy in stage III and IV head and neck cancer
Authors: Kudrimoti M. R. , Warren G. W. , Valentino J. , Spring P. M. , Mohiuddin M. , St. Clair W. H. , Brill Y. , Given C. , Regine W. F. , Arnold S. M.
Published: March 2020

5561

Background: Concurrent cisplatinum based chemotherapy and qd radiotherapy (RT) to 70 Gy is standard therapy for stage III-IV head and neck (H/N) SCCA. Presented is a prospective IRB approved study tailoring the definitive therapy based on response to induction therapy. Methods: 25 patients with Stage III-IV H/N SCCA were treated with 2 cycles of induction therapy every 21 days comprised of carboplatin (AUC 6 day 1), paclitaxel (75 mg/m2 days 1, 8, and 15), and low dose RT (0.5 Gy BID days 1, 2, 8, and 15) for chemosensitization. The response rates of this mode of induction therapy have been presented previously (ASCO 2005 #3184). Patients with complete response (CR) to induction were treated with reduced dose RT at the primary site (reduced from 70 to 60–66 Gy) and 2 cycles of IV cisplatin (100 mg/m2) instead of 3. Those with partial response (PR) or stable disease (SD) were treated with surgery and adjuvant therapy or with altered fractionation regimens. The impact of dose reduction on survival (OS and DFS), failure patterns, compliance and toxicity (according to NCI CTCAE) were used as end points for the study. Results: Patients included 9 with tonsil, 5-L, 3-HP, 3-OC, and 5-BOT. There were 4-T1,9-T2,9-T3,and 3-T4 tumors. The nodal involvement was N0–5, N1–3, N2–13, N3–4. Patients presented with Stage III (28%), IVA (52%), and IVB (20%). Sixty percent had a CR, 32% had a PR, and 8% had SD after induction therapy. Two patients with CR were non-compliant after induction therapy and not further evaluated. With a median FU of 20.5 months (range 11–36 mo) the OS and DFS is 100% (13/13) in the dose reduced group (CR) and 60% (6/10) in the PR/SD treated with more aggressive regimens. The incidence of distant failure is 40% (4/10) in the PR vs 0% (0/13) in the CR. No patients in the dose reduced group required feeding tubes; however 30% (3/10) were required in patients with PR. Compliance with chemotherapy was 79% (10/13) in the CR vs 80% (8/10) in the PR. Conclusions: Our early results show that the patients showing a CR to induction chemotherapy are a favorable group of patients and they may be treated with reduced treatment intensity. This report provides strong evidence that RT dose deescalation for head and neck cancers may be feasible following assessment after induction therapy.

[Table: see text]
Results of intraarterial cisplatin and hyperfractionated radiotherapy in locally advanced cancer of the oropharynx and oral cavity
Authors: Arnold S. M. , Graham W. W. , Valentino J. , Brill Y. , Regine W. , Spring P. , Given C. , Mohiuddin M. , St Claire W. , Kudrimoti M.
Published: March 2020

5563

Background: Intraarterial cisplatin and hyperfractionated radiation (HYPERADPLAT) is an accepted therapy for Stage III and IV head and neck cancer. We present long-term follow-up of patients with OP and OC cancer treated with HYPERADPLAT at a single institution. Methods: 44 patients with Stage III-IV squamous cell carcinomas of the OP or OC were treated with the HYPERRADPLAT regimen consisting of external beam radiotherapy (76.8–81.6 Gy) delivered in 1.2 Gy BID fractions with intraarterial cisplatin (150 mg/m2) administered when patients had reached 60 Gy. Tumor response, disease free survival (DFS), overall survival (OS), and toxicity were assessed for all patients according to NCI CCT criteria. Results: Of 44 patients, 21 had tumors of the base of tongue, 14-tonsil, 4-floor of mouth, and 5-other. Eighty eight percent of patients had T4 tumors and 7% had T3 tumors. Complete tumor response was observed in 86% of patients and 14% had a partial response. Lymph node metastases were present in 84% of patients with 78% of node positive patients having a complete nodal response and 19% with a partial response to treatment. Three-year DFS was 55% and OS was 45%. Locoregional recurrence was noted in 30% of patients and 16% had distant failure. Overall recurrence was noted in 47% of patients with a median time to recurrence of 8 months (range 4–55 months). Median weight loss during treatment was 9% of initial body weight and 28 patients required a feeding tube within 6 months of starting treatment. Grade 3 mucositis was noted in 68% of patients and 3 patients developed Grade 4 toxicity (2 mucosal, 1 hematologic). Conclusions: HYPERRADPLAT results in excellent tumor control that is well tolerated with minimal Grade 4 toxicity in patients with advanced poor prognosis cancers of the OP and OC. These results compare favorably with historically reported control rates and response for patients with a significantly high percentage of T4 tumors of the oropharynx and oral cavity.

No significant financial relationships to disclose.
Randomized, phase III trial comparing liposomal platin with cisplatin in patients (pts) with advanced squamous cell carcinoma of the head & neck (SCCHN) regarding safety and efficacy profiles
Authors: Luftner D. , Siepmann S. , Christian J. , Pollmann D. , Pecher G. , Wernecke K. D. , Possinger K.
Published: March 2020

5564

Background: Based on a metanalysis of > 16,000 patients (Bourhis, ASCO 2004), cisplatin emerges as the essential agent for the treatment of advanced SCCHN. However, its clinical use is impeded by its severe adverse reactions, as renal toxicity. In a randomized, phase III trial we replaced conventional cisplatin by a liposomal formulation of cisplatin (lipoplatin) and compared the safety and efficacy profiles. Methods: The study was designed for two treatment arms: A: 100 mg/m2/d lipoplatin (d 1,8,15) plus 1,000 mg/m2/d 5-FU (d 1–5) q3w for 6 cycles; B: 100 mg/m2/d cisplatin (d 1) plus 1000 mg/m2/d 5-FU (d 1–5) q3w for 6 cycles. Main inclusion criteria selected pts with primary metastatic, relapsed or progressive SCCHN between 18–75 years and creatinin clearance >50ml/min. Main endpoints for this interims analysis were hemato- and nephrotoxicity. First response data were collected. The study was designed for non-inferiority. Results: Out of 41 randomized pts, 30 pts are evaluable for toxicity (15 pts for every arm) and 27 pts (15 pts for lipoplatin, 12 pts for cisplatin) for outcome. In the cisplatin arm hematotoxicity was more frequent (leucopenia grade I/II: 5 pts, grade III/IV: 3 and 1 pts vs 5 pts with grade I/II in the lipoplatin arm). The rate of anemia was similar between the treatment arms. A total of 11 pts in the lipoplatin arm experienced renal toxicity grade I/II as measured by a reduction of the creatinine clearance and 12 pts in the cisplatin arm (grade I/II: 7 pts; grade III: 5 pts). No renal toxicity grade III was developed in the lipoplatin arm until now. Outcome was as follows: lipoplatin arm: PR: 1 pt; SD: 6 pts; PD: 8 pts; cisplatin arm: PR: 7 pts; SD: 3 pts; PD: 2 pts. Thus, the non-PD pts (PR or SD) is 7/15 (47%) in the lipoplatin arm vs 10/12 (83%) cases in the cisplatin arm. Conclusions: Liposomal platin seems to reduce both the hematological and non-hematological toxicity profiles as compared to conventional cisplatin to a clinically relevant extent. As patients with advanced SCCHN have an increased risk of renal toxicity due to poor hydration, the observed reduction of side effects will influence the chance to preserve the dose density of chemotherapy, and thereby, the efficacy of treatment.

No significant financial relationships to disclose.
A phase II study of lapatinib (GW572016) in recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN)
Authors: Abidoye O. O. , Cohen E. E. , Wong S. J. , Kozloff M. F. , Nattam S. R. , Stenson K. M. , Blair E. A. , Day S. , Dancey J. E. , Vokes E. E.
Published: March 2020

5568

Background: Epidermal growth factor receptor (EGFR) inhibitors have demonstrated reproducible activity in patients with R/M SCCHN. HER2 is the preferred dimerization partner for EGFR. Lapatinib is a dual EGFR and HER2 kinase inhibitor that has demonstrated promising preclinical activity in SCCHN models. Methods: This phase II multi-institutional study enrolls patients with R/M SCCHN into 2 cohorts: those without prior exposure to an EGFR inhibitor (arm A) and those with prior exposure to an EGFR inhibitor (arm B). All subjects were treated with lapatinib 1500mg OD. Primary endpoints were response rate (arm A) and progression-free survival (arm B). Results: 42 subjects have been enrolled (27 arm A, 15 arm B; 35 male, 7 female, median age 60 years). Toxicity was generally mild without any dose reductions or patient withdrawal due to adverse effects. Diarrhea was the most frequent toxicity occurring in 40% of patients. Other toxicities observed included fatigue (21%), rash (21%) and nausea (14%). 2 patients experienced grade 3 toxicity (1 diarrhea, 1 emesis). 1 patient had a reduction in left ventricular ejection fraction (60% to 40%) which was asymptomatic and recovered to baseline upon discontinuation of lapatinib. No objective responses were observed in either arm. In an intent-to-treat analysis stable disease was the best response observed in 37% of arm A and 20% of arm B subjects. Median PFS was 1.6 months in arm A and 1.7 months in arm B. Conclusions: Lapatinib as a single agent in R/M SCCHN, although well tolerated, appears to have little activity in either EGFR inhibitor naïve or refractory subjects.

No significant financial relationships to disclose.
Antitumor effects of combined bortezomib and tipifarnib in head and neck squamous cell carcinoma (HNSCC) cells
Authors: Klass C. M. , Chen Z. G. , Zhang X. , Lonial S. , Khuri F. R. , Shin D. M.
Published: March 2020

5581

Background: The dysregulation of the NF-κB and Ras/PI3K/AKT pathways in HNSCC supports our hypothesis that combined treatment with the proteasome inhibitor (PI) bortezomib (B) and the farnesyl transferase inhibitor (FTI) tipifarnib (T) leads to synergistic growth inhibition of HNSCC cells. Methods: Growth inhibitory effects of single agents (B 2.5–100 nM; T 0.625–5μM), combination (B+T) (B 12.5–17.5 nM; T 0.625–5 μM) or sequential treatment (B→T after 2h or T→B) were examined in three HNSCC lines (Tu212, 686LN and Sqcc/Y1) using a sulforrhodamine B assay after 72 h of drug exposure. Combination effect in cells treated concomitantly or sequentially was assessed using the combination index (C.I.: < 1.0, synergy; >1.0, antagonism; ≈1.0, additivity). Apoptosis was measured by flow cytometry. Relevant protein markers were evaluated by Western blot. Cell cycle analysis after flow cytometry used FlowJo software. Statistical analysis was done using a two-sided t-test. Results: Growth inhibition by B alone is very effective in all three lines (IC50 = 9–22nM). T used alone is active only in μM range (IC50 = 0.625–5 μM). The inhibitory effects of B and T were sequence dependent. Simultaneous treatment with 12.5 nM B and 5μM T showed synergistic growth inhibition in all 3 lines [C.I., 0.281–0.54]. B→T showed synergistic effects in all three cell lines [C.I., 0.36–0.76]. However, T→B was less synergistic in two of the three lines [Sqcc/Y1 C.I. = 0.404; Tu212 C.I. = 0.748]. Apoptosis was also sequence dependent with B+T or B→T treatment showing significantly more apoptosis than T→B (p = 0.03). Apoptosis induced by T→B was not different from treatment with single agent B (p = 0.22). Sqcc/Y1 cells treated with B and T showed accumulation in G2M phase and an increased percentage of cells in sub-G1. The observed synergistic inhibitory effect of B+T was associated with downregulation of p-AKT. Conclusions: We conclude that treatment with B+T and B→T synergistically enhances HNSCC growth inhibition and results in both significantly increased apoptosis and G2M arrest. These studies strongly support the clinical development of the sequential combination of a PI and a FTI. (Supported by Millenium Pharm. and the Georgia Cancer Coalition).

[Table: see text]
Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide (EC or HEC) with cyclophosphamide, methotrexate, and fluorouracil (CMF) in 777 women with node-positive (N+) breast cancer (BC): 10-year follow-up results
Authors: Azambuja E. , Paesmans M. , Bernard-Marty C. , Beauduin M. , Vindevoghel A. , Cornez N. , Focan C. , Tagnon A. , Nogaret J. M. , Piccart-Gebhart M.
Published: March 2020

568

Background:
The purpose of this presentation is to provide an update, with longer follow up data, of the results of this Belgian multicentric trial, which had shown a dose response curve for epirubicin at a median follow up of 4 years (Piccart et al, J Clin Oncol 2001; 19:3103–3110)
Methods:
In this prospective, open label, randomized trial of the 1990’s, patients aged from 18 to 70 years were stratified by center, 1–3 vs 4 or more nodes, and menopausal status (pre- vs postmenopausal). The primary hypothesis was that HEC could be associated with an increase in event-free survival (EFS) compared with CMF. Patients received CMF (oral cyclophosphamide days 1–14) for six cycles, EC (epirubicin 60 mg/m
2
, cyclophosphamide 500 mg/m
2
day 1 every 3 weeks) for eight cycles or HEC (epirubicin 100 mg/m
2
, cyclophosphamide 830 mg/m
2
day 1 every 3 weeks) for eight cycles. Tamoxifen followed chemotherapy in postmenopausal women with positive or unknown hormone receptor (HR). Two hundred fifty-five, 267, and 255 eligible patients were treated with CMF, EC, and HEC, respectively.
Results:
The trial results are now updated, with an actuarial median follow-up of 12.2 years. Using Kaplan-Meier estimation, the 10-year EFS is 55% for patients who received CMF, 48% for EC patients, and 58% for HEC patients. The hazard ratios obtained from Cox regression models (HR) are, for EC vs HEC, 1.30 (95% confidence interval [CI], 1.02 to 1.67,
P
= .03); for CMF vs HEC, 1.12 (95% CI, 0.87 to 1.44,
P
= .39); and for CMF vs EC, 1.17 (95% CI, 0.92 to 1.48,
P
= .21). Kaplan-Meier estimates of the 10-year overall survival rates are 65% for patients who received CMF, 65% for EC patients, and 70% for HEC patients, with no significant differences among the three arms.
Conclusions:
The short term results of this trial are nicely confirmed at 10 years: in patients unselected for HR or HER-2 status, the dose intensity of epirubicin matters. Analysis in subsets of patients is ongoing, but will be only hypothesis-generating.

Author Disclosure

Employment or Leadership
Consultant or Advisory Role
Stock Ownership
Honoraria
Research Funding
Expert Testimony
Other Remuneration

AstraZeneca, sanofi-aventis, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Novartis, Pfizer, Schering-Plough

Amgen, AstraZeneca, Eli Lilly, Novartis, Pfizer, Roche, sanofi-aventis, Schering-Plough
Anthracycline regimens versus CMF in the adjuvant treatment of early breast cancer (EBC): A matter of difference
Authors: Gennari A. , Sormani M. , Costantini M. , Pronzato P. , Rosso R. , Bruzzi P.
Published: March 2020

569

Background: Anthracycline-based adjuvant chemotherapy (CT) in EBC was found, in the latest EBCTCG overview, to be associated with a 15% reduction in mortality, when compared to CMF. However, differences among trials, and specifically the use of suboptimal experimental arms (underdosed anthracyclines) and non conventional CMF (i.v.), require a careful interpretation of this finding. Methods: To evaluate the reduction in mortality, associated to different anthracycline and CMF regimens, we performed a systematic overview of abstracted data from published randomised trials comparing CMF with anthracyclines. Those studies including other drugs were excluded. Fifteen retrieved trials, comprising 15.831 women, were divided into 6 groups according to the type of CMF (oral or i.v.), and to the type of anthracycline regimen: 3 drugs (FAC/FEC), 2/1 drugs (AC/EC, A/E) and sequential schedules (Anthra→CMF). From each study, the estimates of the Hazard Ratio (HR; anthra vs CMF) and of its variance were abstracted or estimated from the presented results. HRs from studies of the same group were combined according to standard meta-analytic techniques. Summary estimates of HR for oral or i.v. CMF and for different anthracycline schedules were similarly obtained. Results: The overall comparison confirms a superiority of anthracyclines over CMF (HR 0.83 - 95%CI 0.77–0.90, p<0.001). HRs in the 6 groups of studies are reported in the table . When i.v. CMF is compared to any anthracycline regimen, the HR is 0.76 (95%CI 0.67–0.86, p<0.001; heterogeneity p 0.01), while with oral CMF, the HR is 0.88 (95%CI 0.80–0.97, p 0.01; heterogeneity p 0.06). Conclusions: The magnitude of the survival benefit of anthracyclines over CMF seems to be strongly affected by the type of anthracycline regimen and by the type of CMF, the largest effect being observed in trials using sequential schedules and i.v. CMF. Final results will be presented at the meeting, including evaluation of regimen type and its effects on toxicity and quality of life.

[Table: see text]

No significant financial relationships to disclose.
Phase III study of docetaxel weekly (DW) versus every 3 weeks (D) in patients with metastatic breast cancer: Final results
Authors: Rivera E. , Mejia J. A. , Arun B. , Adinin R. , Walters R. , Brewster A. , Broglio K. , Yin G. , Esteva F. J. , Hortobagyi G. N. , Valero V.
Published: March 2020

574

Background: D is a semi-synthetic taxane with significant activity in breast cancer. D is usually administered on an every 3-weeks schedule, however, studies have demonstrated drug efficacy and a different toxicity profile when administered on a weekly basis. In this study we compared the weekly schedule versus every 3-weeks to define the safest schedule with the highest efficacy. Methods: Patients (Pts) were enrolled if they had stage IV breast cancer and had received no more than one prior chemotherapy regimen for metastatic disease. Prior treatment with D was not allowed but adjuvant paclitaxel (P) was allowed if > 12 months since the last dose. Pts were randomized to receive D at a starting dose of 75mg/m2 on day 1 or DW at a dose of 35 mg/m2/week for 3 weeks followed by 1 week of rest every 28 days. Doses could be escalated to 100 mg/m2 and 40mg/m2, respectively at the discretion of the investigator. Premedication with dexamethasone was given with each regimen. Results: From 1/2001 until 9/2004, a total of 125 pts were enrolled, 63 in the DW arm and 62 in the D arm. Thirty-nine and 10 pts had received prior anthracycline (A) and P respectively in the D arm while 32 and 11 pts had A and P in the DW arm. Median ages were 56 and 54 years in the D and DW arm, respectively. 118 pts were eligible for an efficacy analysis with a response rate of 35.6%; (95% CI, 23.6%, 49.1%) for the D arm vs 20.3%; (95% CI, 11.0%, 32.8%) for DW. There was no difference between D and DW in median PFS and OS, 5.7 vs 5.5 months (p = 0.46) and 18.3 vs 18.6 months (p = 0.34), respectively. There was a higher overall toxicity rate (grade 3 and 4) in the D arm vs DW, 88.1% vs 55.9% (p = 0.0001). There were 48 (81%) and 6 (10%) pts with grade ¾ granulocytopenia with 6 (10%) and 2 (3%) episodes of neutropenic fever in D vs DW, respectively. Grade 3/4 fatigue and myalgias were reported more often in D than DW, 15 (25%) and 8 (13.5%), and 16 (27%) and 2 (3%), respectively. Grade 3 epiphora was similar in both arms, 4 (7%) and 5 (8%) for D and DW, respectively. Conclusions: D has a higher response rate compare to DW but with a more pronounced toxicity profile. This needs to be kept in mind when making a treatment recommendation for patients with metastatic breast cancer. No difference in PFS or OS was observed between both arms.

No significant financial relationships to disclose.
Phase III study of gemcitabine plus vinorelbine (VG) versus vinorelbine (V) in patients (pts) with metastatic breast cancer (MBC) previously treated with anthracyclines (A) and taxanes (T). Final results of GEICAM 2000–04 study
Authors: Muñoz M. , Martín M. , Ruiz A. , Balil A. , García-Mata J. , Calvo L. , Jara C. , Alba E. , Salas F. , Soto C.
Published: March 2020

575

Background: VG has shown to be efficacious and safe in MBC in pts previously treated with AT. This study compared treatment (TT) V with the combination of VG. Primary objective was progression free survival (PFS). Methods: pts previously treated with AT, aged ≥18, ECOG ≤ 2, were randomized to V: 30 mg/m2 day (d) 1, d8, or VG 30/1200 mg/m2 d1, d8, both every 21 days until disease progression. Stratification criteria were previous lines of TT for MBC (0 vs.1 vs.2) and visceral disease (yes vs. no). 126 pts per arm were needed to demonstrate a prolongation in PFS of 2 months (m) (from 3 to 5; HR = 1.67; α and β errors 0.05 and 10). Results: 252 pts (127 V and 125 VG) were recruited between 2001 and 2005. Arms were well balanced: median age was 57 years; median number of metastatic sites 2; visceral disease was present in 75% of pts; 17%, 53% and 29% of pts received study TT as first, second and third line respectively. Median number of cycles were 4 (1–21) in V and 6 (1–26) in VG. Median PFS was 6.3 m (95% CI, 5.3–7.3) for VG and 4.1 m (95% CI, 3.3–4.9) for V (p=0.0011). Objective response rate was 37% (CI 95% 29–46) for VG and 25% (CI 95%: 17–33) for V (p= 0.035). CTC grade 3–4 hematologic toxicity was significantly higher with VG vs. V (65% vs. 43% neutropenia, 33% vs. 17% leucopenia, and 11% vs. 2% thrombocytopenia); febrile neutropenia was present in 10.5% of pts on VG and 6% of pts in V (p=ns). Non-hematological toxicity was low and manageable in both arms. Conclusions: VG demonstrated significant efficacy advantages over V in pts with MBC previously treated with AT, with manageable toxicity. This favorable risk-benefit profile supports the use of this combination in this patient population.

[Table: see text]
Breast cancer epidemiologic risk factors by HER2/neu status
Authors: Chen W. Y. , Colditz G. A. , Rosner B.
Published: March 2020

585

Background: Although breast cancers categorized by estrogen receptor (ER) and progesterone receptor (PR) status are recognized to differ in their associations with standard breast cancer risk factors, little data exist on differences by HER2/neu status. Methods: The Nurses’ Health Study is a prospective cohort study of 121,700 registered nurses aged 30–55 in 1976 who answered biennial questionnaires to update medical and lifestyle factors and disease occurrence. Medical record review was used to confirm invasive breast cancer and abstract ER, PR, and HER2/neu status. Statistical analyses included both proportional hazards models to estimate relative risks and control for potential confounders and polytomous logistic regression to compare the effects. Only cases diagnosed from return of the 1998 questionnaire until June 2002 were included in the analysis since HER2/neu was only routinely assessed beginning with the 1998 follow-up cycle. Results: 211 HER2/neu positive and 770 HER2/neu negative cases were included in the analysis. In this predominantly postmenopausal group aged 52–77 in 1998, HER2neu negative cancers were more likely to be ER+/PR+ (72%) and less likely to be ER-/PR- (11%) than HER2/neu positive ones (58% ER+/PR+ and 24% ER-/PR-), but the majority of cancers were still ER+/PR+. In multivariate models, risk factor associations by HER2/neu status were similar with positive associations seen for family history, benign breast disease, body mass index, current postmenopausal hormone use, and cumulative alcohol consumption. However, when the subgroup of ER-/PR-/HER2/neu negative cancers were evaluated separately (N=83), most of these risk factor associations disappeared with the only significant risk factor being a prior history of benign breast disease. Conclusions: This is the first prospective data study to report on risk factor association by HER2/neu status. For the standard epidemiologic breast cancer risk factors, ER and PR status appear to better represent separate etiologic pathways, rather than HER2/neu status. However, the subgroup of ER/PR/HER2neu negative breast cancers appears to be distinct, although power was limited and HER2/neu status was not confirmed by central review. Additional analyses stratified by ER/PR status will also be presented.

No significant financial relationships to disclose.