bluuebunny/crossref_metadata_2025 huggingface dataset:
BCCIP: A novel marker for radiotherapy benefit in patients with laryngeal cancer
Authors: Rewari A. , Lu H. , Yang Q. , Shen Z. , Haffty B.
Published: March 2020

6006

Background: It has been well established that the functionality of the p53 pathway is related to radiosensitivity in various human cancers. The status of proteins regulating p53 activity may also be valuable markers for radiosensitivity. Recent studies have shown that BCCIP (BRCA2 & CDKN1A interacting protein) is essential for maintaining the transactivation activity of wild type p53. We hypothesize that functional BCCIP may contribute to effective radiotherapy in the clinical setting. To test this hypothesis, we analyzed the expression of BCCIP and p53 in a cohort of laryngeal cancer treated with radiotherapy and assessed whether BCCIP and p53, alone or in combination, would correlate with local control and overall survival. Methods: One hundred thirty-five patients treated between 1975 and 2000 for early stage (stage I & II) squamous cell carcinoma of the larynx were included in the study. Treatment consisted of definitive radiation therapy (RT) with standard fields and fractionation to a median dose of 6,590 cGY. Tissue was collected from pre-RT biopsies and constructed in a tissue microarray, with duplicate cores created for each case. BCCIP and p53 expression was analyzed by immunohistochemistry and qualitatively scored with greater than 10% nuclear reactivity the cutoff for positive staining. Results: Expression of BCCIP and wild type p53 in combination was associated with significant improvements in 5-year local control (68.75% vs. 46.27%, p = .04) and 5-year overall survival (67.68% vs. 34.62%, p = .006) compared to patients who did not express BCCIP. Expression of BCCIP or p53 alone was not found to be independently associated with benefits in local control or overall survival. Conclusions: This study provides clinical evidence that BCCIP contributes to effective local control and overall survival in patients with laryngeal cancer treated with radiation. This benefit may be a result of increased radiosensitivity in patients who have functional BCCIP and p53. Using immunohistochemical methods, BCCIP and p53 co-expression can act as markers to identify sub-groups of laryngeal cancer patients who are more likely to be cured with radiotherapy.

No significant financial relationships to disclose.
Phase II evaluation of cetuximab (C225) combined with induction paclitaxel and carboplatin followed by C225, paclitaxel, carboplatin, and radiation for stage III/IV operable squamous cancer of the head and neck (ECOG, E2303)
Authors: Wanebo H. J. , Ghebremichael M. , Burtness B. , Spencer S. , Ridge J. , Forastiere A. , Ghebremichael M.
Published: March 2020

6015

Introduction: Neoadjuvant C225 with induction chemotherapy and chemo-radiation was studied in stage III/IV head and neck squamous cancer with primary and secondary objectives of 1year event- free survival, pathologic complete response rate at the primary site (PS) (determined by mandatory biopsy week 8) and toxicity. Protocol Design: Operable patients (pts) staged by triple endoscopy, CT/MRI, had gastrostomy, signed IRB approved consent and received induction chemotherapy with weekly C225 250 mg/m2, P 90 mg/m2, C (AUC=2). Restaging PS biopsy was done at week 8, if there was a clinical response. Pts with positive biopsy (or persistent tumor) at PS had restaging biopsy at week 14 after chemo radiation (C225 250 mg/m2, P 30 mg/m2, C(AUC=1) and 50 Gy). If PS Bx was negative patients had completion RT (68–72 Gy, plus continued C225, P,C). If PS Bx was positive at 14 weeks salvage surgery was required. Results: 74 patients were enrolled (67 are evaluable). T and N stage were T1/2 (11%/27%), T ¾ (47%/14%); N O/N1 (11%/23 %), N 2/3 (50%/16%). Site: tonsil 30%, oral cavity/tongue 24%, Post pharynx (BOT) 42%, Larynx 34%; performance status 0/1 (61% / 39%). PS re biopsy was done at week 8 in 40 patients; no residual tumor was detected in 26 (65%). Restaging biopsy after induction and chemo radiation was done at week 14 in 28 pts (14 with persistent tumor and 14 with previous positive biopsy) and was negative in all 28 patients. All 54 patients with negative PS biopsy had completion RT. Data on disease status are incomplete. Post treatment toxicity (Gr 3/4) included acneiform rash (12%), leukopenia/neutropenia 32%/24%, dysphagia (29%), and stomatitis (82%). One grade 5 AE occurred (death from encephalopathy). Conclusion: Neoadjuvant induction C225, plus chemotherapy followed by C225 plus chemo-radiation elicited a complete pathologic response at the primary site, by restaging biopsy (65%) with induction alone, and 100% among sampled patients after chemo RT 50Gy. These preliminary results suggest a high pathologic complete response rate to induction chemotherapy plus cetuximab followed by chemo radiation plus cetuximab. Progression and survival data are not yet mature.

No significant financial relationships to disclose.
Gene copy number of epidermal growth factor receptor (EGFR) by fluorescent in situ hybridization (FISH) in head and neck squamous cell carcinomas (HNSCC) is closely correlated with EGFR protein levels assessed by automated quantitative protein analysis (AQUA)
Authors: Weinberger P. , Psyrri A. , Kountourakis P. , Rampias T. , Sasaki C. , Sasaki C. , Haffty B. , Kowalski D. , Fountzilas G. , Rimm D. , Burtness B.
Published: March 2020

6023

Background: EGFR overexpression correlates with recurrence and with treatment resistance in HNSCC. The mechanisms of EGFR protein overexpression are poorly understood. Nonetheless, previous investigators have not demonstrated a correlation between EGFR gene copy number and protein content, using conventional immunohistochemistry (IHC). The aim of this study was to evaluate the relationship of EGFR gene copy number and protein expression utilizing fluorescence in situ hybridization (FISH) and AQUA, a novel, immunohistochemical method of automated quantitative in situ proteomic analysis which permits subcellular localization. Methods: A tissue microarray composed of 137 HNSCC treated with (chemo)radiation was constructed and analyzed for EGFR copy number by FISH (Vysis/Abbot) and EGFR protein expression (DAKO antibody) using AQUA analysis of EGFR staining scored on a scale of 0–255 and by conventional IHC. Agreement was assessed using kappa. Results: Sixteen (15%) of one-hundred six tumors with FISH results demonstrated EGFR high polysomy and/or gene amplification (FISH+). AQUA demonstrated a range of 3.6–102.2; protein levels assessed by AQUA in the FISH amplified cases were significantly higher (p =0.008) than in the FISH non- amplified ones. Using the EGFR 75th percentile as a cut-off, AQUA and FISH showed significant agreement (percentage of overall agreement 82%, kappa=0.458, p=0.003). To the contrary there was no concordance between FISH and conventional IHC results in this series. Conclusions: The discrepancy between EGFR gene amplification rate and protein expression by IHC reported previously may be due to the limitations and nonquantitative nature of conventional IHC. EGFR protein content correlates with gene copy number if protein content is quantitated and automatically analyzed, as with AQUA.

No significant financial relationships to disclose.
Updated results of a phase II trial integrating gefitinib (G) into concurrent chemoradiation (CRT) followed by G adjuvant therapy for locally advanced head and neck cancer (HNC)
Authors: Ahmed S. M. , Cohen E. E. , Haraf D. J. , Stenson K. M. , Blair E. , Brockstein B. E. , Lin S. , Lester E. , Dekker A. , Williams R. , Vokes E. E.
Published: March 2020

6028

Background: This study was undertaken to evaluate the tolerability and efficacy of substituting G for paclitaxel into a well- described CRT regimen (Clin Cancer Res 9: 5936; JCO 21: 320) and continuing G as adjuvant therapy. Endpoints included complete response (CR) rate to CRT, progression-free (PFS), disease-specific (DSS) and overall survival (OS), and local & distant control rates. Methods: Previously untreated subjects with stage III, IVa, or IVb squamous cell, poorly differentiated carcinomas, or lymphoepithelioma were enrolled. Organ sparing surgery was allowed. Subjects received 2 cycles of carboplatin/paclitaxel induction followed by CRT with G (250 mg PO qd), 5- fluorouracil, hydroxyurea, and twice daily radiation on day 1–5 of five 14d cycles. G was continued for 2 years from the start of CRT. Results: From 2/03 to 10/04, 67 eligible subjects accrued including 51 males; median age 56; ECOG PS 0 in 47, 1 in 19, and 2 in 1; stage IV in 61 (91%). With median follow-up of 858 days, 9 have had progressive disease (PD, 3 distant, 5 local, 1 with both) and 15 have died (12 related to HNC). Estimated OS=83% at 2y, 73% at 3y; PFS=77% at 2y, 64% at 3y; and DSS=86% at 2y, 80% at 3y. In 56 evaluable subjects we observed 51 CR (91 %), 4 partial responses and 1 PD after CRT. Non-evaluable subjects underwent surgery prior to CRT (10), or died prior to evaluation (1). Grade 3/4 toxicity included mucositis (75%/10%), dermatitis (29%/3%), rash (4%/0%) and diarrhea (1%/0%). Sixty-two patients received maintenance gefitinib, with 60 reliably reporting doses (median days on gefitinib=667). Reasons for holding G included LFT abnormalities, patient refusal, diarrhea, rash, recurrence, hospitalization for acute illness, and early death. Conclusions: Adding G to concurrent CRT after induction therapy, and as adjuvant therapy is tolerable and feasible. Favorable survival and CR data suggest that this is a promising regimen for patients with locally advanced HNC.

[Table: see text]
Analysis of magnetic resonance imaging (MRI) in the detection of mammographically occult breast carcinoma
Authors: Vallow L. , Packianathan S. , Feigel D. , DePeri E. , Buskirk S. , Perez E. A.
Published: March 2020

603

Background: Breast MRI may be useful for detecting mammographically occult ipsilateral carcinoma in newly diagnosed breast cancer. Our initial experience with breast MRI, demonstrated 16% of patients to have additional breast disease detected only by preoperative MRI. We further analyzed our findings to identify an association between patient factors and MRI detected disease. Methods: Preoperative MRI scans of 390 women with newly diagnosed breast cancer were reviewed. Using only patients with pathologic verification, the incidence of mammographically occult ipsilateral cancer was determined. Patient and tumor characteristics were further analyzed to identify factors which may predict pathologically positive MRI findings. Results: Of the 390 women undergoing preoperative MRI, 120 (31%) had ipsilateral findings requiring biopsy. Pathologically verified additional ipsilateral cancer was detected in 62 (16%). Multicentric disease was detected in 32 (52%) and multifocal or more extensive local disease in 30 (48%). The median age of all patients was 62 (27% premenopausal) whereas the median age of those with MRI detected additional carcinoma was 55 (44% premenopausal). Of those with additional disease detected by MRI, 74% had index lesions =1 cm and 63% node negative. The most common histology of the index lesion was infiltrating ductal carcinoma in 64%. In the 62 patients found to have additional disease by MRI the most common histology included infiltrating ductal carcinoma (58%), ductal carcinoma-in-situ (34%) and infiltrating lobular (8%). The histology of the MRI detected additional disease was identical to the index lesion in 71%. Conclusions: In women with newly diagnosed breast cancer, there was a 16% incidence of pathologically proven, mammographically occult ipsilateral disease detected by MRI. Patients found to have additional disease tended to be younger, premenopausal or have index tumors =1cm. The contribution of preoperative MRI in breast cancer management continues to evolve. A lower threshold for obtaining breast MRI may be appropriate in selected subsets of breast cancer patients.

No significant financial relationships to disclose.
Phase II study of erlotinib combined with cisplatin and radiotherapy for locally advanced squamous cell carcinoma of the head and neck (SCCHN)
Authors: Herchenhorn D. , Dias F. L. , Pineda R. M. , Fonseca A. J. , Bezerra M. , Ferreira C. G. , Knust R. E. , Fontão K. , Martins R. G.
Published: March 2020

6033

Background: Preclinical data indicates synergy of erlotinib with both cisplatin and radiotherapy (RT). We previously reported the phase I results with the dose of erlotinib defined as 150 mg/day. Methods: Patients (pts) with stages III and IV SCCHN were included. Treatment consisted of RT (70.2 Gy in 8 weeks), and cisplatin (C) (100mg/m2, q 21 days for 3 doses), both starting on Day 8. Erlotinib (E) was started on Day 1 and continued until the end of RT. Patients with N2/N3 disease were evaluated for elective neck dissection post RT. Results: Thirty one pts have been accrued to the study. Median age was 55 years (35–73), 13 pts had larynx carcinoma (stage III 9pts, IVA 3pts, IVB 1pts), 13pts oropharynx (stage III 2pts, IVA 8pts, IVB 3pts) and 5pts hypopharynx (stage III 1pt, IVA 4pts). Twenty five pts completed treatment and are evaluable for response and toxicity. Grade III or IV toxicity included: in-field dermatitis (14pts), nausea (13pts), mucositis (9pts), emesis (8pts), cutaneous infection (3pts), acneiform rash (7pts), fatigue (7pts), dysphagia (6pts), respiratory infection (4pts), neutropenia (1pt), diarrhea (1pt) and 1pt died due to sepsis. The dose of C was reduced in 4pts and withheld in 3pts; RT was delayed in 6 pts (median of 8 days). Twenty one pts (84%) required enteral feeding. Response was accessed by endoscopy with biopsy and CT/MRI scans. Twenty one pts (84%) had complete pathological response, 2 had residual disease and were submitted to salvage surgery, and 1 had disease progression. The median follow-up is 10.8 months. Five pts (23%) had a local relapse. Nineteen pts are disease-free (16 with organ preserved), 2 alive with disease, and 3 pts died due to disease progression. Conclusions: The combination of RT+C+E showed a high complete pathological response and acceptable toxicity, despite the high incidence of grade III/IV in-field dermatitis. These results encourage the design of a phase III trial. Final results will be presented at the meeting.

No significant financial relationships to disclose.
A phase II trial of gefitinib in recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy
Authors: Chua D. T. , Sham J. , Au G.
Published: March 2020

6042

Background: Epidermal growth factor receptor (EGFR) is commonly expressed in nasopharyngeal carcinoma (NPC) and strong EGFR expression appears to correlate with poor survival. Gefitinib, a small-molecule inhibitor of the EGFR tyrosine kinase, has been shown to inhibit the growth of NPC cell lines. Methods: Nineteen patients with recurrent or metastatic NPC were recruited into the study. Eligibility criteria included: radiographic progression of disease, ECOG PS < 2, 1 or more prior platinum-based chemotherapy regimens, normal organ function. Fifteen patients were treated for first relapse, 3 for second relapse, and 1 for third relapse. Local disease was present in 8, nodal disease in 3, and distant metastases in 14. All patients had previously received platinum-based chemotherapy as adjuvant and/or palliative treatments, and 89.5% had 2 or more regimens. Patients received gefitinib 250 mg po daily. Median treatment duration was 10 weeks and median follow-up time was 9 months. Results: Minor response was observed in 2 patients treated for advanced local recurrence. There were no complete or partial responders. Seven patients had stable disease and 12 had progressive disease. Median time to progression was 4 months and median survival was 14 months. Progression-free rate at 6 months was 22% and 1-year survival rate was 70%. Treatment was generally well tolerated and only grade 1–2 adverse events were observed, with acneiform rash (68.5%), fatigue (36.9%), diarrhea (31.6%), and anorexia (31.6%) most common. In 15 patients with symptoms related to NPC, 5 reported improvement, 5 reported no changes, and 5 reported worsening during gefitinib treatment. Conclusions: Gefitinib has little activity in terms of response rate in recurrent and metastatic NPC, although disease stabilization and symptomatic improvement were observed in some patients. Evaluation of markers of EGFR pathway on tumor tissue is currently being performed.

No significant financial relationships to disclose.
Interaction of EGFR and IGF-1R signals to modulate the anti-proliferative and biochemical responses of head and neck squamous cancer (HNSCC) cells to EGFR inhibitors
Authors: Thomas C. Y. , Jameson M. , Beckler A.
Published: March 2020

6045

Background: Epidermal growth factor receptor (EGFR) inhibitors improve the efficacy of radiotherapy for HNSCC and as single-agents induce tumor responses or stabilization in a minority of patients. The molecular mechanisms that dictate the spectrum of observed responses are not well understood. Methods/Results: Exposure of the HNSCC lines SCC-9 and SCC-25 in vitro to the EGFR inhibitors PD158780, lapitinib, or cetuximab suppressed cell proliferation and cell cycle progression into S-phase. Immunoblots showed that PD158780 inhibited autocrine activation of the EGFR, reduced phosphorylation of the downstream signaling proteins AKT and Erk, and affected cell cycle regulatory molecules (reduced Rb phosphorylation, decreased cyclin D1 levels, and induced p27kip1). However, stimulation of the cells with an insulin-like growth factor-1 (IGF-1) analog produced a dose-dependent resistance to the anti-proliferative effects of the EGFR inhibitors. The resistance of SCC-25 cells correlated with IGF-1-induced maintenance of AKT and Rb phosphorylation and cyclin D1 expression. Conversely, the EGFRs also acted downstream of the activated IGF-1 receptors as concomitant EGFR inhibition dampened the proliferative response of the cells, reduced Erk phosphorylation and increased p27kip1 expression. Experiments with the metalloproteinase inhibitor TAPI-2 suggested that the IGF-1 activates the EGFRs through proteolytic cleavage of precursor forms of EGFR ligands. Conclusions: The proliferative and biochemical responses of HNSCC cells to EGFR inhibitors are influenced by cross-talk between the EGFR and IGF-1 receptors. One implication of this work is that the clinical response of HNSCCs to EGFR inhibitors may depend on the relative contribution of autocrine EGFR signaling to activation of specific downstream growth factor signaling pathways, whether or not these receptors are the primary or secondary source of these signals.

No significant financial relationships to disclose.
Plasma EBV DNA and cell-free GAPDH DNA as prognostic factors of locally advanced nasopharyngeal carcinoma
Authors: Chen J. , Ting L. , Ko J. , Lou P. , Wang C. , Yang T. , Hong R.
Published: March 2020

6053

Background: Plasma cell-free nucleic acids have been investigated to be potential prognostic and predictive markers of treatment response, residual disease, and survival of cancer patients. However, these nucleic acids will be confounded by normal cell death, which might be caused by cancer-related inflammation, infection, or chemotherapy. Nasopharyngeal carcinoma is endemic in Taiwan, highly related to EBV infection. Plasma EBV DNA level has been suggested to be predictive of disease status and outcomes. We try to find out whether plasma EBV and cell-free glyceraldehydes-3-phosphate dehydrogenase DNA before definite treatment of locally advanced NPC predict tumor outcomes better. Methods: 144 stage IV (AJCC version 6) NPC patients received induction chemotherapy followed by concurrent chemoradiotherapy in National Taiwan University Hospital from 1998 to 1999. Pre-treatment blood samples were colleted for real-time quantitative polymerase chain reactions of EBV and GAPDH DNA. The results will be analyzed by SPSS version 13 to see if correlated with tumor extent, locoregional/distant failure, and overall survival. Results: Our patients were mainly composed of T4(97%) and N2(56%) patients. 23 % were in N3 stage. Plasma EBV and cell-free GAPDH DNA levels were not correlated with T stage. Plasma EBV DNA level was significantly correlated with N3 status(Mann-Whitney test p=0.021). After Cox regression model, only age (p=0.024) was a significant predictor of recurrence-free survival; N3 status(p=0.007) and positive plasma EBV DNA (p=0.002) predicted shorter metastasis-free survival. N3 status (p=0.031) and positive plasma EBV DNA (p=0.002) were significantly related to poor survival by log-rank test; whereas T4 lesions (p=0.524) and plasma cell-free GAPDH DNA level (p=0.182) were not. After multivariate Cox regression, positive plasma EBV DNA (hazard ratio 4.936 p=0.006) was the only significant predictor of poor survival. Conclusions: To use circulating DNA as prognostic marker, a specific one, such as EBV DNA, might be better than a non-specific one, like GAPDH DNA. This is important in the development of tumor markers for other solid tumors.

No significant financial relationships to disclose.
A phase I dose escalation study of pemetrexed in patients with advanced head and neck squamous cell cancer (HNSCC)
Authors: Morrow P. H. , Glisson B. S. , Ginsberg L. E. , Lippman S. M. , Kies M. S. , Blumenschein G. R. , Ayuste R. C. , Feng L. , Papadimitrakopoulou V. A. , Kim E. S.
Published: March 2020

6055

Background: Despite recent advances in therapy, patients (pts) with recurrent or metastatic HNSCC continue to demonstrate a poor median survival. In these pts, early trials with pemetrexed, a novel antimetabolite that acts upon several enzymes involved in pyrimidine and purine synthesis, have demonstrated promising efficacy and tolerability. Prior studies found that the administration of oral dexamethasone with pemetrexed reduced the incidence of skin rash. Later, vitamin supplementation (B12 and folic acid), given in addition to the dexamethasone, further diminished side effects. However, no trial has yet evaluated the appropriate steroid dose and its relation to the dosing of pemetrexed, in the setting of vitamin supplementation. We conducted a phase I trial to determine the maximum tolerated dose, toxicity, and preliminary efficacy of pemetrexed when given with different schedules of, or in the absence of, dexamethasone in pts with advanced HNSCC who had been treated with at least one or more chemotherapy regimens. Methods: Eligible pts had metastatic or recurrent HNSCC, prior treatment with one or more chemotherapy regimens, ECOG PS =2, and life expectancy >3 months. A conventional algorithm-based dose escalation design was applied, with three predefined dose levels (DL) of pemetrexed (500 mg/m2, 600 mg/m2, and 700 mg/m2) within each schedule of dexamethasone (none, 20 mg IV on day 1, and 4 mg orally bid for 3 days). Results: A total of 23 pts have been enrolled; 18 pts were evaluable. Median age was 57 years (range 47–82). Median ECOG PS was 1 (range 0–2), and 75% of pts were male. Number of prior chemotherapy regimens were as follows: 1 (40%), 2 (35%), 3 (15%), and 4 (10%). Preliminary data demonstrated only 2 treatment-related adverse events that were grade 3 or greater: anemia (DL1) and pneumonia (DL 1). In all, 13 pts have received pemetrexed with less than standard recommended dexamethasone dosing (none or IV), including 7 pts who received no dexamethasone. Of the 18 evaluable pts, 1 pt had a partial response and 2 pts had stable disease. Conclusions: This represents the first study that demonstrates that steroids may not be required as premedication with pemetrexed. Due to the limited toxicity observed, trial enrollment continues with dose escalation.

[Table: see text]
Tumor response criteria and biomarkers associated with increased survival following adenoviral p53 gene therapy (ADVEXIN) in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN)
Authors: Nemunaitis J. J. , Clayman G. , Hamm J. , Bier-Laning C. , Minn H. , Van Echo D. , Yoo G. , Menander K. , Sobol R. E. , Goodwin W. J.
Published: March 2020

6057

Background: There is a growing body of data indicating that conventional WHO and RECIST criteria do not optimally identify tumor responses associated with increased survival. Methods: We compared several response criteria to assess the efficacy of intratumoral adenoviral p53 gene therapy (Advexin) in a Phase 2 trial of 106 patients with recurrent SCCHN. Results: The percentage of patients with tumor responses defined by reductions in bi-dimensional tumor area by CT scans of 50%, 30%, 25%, 10% or stable disease of > 3 months were 8%, 10%, 11%, 16% and 20% respectively. The median survival for the entire population was 5.9 months while the responder populations defined by tumor decreases of 50%, 30%, 25%, 10% or stable disease > 3 months had median survivals of 40.8, 17.0, 13.7, 12.3 and 11.4 months respectively. There was a statistically significant increase in median survival for each of the responder populations compared to non-responders (p < 0.0009 for each comparison by logrank test). Statistical significance was maintained for the response definitions in landmark analyses excluding patients with survivals less than 3 and 6 months respectively. Locoregional disease control (CR + PR + SD > 3 months) was a stronger predictor of survival by Cox Proportional Hazard analysis (p = 0.0002) than conventional > 50% tumor reduction CR + PR response criteria (p = 0.005). With respect to abnormal p53 detected by immunohistochemistry (≥20% positive cells), 75% of patients (12/16) with p53+ tumors demonstrated locoregional disease control compared to only 18% (2/11) with p53− tumors p=0.0063 Fisher’s Exact Test. In addition, the median survival of patients with abnormal p53 was 11.6 months compared to only 3.5 months in patients with normal p53 (p=0.0007 Logrank Test). Conclusions: Our findings indicate that abnormal p53 is a predictive biomarker that identifies a subset of patients most likely to benefit from p53 gene therapy and that recurrent SCCHN tumor response definitions based upon smaller reductions in tumor size or the absence of progression (stable disease > 3 months) more accurately identified Advexin treated patients with increased survival than conventional response criteria.

[Table: see text]
Phase II neoadjuvant docetaxel/cisplatin followed by concurrent cisplatin/radiotherapy for locally advanced nasopharyngeal cancer
Authors: Kandil M. S. , Alnasser H. S. , Bandey S. A. , Almutairy A. S. , Ammar F. A. , Saadeddin A. A. , Murshid E. M. , Asiri M. A. , Zahrani A. M.
Published: March 2020

6059

Background: Neoadjuvant cisplatin/docetaxel are active agents for locally advanced nasopharyngeal cancer (LANPXCA). The efficacy and tolerability of neoadjuvant cisplatin/docetaxel followed by concurrent cisplatin with radiotherapy are explored in a phase II trial. Methods: From Jan 2003 to Jan 2005; 23 patients with LANPXCA stage III, IVA, IVB, (AJCC 2002), were treated with 3 cycles of neoadjuvant docetaxel 60mg/m2, 1 hour IV infusion D1 and cisplatin 60 mg/m2, 2 hours IV infusion D1 with prophylactic GSCF as 5μg/kg sc D3–7,(recycle D22). This was followed by 2 cycles of cisplatin 100 mg/m2, 2 hours IV infusion D1 , (recycle D22), concurrently with radiotherapy aiming at 70Gy / 35 fractions / 7 weeks. The median follow up was 27.9 months (18.3–47.3). Results: The median age was 38 years (16–68) and male to female ratio was 7.66:1. Neck mass 95.7%, neck pain 73.9%, nasal obstruction 65.2%, , headache 56.5%, impaired hearing 52.2%, and epistaxis 52.2% were the commonest symptoms. All patients had G3 squamous cell carcinoma. The majority of patients were stage IV 52.2% while 47.8 % were stage III. Grade one ECOG performance status was the commonest 52.2% while 47.8% were G2. The treatment was tolerable with commonest G3 acute toxicities were dysphagia 43.4% , and oral mucositis 8.7%. The commonest G3 late toxicities were dry mouth 17.4% and impaired hearing 13%. Complete remission was achieved in 22/23 patients 95.7% while 1/23 patients 4.3% was partial responder. Failure sites include; Distant; liver and/or bone 8.7%, local; skull base 4.3% or local and distant 4.3%.The Kaplan Meyer 47 month disease free survival was 82.61% while the 47 month overall survival was 91.3%. Conclusion: Neoadjuvant docetaxel / cisplatin followed by concurrent Cisplatin with radiotherapy is an effective and tolerable outpatient treatment for LANPXCA.

No significant financial relationships to disclose.
Phase I trial of chemotherapy combination with docetaxel, cisplatin and S-1 (TPS) in patients with locally advanced or recurrent/ metastatic head and neck cancer (HNC)
Authors: Tahara M. , Araki K. , Kiyota N. , Takeuchi S. , Fuse N. , Minashi K. , Minami H. , Ohtsu A.
Published: March 2020

6064

Background: An oral fluoropyrimidine, S-1, has shown high efficacy against head and neck cancer (HNC) with a response rate of 34% and preclinical data has demonstrated a possible synergy with platinums and taxanes. The aim of this study was to determine the maximum tolerated dose (MTD) of a combination therapy with TPS in patients (pts) with locally advanced or recurrent/ metastatic HNC. Methods: The eligibility criteria were: histologically proven squamous cell carcinoma of the head and neck with recurrent/metastatic and locally advanced lesions, PS 0–1, age =75 years, adequate organ function, and no prior chemotherapy. Chemotherapy consisted of 1-hour infusion of docetaxel at escalating doses of 50 and 60 mg/m2, 2-hour infusions of cisplatin at 70 mg/m2/day on day 1 and S-1 twice daily on days 1–14 at escalating doses of 40, 60, and 80 mg/m2/day. The treatment was repeated every 4-weeks. Results: Twenty two pts were enrolled. These were 17 males and 5 females with a median age of 50 years (22–74). There were 11 locally advanced and 11 metastatic cases. Median of 3 cycles were administrated (range 1–6; total 77 cycles). Anorexia, nausea, neutropenia and anemia were the most frequently observed adverse events. Grade 3 or 4 hematological toxicities were neutropenia (59%), febrile neutropenia (0%), anemia (14%) and thrombocytopenia (0%). Although a total of 12 pts were treated with TPS at doses of 60/70/80 mg/m2/day, one-dose limiting toxicity (grade3 infection) was observed at these doses, but MTD was not reached. As the approved dose of S-1 is 80 mg/m2, further dose escalation was not conducted. In a total of 22 pts treated with the TPS, 3 (1 locally advanced, 2 metastatic cases) achieved complete response and 11 (7 locally advanced, 4 metastatic cases) achieved partial response according to RECIST with an overall response rate of 64%. Conclusions: The TPS combination was well tolerated in pts with locally advanced or recurrent/ metastatic HNC. Although MTD was not reached and the data were preliminary, the antitumor activity was very promising, and this warrants further investigation.

No significant financial relationships to disclose.
Clinical and translational studies of depsipeptide (romidepsin), a histone deacetylase (HDAC) inhibitor, in patients with squamous cell carcinoma of the head and neck (SCCHN): New York Cancer Consortium Trial P6335
Authors: Haigentz M. , Kim M. , Sarta C. , Keresztes R. S. , Smith R. V. , Belbin T. J. , Mariadason J. M. , Greally J. M. , Shapiro G. I. , Haddad R. I.
Published: March 2020

6065

Background: Unresectable recurrent and metastatic SCCHN is incurable and associated with dismal prognosis. Our objective is to evaluate the clinical activity of depsipeptide (DEP) and its effects of on PBMCs, SCCHN tumors and oral mucosa tissues in an NCI/CTEP sponsored phase II trial. Methods: Eligibility criteria include PS 0–2, any number of prior therapies and no history of significant cardiovascular disease. DEP was administered at 13 mg/m2 IV over 4 hrs on days 1, 8, and 15 of 28 day cycles. A two-stage design was utilized, with commencement to the second stage (total 46 pts) if at least 8 of 18 pts achieve disease control at 8 weeks by RECIST. Results: To date, 10 pts (7M/3F) have been accrued, all with samples for correlative studies. Two pretreated pts (2 and 4 prior therapies for recurrent/metastatic disease) have achieved disease stabilization, including one with clear histone H3 hyperacetylation in PBMCs immediately following the first 4 hr infusion of DEP. Common toxicities to date have included fatigue and weakness, usually mild. Myelosuppression is uncommon. Aside from G3 hypotension in 1 pt, no cardiovascular toxicities have been attributed to DEP. To date, 2 of 2 pairs of pre- and post-treatment (cycle 1, day 16) biopsy specimens have demonstrated increased expression of p21Waf1/Cip1 by immunohistochemistry post-DEP, consistent with HDAC inhibition by DEP in tumor cells. Additionally, 3 pairs of tumor biopsies and 4 pairs of mucosal brush biopsies have been analyzed by differential gene expression profiling using microarrays containing 27,323 cDNA clones; 208 cDNA clones of interest appear to be upregulated in response to DEP in at least 3 of the 7 comparisons. Analysis also includes CpG island methylation status of candidate tumor suppressor loci in tumor and mucosal tissues. Conclusions: DEP appears well tolerated by SCCHN pts, with infrequent myelosuppression and minimal if any cardiovascular toxicity in pts without pre-existing disease. Effects of DEP on PBMCs, tumor and mucosal tissues are consistent with HDAC inhibition in vivo. Accrual to the clinical trial is ongoing. Supported by ASCO Career Development Award, NIH CA110342 and N01-CM-62204.

No significant financial relationships to disclose.
Clinical study of thyroid cancer among a pediatric population born after Chernobyl (first report)
Authors: Gorobeiko M. B. , Larin O. S. , Cherenko S. M.
Published: March 2020

6069

Background: To evaluate the clinical and patologic results of surgical treatment of children born after Chernobyl and to compare these findings with well-known data of the group of patients who were children at the time of Chernobyl. To compare the clinical and pathologic features of thyroid cancer of children born after the Chernobyl versus those born prior to 1986. Methods: Comparison of clinical and pathologic result of surgical treatment of 141 patients born after Chernobyl (Group 1) and 589 patients (Group 2) aged 0–18 at the time of the disaster (1986) among the single institution clinical cohort within years 1995–2005. Results: In Group 1 there were 31 cancers (22%) vs. 243 (41%) in Group 2 (p<0.05 between Group 1 and Group 2). The rate of extrathyroid invasion was 69% vs. 36% (p<0.05 between Group 1 and Group 2). In Group 1, 17/21(80%) patients with extrathyroid invasion were found to have regional neck metastases (8 unilateral, 9 bilateral).The mean age in this subgroup was 13.4 ± 2.11 years but in the “benign subgroup” of Group 1 the mean age is 16.2 ± 0.77 years.In Group 2, 49/88 (55%) patients with extrathyroid invasion only had regional metastases. The mean age in this subgroup is 31.1 ± 4.7 years (p<0.05 between Group 1 and Group 2). We found cancer multifocality in 1 patient (3%, Group 1) vs. 55 (23%, Group 2).There were 19 cases (13.5%) of atypical adenomas in Group 1 vs. 46 (8%) in Group 2 (p<0.05 between Group 1 and Group 2). Histological types: solid follicular variant of papillary carcinoma (typical for radiation-induced children carcinomas with short latency) was found in 3 cases in Group 1 (9.5%) vs. 76 (31%) in the Group 2 (p<0.05 between Group 1 and Group 2). There was only one case of follicular thyroid cancer in Group 1 (3%) vs. 9% in Group 2. We did not find any relationship of cases of cancer in Group 1 to the Chernobyl-polluted area (only 3 patients − 10% from the nearest to Chernobyl regions) vs. 192 patients (80%) in Group 2 (p<0.05 between Group 1 and Group 2). Among patients with tumors of uncertain malignant potential 9 patients (6%) were from Chernobyl-polluted area vs.72% in Group 2 (p<0.05 between Group 1 and Group 2). Conclusions: Our data demonstrates higher likelihood of aggressive well-differentiated thyroid cancer among a pediatric population independently from Chernobyl irradiation and connected with another etiological factors of genesis of tumor.The solid-follicular variant of papillary cancer and multifocality are typical for radiation-induced carcinoma in children.

No significant financial relationships to disclose.
Intraoperative radiotherapy (IORT) with low-energy x-rays for breast cancer
Authors: Kraus-Tiefenbacher U. S. , Herskind C. , Bauer L. , Scheda A. , Wenz F.
Published: March 2020

607

Background: IORT for breast cancer using either electrons or low-energy x-rays is of increasing interest over the last few years. In our institution, IORT is delivered by a mobile x-ray source (Intrabeam™) producing isotropic 50 kV x-ray fields. Because this treatment method includes single high doses to the normal breast tissue, careful and long-term evaluation of early and late toxicity is mandatory. To date there are still fewdata on long-term follow-up of patients treated with low-energy x-rays. Methods: Between 2/02 and 12/06 204 breast cancer patients received IORT either as a tumour-bed boost (133) followed by 46 Gy external beam radiotherapy (EBRT) or as partial breast irradiation (PBI) only (71). Median age was 66.4 years (35–95), median tumour size was 9 mm (1–45). Spherical applicators (median 4. 0 cm) were inserted into the tumour-cavity and a single dose of 20 Gy was given. Follow-up (f/u) included physical examination and ultrasound 1 week, 2 months, then every 6 months after therapy and mammography at yearly intervals. Radiobiological modelling of the expected spatial distribution of late reactions was done for typical cases using the linear-quadratic model with special consideration of relative biological effectiveness, spatial dose distribution and dose rate. Results: Median f/u was 28 months (1–56). Minor postoperative side effects included erythema (5%), delayed wound healing (4%), mastitis (1%) and hematoseroma (4%). A fibrotic induration of the tumour bed was observed in 9, 18, 24, 23, 26% and 24% of the patients at 2, 6 12, 24, 36 and 48 month f/u. These fibrosis rates were distributed equally in both groups. Reoperation was required in 2 patients after 10 (fibrosis) and 12 months (fat necrosis). Conclusions: Although two thirds of the patients were treated with a combination of IORT and EBRT, acute reactions in all patients were mild. A fibrotic induration confined to the tumourbed was observed in up to 25% of all patients after 2 years. The low level of clinically observed late reactions so far is in agreement with predictions from radiobiological modelling.

No significant financial relationships to disclose.
Validation of weekly-dose cisplatin combined with radiation therapy in locally advanced head and neck cancer
Authors: Boulmay B. C. , Riggs C. E. , Lawson M. , Morris C. , Mendenhall W. M.
Published: March 2020

6076

Background: Impressive outcomes have been achieved using multiagent neoadjuvant and concomitant chemotherapy combined with radiation in definitive treatment of head and neck cancer; these are associated with significant toxicities. The purpose of this study was to determine the efficacy and toxicities of single-agent weekly (CDDP) during curative-intent radiation therapy. Methods: 36 patients with AJCC Stage II (3%), Stage III (14%), Stage IV (83%) squamous cell carcinoma of the larynx, hypopharynx, oropharynx and oral cavity treated from 6/2000 to 11/2003 were retrospectively reviewed. Subjects received 72 Gy irradiation given either by hyperfractionation or IMRT technique with CDDP 30 mg/m2/wk throughout the radiation course. Cisplatin was held for Grade III/IV toxicities. The endpoints were best response, percentage of Grade III/IV toxicities, disease-free survival (DFS), overall survival (OS). Results: The median number of cycles of CDDP administered was 6. Grade III/IV toxicities: 11% of patients had anemia, 6% thrombocytopenia, 33% leukopenia, 0% renal failure, and 25% developed Grade III/IV mucositis; 1 patient (3%) died due to complications directly related to therapy. Responses to therapy included 72% CR, 17% PR, and 5% SD. Median follow-up for all patients was 19 months (34.5 months for living patients), DFS at 3 years (yrs.) was 59%, and OS at 3 yrs, was 40%. Nine patients died of disease up to 2.6 (median, 0.7) yrs. after treatment, while 11 died of intercurrent diseases up to 5.1 (median, 1.8) yrs. later. Fifteen are alive (2 with recurrence) at median 2.7 yrs. after treatment. Conclusion: Concomitant weekly CDDP with full-course radiation is feasible, tolerable, highly active, and comparable to more complex, costly and toxic regimens. Intercurrent disease was a significant contributor to mortality in our population. Our regimen is an attractive alternative to sequential chemoradiotherapy programs.

No significant financial relationships to disclose.
Economic evaluation of the TAX 324 trial comparing docetaxel plus cisplatin and 5-fluorouracil (TPF) versus standard treatment with cisplatin and 5-fluorouracil (PF) as induction chemotherapy followed by concurrent chemoradiation therapy in locally advanced squamous cell carcinoma of the head and neck (SCCHN)
Authors: Parthan A. , Posner M. R. , Brammer C. , Beltran P. , Jansen J.
Published: March 2020

6079

Background: The TAX 324 phase III trial showed that induction chemotherapy with TPF followed by chemoradiotherapy improves survival and time to progression in patients with locally advanced SCCHN compared with PF [Posner MR, et al. ASCO 2006]. A Markov state-transition model was developed to estimate the cost-effectiveness of TPF. Methods: The Markov model includes four health states (based on WHO criteria for measuring objective response): stable, responsive, progressive disease, and death. TAX 324 efficacy data were used to derive transition probabilities between health states. Adverse event rates were also derived from TAX 324. Data for resource utilization and costs from a UK perspective were derived from the literature and clinician inputs from an advisory board. The global score of the Health Related Quality of Life Questionnaire Core-30 (QLQ-C30) was mapped to the EQ-5D in order to derive utilities and quality adjusted life years (QALYs). Results: A patient in the TPF arm survived longer versus PF (5.4 vs. 2.7 years). Comparison of TPF vs. PF resulted in an incremental gain of 2.7 life years and 2.1 QALYs. The incremental discounted costs/QALY gained for TPF vs. PF was £1,988/QALY, which is below the £20,000 cost-effectiveness threshold suggested by NICE as a guide to the acceptability of a technology. At this threshold, there is a 96.1% probability that TPF is cost-effective compared with PF. Conclusion: Docetaxel, when given as induction chemotherapy followed by concurrent chemoradiotherapy in combination with cisplatin and 5-fluorouracil (TPF), leads to a substantial increase in life expectancy, and is cost-effective compared with PF for locally advanced SCCHN.

No significant financial relationships to disclose.
Prognostic value of age in nasopharyngeal carcinoma patients: A single institution analysis
Authors: Downing N. L. , Wong P. , Petrik D. , Hara W. , Le Q.
Published: March 2020

6080

Background: Nasopharyngeal carcinoma (NPC) has a bimodal age distribution with peaks at 15–25 and 40–50 years of age, though it is unclear if the prognosis differs significantly between the two age groups. Here, we compare treatment outcomes between two age groups of patients treated at a single institution. Methods: We retrospectively analyzed the data of 99 NPC patients who received definitive treatment at our institution between March 1985 and June 2004. All patients received a median dose of 66 Gy of external beam radiation therapy and 70% received either concurrent or induction chemotherapy. We compared patient, tumor, and treatment characteristics as well as treatment outcomes in juvenile patients (age = 25 years at diagnosis), versus adult patients (age > 25 years at diagnosis). Survival curves were estimated by the Kaplan-Meier method. Results: There was a significant difference in the ethnic composition between the age groups, with more Asians and fewer Whites and Hispanics in the adult group (see table ). Also, there was a significant difference between the groups in the proportion of patients receiving chemotherapy, especially induction chemotherapy (see table ). There was no difference in the distribution of tumor stage and WHO histology between the two age groups. At a median follow-up for all patients of 42 months (range 4 to 234), there were no statistically significant differences in treatment outcomes between the two age groups although the survival data numerically favored the juvenile patients (see table ). Conclusions: Although there were significant differences in racial distributions and treatment characteristics between the two age groups, treatment outcomes were similar. Aggressive treatment with radiotherapy and chemotherapy resulted in excellent outcomes for both patient populations.

No significant financial relationships to disclose.

[Table: see text]
Phase I study of panitumumab, chemotherapy and intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC): Early results
Authors: Wirth L. J. , Posner M. R. , TIshler R. B. , Haddad R. I. , Goguen L. , Clark J. R. , Allen A. M.
Published: March 2020

6083

Background: Both chemotherapy and epidermal growth factor receptor (EGFR) antibody therapy improve outcomes in HNC when added to radiotherapy. This phase I study investigates the addition of the fully human anti-EGFR antibody, panitumumab, to chemoradiotherapy (CRT) for HNC. Methods: Treatment naïve adults with stage III/IV HNC (primary sites include oropharynx and unknown primary) with normal hematologic, renal, and liver function are currently enrolling in a 2-part study. Part A determines the maximum tolerated dose (MTD) of paclitaxel in 2 dose levels (DLs) (15 and 30 mg/m2 wkly×7 wks) with fixed-dose carboplatin and panitumumab (AUC of 1.5 and 2.5 mg/kg wkly, respectively) plus IMRT (70 Gy). Patients (pts) are enrolled in sets of 3. Part B determines the MTD of 5-FU in 2 DLs (800 and 900 mg/m2 days 1–4, Q21d) with fixed-dose docetaxel, cisplatin and panitumumab (75 mg/m2, 100 mg/m2 and 9 mg/kg, Q21d, respectively) for 3 cycles followed by panitumumab + CRT, as determined in Part A. Results: To date, 8 pts (n=3 at DL 1, n=5 at DL 2) have enrolled in Part A. One dose-limiting toxicity has occurred in DL 2: grade (gr) 4 febrile neutropenia. Other adverse events include gr 3/4 mucositis (n=6), gr 3/4 radiation dermatitis (n=6), gr 2 acneiform rash (n=6), gr 3 dysphagia (n=6) and gr 2 oral pain (n=6). Dose-reduction has not been necessary thus far. Enrollment will continue in a cohort of 10 pts in DL 2. Of 4 pts evaluated for response, 4 had complete response in the primary and neck, and 1 had a residual neck mass. This pt had 1 positive node on neck dissection. Conclusions: Preliminary results suggest that panitumumab can be added to CRT for treatment of HNC without magnifying the expected toxicities with CRT. Part B will investigate panitumumab + sequential therapy for HNC once the MTD of Part A is established.

No significant financial relationships to disclose.