bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II open clinical trial to evaluate efficacy and safety of neoadjuvant trastuzumab in HER2-positive locally advanced breast cancer (LABC)
Authors: Arce-Salinas C. H. , Lara F. U. , Leon E.
Published: August 2020

592

Background: LABC in Mexico represents between 50–60% of the new diagnosed cases, and 25–30% of those cancers are HER-2/neu positive. Primary systemic therapy trastuzumab-based combination chemotherapy (ChT) has shown clinical benefit and pathologic complete response rates are obtained between 17%-67%. The aim of this study was evaluate the complete pathologic response (pR) rate with the combination of four cyles of FAC (5FU/Doxorubicin/Cyclophosphamide) followed by weekly paclitaxel (PTX) and trastuzumab. As secondary endpoint was evaluate cardiac safety. Methods: All patients with LABC HER-2 positive (IHC 3+ or FISH amplification) with stages IIb-IIIc were included, patients with palpable nodes underwent fine needle aspiration to confirm metastatic nodal disease (MND), other inclusion criteria was FEVI ≥55% determined by MUGA, hematologic, renal and hepatic function normal. We exclude inflammatory breast cancer. All patients received 4 cycles of FAC followed by weekly PTX (80 mg/m2) concomitantly with trastuzumab, 2 mg/kg, at the end of treatment surgery was performed, and pR was evaluable. Complete pR was defined as the absence of tumor cells in breast and axillary nodes. Disease free survival (DFS) was calculated with Kaplan-Meier method. Protocol was approved by local ethical committee. NCT 00533936. Results: We included 92 patients, median age was 48 (27–68) yrs. Median tumor size was 6 (5.4–6.5) cm, 84.9% had MND. Efficacy analysis was made in 71 patients; 21 patients are still under treatment. Overall clinical response was reached in 71% (complete 37% and partial 42%). Eleven patients were considered inoperable (skin affection, larger size > 5 cm or fixed to chest wall and received radiotherapy 50 Gy). Complete pR was reported in 48% of cases. Median follow-up was 17.4 (CI95% 14.9, 17.6) mo and media of DFS was 25.1 (CI95% 23.5, 26.7) mo. We found cardiac toxicity (CT) grade 3 in 1.1%, and grade 2 in 3.2%. Conclusions: Combination of PTX and trastuzumab after 4 cycles of FAC is highly active in terms of complete pR. This scheme was tolerated, with CT grade 3–4 in less than 2%.

No significant financial relationships to disclose.
Utility of a multigene prognostic algorithm in combination with TP53 expression for prediction of benefit from adjuvant taxane-containing chemotherapy in node-positive breast cancer patients
Authors: Kronenwett R. , Stropp U. , Briasoulis E. , Gehrmann M. , Razis E. , Hennig G. , Bafaloukos D. , Wirtz R. M. , Economopoulos T. , Fountzilas G.
Published: August 2020

593

Background: Recently, we have shown that the Siemens Prognostic Score (SPS) based on mRNA expression of nine informative genes predicted outcome in node-positive (N+) patients with breast cancer (SABCS 2008, abstract 6044). The aim of this retrospective biomarker study was to examine the utility of the SPS in combination with TP53 expression to predict benefit from adjuvant taxane therapy. Methods: The 211 N+ patients included in this study were treated in the context of a randomized two-arm phase III study (E-T-CMF vs. E-CMF) investigating adjuvant dose-dense sequential chemotherapy with epirubicin (E) followed by CMF with or without paclitaxel (T). RNA was isolated from formalin-fixed, paraffin-embedded tissue samples, using a Siemens proprietary method, followed by kinetic one-step RT-PCR for assessment of mRNA expression of the nine SPS genes, TP53 and two normalization genes. The continuous SPS was calculated using a linear combination of expression values of the SPS genes. Patients were separated into a high- and low-risk group using a cutoff at the median of the SPS. Optimal cutoff for low or high TP53 expression was defined on the basis of a ROC curve in SPS high-risk patients. Distant metastasis-free survival (MFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared using the log-rank test. Results: For patients with high SPS or high TP53 expression, we observed a trend for a better MFS in the E-T-CMF arm (SPS: p = 0.18; HR = 0.66; TP53: p = 0.23; HR = 0.67; n = 211). Combining both parameters, patients with high SPS and high TP53 expression (n = 44) had a significantly better MFS following E-T-CMF compared to E-CMF (5-year MFS 80% vs. 40%, p = 0.003, HR = 0.21; OS: p = 0.09; HR = 0.34). On the other hand, patients with high SPS and low TP53 expression (n = 32) showed a trend for a worse outcome with E-T-CMF (MFS: p = 0.09; HR = 3.54; OS: p = 0.35, HR = 1.90). Conclusions: Our prognostic algorithm combined with TP53 mRNA expression predicts the benefit from the addition of paclitaxel to E-CMF and might be used for identification of patients who should be considered for adjuvant taxane therapy. This hypothesis needs to be confirmed in an independent clinical study.

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Oral vinorelbine (NVBo) and anastrozole (A) as neoadjuvant treatment of locally advanced (LA) breast cancer (BC) in hormone receptor positive (HR+) postmenopausal patients: Results of an international phase II trial
Authors: Riggi M. , Moreno-Lopez E. M. , Rolski J. , Petruzelka P. , Ferrero J. M. , Tellez-Bernal E. , Vaissiere N. , Lucas C.
Published: August 2020

600

Background: Two recent randomized studies with anastrozole, as single agent or with an unspecified cytotoxic, produced an objective response rate (RR) of 24 and 39.5% by ultra-sound (US) [baseline primary tumor diameters (PTD) of 2.6 cm (median) and 3.6 cm (mean), respectively] in LA BC. This trial assessed the effect of the combined NVBo-A therapy. Methods: 55 assessable HR+ patients (pts) with LA breast cancer (tumor size > 3 cm) were expected, including 10 with pharmacokinetics (PK). Pts received 3 (if progression or complete response) to 6 courses of NVBo at day 1(D1) and 8 every 3 weeks (60 mg/m2 escalated to 80 mg/ m2 at cycle 2) with 1 mg of A daily. Both US (primary criteria) and calliper assessments were performed at cycle 3 and 6, with surgery within 4 weeks of the last D1 NVBo. Anastrozole interaction on NVBo was studied by comparing NVBo PK between D1 and D8. NVBo interaction on A was assessed by comparing trough concentrations between D8 and D21. Results: Between July 2005 and June 2008, 60 women were enrolled. The first 58 pts were analyzed: at baseline, median age 64.9 years, median and mean PTD 3.7 and 4 cm, respectively; 59% N1–2(17% N2), with a feasible breast conservative surgery (BCS) in only 12%; 19% were inoperable. The RR was 59% (95% CI 45–71%) by US and 69% (55–80%) by calliper. Clinical nodal invasion on TNM (N+) regressed by 32%. 10/11 inoperable pts at baseline became operable. Among 51 resections (concurrent events 4 pts, unresectable 3 pts) 20% were BCS. The pCR was 3.9%. Grade (G) 3–4 toxicities: haematological toxicities (neutropenia) in 6 pts; hepatic enzymes G3 1 pt; gastrointestinal toxicities G3 5 pts and 1 G4 musculoskeletal pain. PK interim analysis showed an absence of interaction between the 2 drugs. Conclusions: NBVo plus A led to an increased RR compared with previous experiences with A alone or not (IMPACT, PROACT trials). The operability rate was notably improved from baseline in this population with unfavorable characteristics and BCS was slightly increased. This combination treatment was well tolerated and pts could benefit from an oral therapy allowing preservation of daily living activities.

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Mass spectrometry profile as a predictor of overall survival benefit after treatment with epidermal growth factor receptor inhibitors in head and neck squamous cell carcinoma
Authors: Chung C. H. , Seeley E. H. , Grigorieva J. , Yarbrough W. G. , Gilbert J. , Murphy B. A. , Argiris A. , Caprioli R. , Carbone D. P. , Cohen E. E.
Published: August 2020

6000

Background: Our previous study has shown that a matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS) profile in serum or plasma can predict lung cancer patient survival after treatment with epidermal growth factor receptor inhibitors (EGFRI). We examined the ability of this same MALDI-MS profile in plasma or sera to predict for survival benefit of EGFRIs in patients with head and neck squamous cell carcinoma (HNSCC). Methods: Spectra were obtained in triplicate using MALDI-MS from 314 samples obtained from five HNSCC cohorts treated with 1) gefitinib (G, n = 100); 2) erlotinib and bevacizumab (E/B, n = 81); 3) cetuximab (C, n = 21); 4) surgery (S, n = 78); and 5) palliative chemotherapy (PC, n = 34). Each sample was classified into “good” or “poor” outcome groups and overall survival was examined using this MALDI-MS classifier (VeriStrat, Biodesix, Steamboat Springs, CO). Results: Successful classification could be achieved in 311/314 (98%) of the samples. In all EGFRI-treated cohorts, the classifier predicted survival benefit while the cohorts without EGFRI-treatment showed no survival difference by log-rank testing (G: p = 0.007, HR 0.41, 95%-CI 0.22–0.79; E/B: p = 0.02, HR 0.20, 95%-CI 0.05–0.78; C: p=0.06, HR 0.26, 95%-CI 0.06–1.06; and PC: p = 0.76, HR 0.88, 95%-CI 0.4–1.97), independent of performance status, age, gender and smoking history. Conclusions: This study suggests that the same predictive algorithm for MALDI-MS generated from patients with lung cancer treated with EGFRIs is also predictive of survival outcome in HNSCC patients treated with both TKIs and cetuximab, and may allow rational selection of patients most likely to benefit from an EGFRI monotherapy.

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Survival outcomes by tumor human papillomavirus (HPV) status in stage III-IV oropharyngeal cancer (OPC) in RTOG 0129
Authors: Gillison M. L. , Harris J. , Westra W. , Chung C. , Jordan R. , Rosenthal D. , Nguyen-Tan P. , Spanos W. J. , Redmond K. P. , Ang K. ,   Radiation Therapy Oncology Group
Published: August 2020

6003

Background: The favorable prognosis for HPV-positive (pos) OPC requires confirmation in a clinical trial of sufficient size to account for confounding variables including smoking. Methods: A correlative study was performed to evaluate the association of tumor HPV status (THS) and survival in a randomized phase 3 trial comparing standard fractionation (FX) radiotherapy (RT) and cisplatin (cis) (100 mg/m2, days 1, 22, 43) to accelerated FX-RT and cis (100 mg/m2, days 1, 22). THS for OPC cases was determined by HPV16 in situ hybridization (ISH). Two-year overall (OS, death) and progression-free survival (PFS, progression, salvage surgery, death) for patients with HPV-pos and HPV-negative [neg] OPC were estimated along with 95% confidence intervals (CIs) by Kaplan-Meier method and compared by log-rank test. Hazard ratios (HR) for OS/PFS comparing HPV-pos to HPV-neg OPC after adjustment for treatment assignment, age, race, T and N stage, and smoking (< or ≥ 20 pack-years [p-y]) were estimated by use of Cox models along with 95% CIs with multiple imputation for cases with undetermined THS and/or missing p-y. Results: THS was evaluable for 73% (317/433) of OPC cases and 60.6% (55.2–65.9) were HPV16-positive. OS/PFS outcomes were similar for cases with and without HPV determination. After median follow-up of 4.4 years, cases with HPV-pos OPC had better OS (p < 0.0001; 2-year 87.5% [82.8–92.2] vs 67.2% [58.9–75.4]) and PFS (p < 0.0001; 2-year 71.9% [65.5–78.2] vs 51.2% [42.4–59.9]). Patients with HPV-pos OPC had a 59% reduction in risk of death (HR 0.41 [0.27–0.64]) and a 46% reduction in risk of progression or death (HR 0.54 [0.37–0.78]). Results with and without imputation were consistent. The hazard of death was elevated for HPV-neg OPC with ≥ 20 p-y (HR 4.33), HPV-neg OPC with < 20 p-y (HR 2.41), and HPV-pos OPC with ≥ 20 p-y (HR 1.79), relative to HPV-pos OPC with <20 p-y. Second primary tumors were less common among HPV-pos cases and patterns of first failure were similar. Conclusions: Tumor HPV status is strongly associated with OS/PFS among OPC patients receiving standard of care chemo-radiation, and should now be a stratification factor for all clinical trials including OPC cases, and separate trials based on THS should be considered.

No significant financial relationships to disclose.
Phase II study of bevacizumab (B) plus cisplatin (C) plus intensity-modulated radiation therapy (IMRT) for locoregionally advanced head and neck squamous cell cancer (HNSCC): Preliminary results
Authors: Pfister D. G. , Lee N. Y. , Sherman E. , Lisa D. , Carlson D. , Stambuk H. , Shen R. , Kraus D. , Shah J. , Fury M. G.
Published: August 2020

6013

Background: For patients with locoregionally advanced HNSCC, concurrent high-dose cisplatin + radiation therapy is a historical standard of care. HNSCC tumors expressing high levels of VEGF have been associated with worse prognosis, and bevacizumab may sensitize tumors to cisplatin and radiation. Methods: Percutaneous gastrostomy (PEG) tube was placed pre-treatment for all patients. Planned treatment consisted of definitive IMRT (total, 70 Gy) with concurrent C (50 mg/m2 days 1, 2, 22, 23, 43, 44) and B (15 mg/kg days 1, 15, and 43). The initial version of the protocol called for an additional 6 months of maintenance B, but this was discontinued in an amendment after a G4 pulmonary hemorrhage event in subject 1 during maintenance treatment. 1o endpoint was 2-year PFS. Results: 42 previously untreated patients (34 M, 8 F), median age 55 (27–75), with stage III/IV, M0 HNSCC (oropharynx 39, larynx 3) enrolled. HPV status by ISH: 16 pos, 14 neg, 12 unknown). All patients have completed treatment. CTCAE v3.0 toxicities (% patients) have included: functional mucositis G3 (76 %); nausea G3 (24%); vomiting G3 (17%); neutropenia G3 (31%), G4 (10%); hemoglobin G3 (17%); hyponatremia G3 (14%). Median weight loss during treatment was 8.9 kg (2.1–26 kg). There were two deaths within 90 days of last treatment: 1 aspiration pneumonia, 1 sudden death. Median follow up is approximately 9 months (range, <3 to 24 months). Locoregional control rate is 100%. Three patients have developed distant metastasis. Estimated one-year PFS is 83% (± 10%) and estimated 1 year OS is 88% (± 6%). At a median of 8 months after completion of radiation therapy, PSS-HN scores were 100 for eating, speech, and diet in respectively 88%, 76%, and 53% of surveyed patients (n = 17). Conclusions: The addition of B to C + IMRT did not appear to increase toxicity to unacceptable levels, and preliminary efficacy results are encouraging.

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Phase II trial of concurrent 5-fluorouracil, hydroxyurea, cetuximab, and intensity moduled radiation therapy (IMRT) for locally advanced head and neck cancer
Authors: Kao J. , Policarpio L. , Teng M. , Burri R. , Genden E. , Packer S.
Published: August 2020

6014

Background: This phase II study was conducted to evaluate the tolerability and efficacy of incorporating cetuximab and simultaneous integrated boost intensity modulated radiation (SIB-IMRT) into a well-described 5-fluorouracil (5-FU) and hydroxyurea (HU)-based chemoradiation regimen. Endpoints included overall survival (OS), locoregional (LRC) and (DC), quality of life and toxicity. Methods: Patients with stage IVa-IVb or high-risk stage III squamous cell carcinomas were enrolled on a phase II trial. Prior organ-conserving surgical therapy or induction chemotherapy was allowed off protocol. SIB-IMRT was prescribed to low (43.2 to 48 Gy) and intermediate (54 to 63 Gy) risk volumes. A separate IMRT conedown plan was targeted to gross disease (72 Gy). The median radiation dose was 72 Gy (range 60 to 72 Gy) administered in 1.5 Gy fractions BID on weeks 1, 3, 5, 7 ± 9. Concurrent systemic therapy consisted of 5-FU (600 mg/m2), HU (500 mg BID) and cetuximab (250 mg/m2). Results: From January 2007 to April 2008, 33 subjects enrolled. Characteristics included 24 males; median age 59; ECOG performance status was 0 in 12. Disease was stage IVa-b disease in 31 (94%), T3–4 in 16 (48%), N2–3 in 23 (70%), and oropharynx primary in 15 (45%). Median follow-up in surviving patients is 15 months (range 6 to 22 months). The 1 year LRC, DC and OS is 91%, 82%, and 92%, respectively. Grade 3 toxicity consisted of mucositis (33%), radiation dermatitis (15%), anemia (15%), and leukopenia (15%), and neutropenia (9%). There were no grade 4–5 events. The majority of patients (64%) were able to tolerate treatment without a feeding tube. Median patient reported University of Washington QOL-R scores before, immediately after, 3 months and 8 months after chemoradiation were 85.5 (±14), 65 (±13), 76.5 (±15), and 84.5 (±9), respectively. Conclusions: Concurrent 5-FU, HU, cetuximab, and SIB-IMRT is a promising and reasonably well tolerated approach to incorporating molecularly targeted therapy in the curative therapy of locally advanced head and neck cancer.

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A single-arm phase II trial to evaluate the combination of cetuximab plus docetaxel, cisplatin, and 5-fluorouracil (TPF) as induction chemotherapy (IC) in patients (pts) with unresectable SCCHN
Authors: Mesia R. , Vázquez S. , Grau J. J. , García-Sáenz J. A. , Bayona C. , Galceran J. C. , Irigoyen A. , Lozano A. , Mañós M. , Cruz J. J. ,   on behalf of the Spanish Head and Neck Cancer Research Group
Published: August 2020

6015

Background: TPF combination is the new standard IC. Adding cetuximab to PF chemotherapy is superior to PF alone in metastatic disease. We incorporated cetuximab into IC with TPF and subsequent radiotherapy (RT) in unresectable SCCHN. Methods: Phase II trial conducted in 7 Spanish hospitals. Previously untreated pts aged 18–70 yrs, ECOG PS 0–1 with unresectable SCCHN were eligible. Induction comprised T 75mg/m2 day 1, P 75mg/m2 day 1, F 750mg/m2 days 1–5, and cetuximab 250mg/m2 days 1, 8, and 15 (initial dose 400mg/m2 on cycle (C) 1, day 1), repeated every 21 days x 4 C, with prophylactic antibiotics and G-CSF support. Subsequently, pts received accelerated RT with a concomitant boost (69.9Gy) and cetuximab 250mg/m2 weekly. The primary endpoint was the objective response rate (RR) to cetuximab TPF as neoadjuvant therapy. Simon's optimal two-stage design was used to calculate the sample size of 49 evaluable pts. Results: 50 pts were enrolled: median age 54 yrs (33–68); 44 male; all stage IV (T4=31, N2–3=40). Primary sites were: oropharynx, 23; hypopharynx, 16; oral cavity, 5; larynx, 4.41(82%) pts received all 4 cycles of cetuximab TPF; 47 pts received ≥2 C and were evaluable for response using RECIST. 3 pts received <2 C (2 deaths from intercurrent disease and febrile neutropenia, 1 secondary neoplasm diagnosed). The table shows RR. Serious grade 3/4 adverse events (AEs) were: neutropenia 24%; neutropenic fever 20%; infection 6%; thrombocytopenia 4%; diarrhea 12%; hepatotoxicity 4%; hypomagnesemia 2%. Grade 3 AEs were: nausea/vomiting 2%; mucositis 6%; renal failure 4%; asthenia 4%; rash 4%; hypotension 4%. There were 2 AE-related deaths (febrile neutropenia and hepatic insufficiency). Conclusions: The addition of cetuximab to TPF IC in pts with unresectable SCCHN yields a high RR, mainly CR, potentially prolonging survival. Cetuximab TPF combination should be given to pts with good PS with specialized support provided.

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Phase I evaluation of vandetanib with radiation therapy (RT) ± cisplatin in previously untreated advanced head and neck squamous cell carcinoma (HNSCC)
Authors: Papadimitrakopoulou V. , Frank S. J. , Blumenschein G. R. , Chen C. , Kane M. , Cohen E. E. , Langmuir P. , Krebs A. D. , Lippman S. M. , Raben D.
Published: August 2020

6016

Background: Vandetanib is a once-daily oral anticancer agent that selectively targets VEGF, EGF and RET receptor tyrosine kinases. We report preliminary results from an ongoing open-label phase I study of vandetanib with RT ± cisplatin in patients (pts) with previously untreated, unresected, locally advanced (stage III-IV) HNSCC. Methods: Eligible pts received once-daily vandetanib for 14 days followed by either 1) concomitant vandetanib + RT (2 Gy/d, 5 d/wk; total 70 Gy) + cisplatin (30 mg/m2, 2 h iv infusion/wk) for 7 wks, or 2) concomitant vandetanib + RT (2.2 Gy/d accelerated fractionation, 5 d/wk; total 66 Gy) for 6 wks. The primary objective was to determine the safety, tolerability and maximum tolerated dose (MTD) of vandetanib in both regimens. The first pt cohort received vandetanib 100 mg/day; escalation to 200 mg and 300 mg in subsequent cohorts was permitted providing <2/6 (33%) pts in the preceding cohort experienced a dose-limiting toxicity (DLT). Cohort expansion at the MTD of vandetanib was also planned. Results: As of Dec 1 2008, 24 pts (median age 53.5 yrs; 19 male; all M0) had received treatment with vandetanib + RT + cisplatin (n=18) or vandetanib + RT (n=6). In the triplet arm, no DLTs occurred in the initial vandetanib 100 mg cohort (n=6); an additional 6 pts were enrolled to receive vandetanib 200 mg but this dose was considered to exceed the MTD since DLTs were reported in 3/5 evaluable pts (Table). Vandetanib 100 mg was therefore declared the MTD with RT + cisplatin and cohort expansion at this dose continues. In regimen 2), 6 pts have received vandetanib 100 mg + RT and evaluation of this initial cohort is ongoing. Conclusions: This study, which continues to recruit, is the first to evaluate dual targeting of VEGFR/EGFR tyrosine kinases with chemoradiation or radiation alone in HNSCC pts. Among the 24 treated pts, 2 have completed the 2-year follow up, 1 death occurred that was causally related to cisplatin, and 21 remain in follow up or continue to receive treatment.

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Final results of a 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. , Okano S. , Fuse N. , Minashi K. , Yoshino T. , Doi T. , Minami H. , Ohtsu A.
Published: August 2020

6021

Background: An oral fluoropyrimidine, S-1, has shown high efficacy against head and neck cancer (HNC), with a response rate of 34%. We investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin and S-1 (TPS) in patients (pts) with locally advanced or recurrent/metastatic HNC. Methods: Eligibility criteria were histologically proven HNC, PS 0–1, age ≤75 years, adequate organ function, and no prior chemotherapy. Treatment consisted of 1-hour infusion of docetaxel at escalating doses of 50, 60 and 70 mg/m2, 2-hour infusion 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. This regimen was repeated every 3 or 4 weeks. Pts with locally advanced HNC received concurrent chemoradiotherapy after completion of 3 cycles of TPS. Results: Forty pts were enrolled, consisting of 33 males and 7 females with a median age of 50 years (range 22–74 years). Twenty-nine cases were locally advanced cancer and 11 were metastatic cancer. 116 cycles (median = 3, range 1–6) were administered in 6 dose levels. Grade 3 or 4 hematological toxicities were neutropenia (59%), febrile neutropenia (13%), and anemia (8%), whereas no grade 3 or 4 thrombocytopenia was seen. Two dose-limiting toxicities (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg/m2/day every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 pts treated at dose level 6 (TPS: 70/70/60 mg/m2/day every 3 weeks), three DLTs were seen, namely one grade 3 diarrhea, one grade 3 ALT/AST and one grade 2 creatinine elevation. Of a total of 40 pts, 6 achieved a complete response and 22 a partial response according to RECIST, giving an overall response rate of 70%. Conclusions: The TPS combination was well tolerated. The recommended phase II dose was determined to be TPS at 70/70/60 mg/m2/day every 3 weeks. Antitumor activity was highly promising, and warrants further investigation.

No significant financial relationships to disclose.
Phase II study of sunitinib in patients with recurrent and/or metastatic squamous head and neck carcinoma: The GORTEC 2006–01 study
Authors: Machiels J. H. , Henry S. , Zanetta S. , Kaminsky M. , Michoux N. , Bompas E. , Dillies A. , Faivre S. , Schmitz S. , Guigay J.
Published: August 2020

6024

Background: Up to 90% of head and neck squamous cell carcinoma (HNSCC) express the vascular endothelial growth factor (VEGF) or the VEGF receptors (VEGFR) 1–3. Angiogenic factors could have prognostic implication making anti-angiogenic therapies an attractive treatment modality. Sunitinib inhibits multiple tyrosine kinase receptors including VEGFR1–3 and PDGFR. Methods: Palliative HNSCC in PD after platinum therapy received sunitinib 37.5 mg/day continuously. The primary endpoint was the disease control rate (SD, PR, CR) at 6–8 wks. A two-stage design was used (Simon; a = 0.15,b = 0.10, H0 = 10%, H1 = 25%) meaning that at least 6 patients out of 37 should achieve a SD. Dynamic contrast enhanced (DCE) magnetic resonance (MR) perfusion-weighted imaging before and 6 wks after treatment initiation was performed on a 3T system. Results: 37 pts (M/F:28/9;PS 0/1:5/32) were included.11 pts were not evaluable by imaging due to rapid clinical PD (7 pts) or toxicity (4 pts) and were considered in PD.PR was found in 1 pts, SD in 18, and PD in 18 (RECIST). Among the SD, 6 had a minor response and 5 had an unconfirmed PR (maximum % reduction in sum of the largest diameters: 2%, 4%, 7%, 10%, 16%, 17%, 30%, 45%, 48%, 65%, 73%). PR could not be confirmed due to PD within 4 wks (3 pts) or treatment termination due to toxicity (2 pts). 4 pts had MR DCE monitoring. In 3, a significant decrease in the volume transfer constant Ktrans measuring the tumor perfusion and endothelial permeability was found during sunitinib treatment. The main Gr3–4 toxicities (N pts) were fatigue (12), tumor bleedings (2), LVEF decrease (2), hypertension (2). Gr5 tumor bleedings occurred in 4 pts. Other local complications included apparition/worsening of tumor skin ulceration or tumor fistula in 15 pts. Conclusions: This trial met its primary endpoint with modest activity of sunitinib in HNSSC. The rate of complications (i.e., fatal bleedings) outlines the importance of a better patient selection. DCE-MRI may be useful to predict response.

No significant financial relationships to disclose.
Use of DNA repair pathway analysis to predict overall survival in head and neck cancer patients treated with TFHX chemoradiotherapy
Authors: Seiwert T. , Weaver D. T. , Wang X. , Kutok J. , Cohen E. , Stenson K. , Vokes E.
Published: August 2020

6033

Background: Concurrent chemoradiotherapy is a standard-of-care for head and neck cancer. Radiotherapy and chemotherapeutic agents damage DNA; lack of adequate repair induces tumor cell death. The network of DNA repair pathways was examined to predict TFHX chemoradiotherapy outcomes. Methods: Biopsy specimens (paraffin) from 60 HNC patients were evaluated from tissue microarrays. Samples originated from patient groups from phase I/II studies: 1) poor-prognosis radiation-naïve, 2) re-irradiation. All were treated with TFHX-based chemoradiotherapy. DNA repair biomarkers XPF, pMK2, PAR, pH2AX, FANCD2, ATM, BRCA1, RAD51, ERCC1 (clone 8F1), and p53 were explored using IHC, automated image processing, and machine reading (>500 cells/read), for nuclear and cytoplasmic quantity, area, and intensity, and correlated with clinical outcome. Results: There was low inter-core variability per tumor with median patient ranking signal to noise ratio of 15.0 across all markers. Patients were stratified into short and long survival groups by determination of critical marker thresholds. Five DNA repair biomarkers (RAD51, ATM, BRCA1, XPF, FANCD2) exhibited univariate significance for overall survival (p = 2.65e-3, 1.53e-2, 4.77e-4, 8.57e-5, 1.32e-3)(additional clinical parameters multivariate analysis was not feasible due to sample size). ERCC1 was not statistically significant (p = 1.0). Pairwise biomarker combinations improved survival group discrimination. Combination of 4 DNA repair biomarkers (FANCD2, BRCA1, ATM, XPF) was also significant (p = 1.31e-4). Discriminant analysis demonstrated higher fractions of correctly identified patients in good/poor survival groups from four-marker tests. Conclusions: Five DNA repair biomarkers predicted overall survival following TFHX-based chemoradiotherapy. By contrast ERCC1 (8F1) was not significant. Combination of markers improved predictive ability in this study. The analysis of DNA repair pathways, particularly in homologous recombination, DNA damage response, and nucleotide excision repair, may be clinically useful. Validation in a larger, homogeneous patient population, and using platinum-based chemoradiotherapy, is indicated and currently ongoing.

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Feasibility and toxicity of docetaxel before or after fluorouracil, epirubicin, and cyclophosphamide as adjuvant chemotherapy for early-stage breast cancer
Authors: Abe H. , Umeda T. , Kawai Y. , Tanaka M. , Shimizu T. , Chou H. , Kubota Y. , Mekata E. , Kurumi Y. , Tani T.
Published: August 2020

604

Background: As adjuvant chemotherapy for breast cancer, the addition of docetaxel to regimens containing anthracyline has been shown to be effective. However, tolerance and safety associated with the administration order of the two drugs have not been evaluated. Methods: Breast cancer patients with node-positive or high-risk patients with node-negative were eligible. The treatment completion rate and toxicity were evaluated in 2 arms who underwent a total of 6 courses of the following regimens: Arm A: 3 courses of fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC100: q3w) followed by 3 courses of docetaxel (DOC100: 100 mg/m2, q3w); and Arm B: 3 courses of DOC100 (q3w) followed by 3 courses of FEC100 (q3w). Results: June 2006 to April 2008, 42 patients were registered. To the present, analysis has been completed in 21 patients in arm A and 21 in arm B. The mean age of patients was 49.1 years and 53.8 years, respectively. In arm A, the stage of cancer was 1 in 4 patients, 2a in 10, and 2b in 7, in arm B, the stage of cancer was 1 in 3 patients, 2a in 9, and 2b in 9. The adjuvant chemotherapy completion rate was 100 % for arm A and 95.2 % for arm B. The relative dose intensity (RDI) was 94.2 % for FEC100 and 97.8 % for DOC100 in arm A, and 98.9 % for DOC100 and 95.2 % for FEC100 in arm B. In arm A, grade 3 or higher hematological toxicity was observed in 9 patients, and febrile neutropenia developed in 3 patients with FEC100. In arm B, grade 3 or higher hematological toxicity was observed in 7 patients, but febrile neutropenia was not noted in any patients. Grade 3 or higher non-hematological toxicity was observed with FEC100 in 2 patients each in the two arms. Grade 1 or 2 edema developed in 11 patients with DOC100 in the two arms. Conclusions: In both arm A and B, adverse events associated with FEC100 were frequently observed but spontaneously recovered, or adequate management was possible by supportive therapy. Adverse events associated with DOC100 were mild. The regimens in both arms A and B were safe regarding adjuvant chemotherapy for early stage breast cancer. However, DOC100 followed by FEC100 may be more tolerable and effective.

No significant financial relationships to disclose.
Upfront chemotherapy and accelerated radiotherapy with EGFR inhibition for locally advanced inoperable head and neck cancer
Authors: Mercke C. , Wickart-Johansson G. , Sjödin H. , Adell G. , Nyman J. , Haugen H.
Published: August 2020

6040

Background: Concomitant chemoradiotherapy (CT/RT) is the standard treatment for locally advanced head and neck squamous cell carcinoma. However, late toxicity is substantial.This phase II trial explores the feasibility and efficacy of combining neoadjuvant TPF and accelerated RT where the concomitant cytostatic component is replaced with cetuximab (E), a chimeric IgG1 mAb against EGFR. Methods: Patients (pts) had previously untreated stage III/IV M0,WHO 0–1, unresectable squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx and were scheduled for 2 cycles of TPF (docetaxel 75 mg/m2 and cisplatin 75 mg/m2 day 1 and 5-FU 1,000 mg/m2 96 hours CI) every 3 weeks followed by RT (68 Gy/4.5 weeks) with E given one week before (400 mg/m2) and weekly during RT (250 mg/m2). A brachytherapy boost of 8 Gy was given to pts with oral cavity or oropharyngeal tumours. Neck dissection was planned for pts with N2–3 and complete response (CR) at the primary tumour. Tumour response was evaluated according to RECIST with CT, MRI or PET/CT after CT and at 6 weeks follow up. Toxicity (CTC 3.0) and quality of life (EORTC QLQ 30) was registered during and after treatment. Results: From 070401 to 081115 68 pts were enrolled, 56 had stage IV disease (T4, n = 14, N3, n = 9). Median age 57, 60 males, 3 oral cavity, 44 oropharynx, 10 larynx, and 11 hypopharynx. 30 pts were followed beyond 6 weeks and evaluated for response and early toxicity: stage IV disease 24 (T4, n = 6, N3, n = 3), median age 60, 25 males, 18 oropharynx, 5 larynx, and 7 hypopharynx. Remissions after TPF/after RT: CR 1/10, PR 15/18, SD 14/1, and PD 1. TPF as prescribed: 28/30 (pat refusal 1, renal insuff 1, dose reduction 0/28); E as prescribed: 22/30 (dermatitis 4, hypersensitivity 3, liver tox 1). Vital tumour in resected specimen 0/13. Alive at follow-up 29/30 (1 local failure). Conclusions: TPF followed by RT concomitant with E is feasible with manageable toxicities. Dermatitis in the irradiated neck, at least with the present accelerated fractionation, is troublesome to some patients but does not interrupt treatment and heals rapidly. To dispose of feeding tubes after disappearance of acute mucosal reactions has not been a problem. Early survival results are promising. Toxicity and survival results will be updated.

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TPF induction chemotherapy (CT) followed by concomitant cisplatin/radiotherapy (cCTRT) in locally advanced nasopharyngeal cancer (LANPC)
Authors: Bossi P. , Parolini D. , Bergamini C. , Locati L. D. , Orlandi E. , Franceschini M. , Palazzi M. , Olmi P. , Potepan P. , Licitra L.
Published: August 2020

6046

Background: Recent meta-analysis showed better event free survival in LANPC with induction CT. In head and neck cancer, docetaxel, cisplatin and 5 FU (TPF) induction chemotherapy led to survival gain over cisplatin and 5FU alone. We studied feasibility and activity of TPF induction CT followed by cCTRT in LANPC. Methods: From October 2004 to May 2008, 45 pts with LANPC were treated at our Institution with 2 to 4 cycles (median 3) of induction TPF (docetaxel 75 mg/sm and cisplatin 75 mg/sm on day 1, and 5-FU 750 mg/sm/day ci for 96 hrs. Prophylactic ciprofloxacin was administered for 10 days each cycle, while use of G-CSF was not allowed. Following CT, pts received full doses radiotherapy (RT) concurrent with cisplatin 100 mg/sm q 21 days. Intensity modulated radiotherapy (IMRT) was delivered to 34 pts (76%). All but two pts had non-keratinizing carcinoma. Stage IV pts were 60%, stage III 34%, and 6% stage II. T4 was present in 24% and N3 disease was diagnosed in 42% of the pts. Results: TPF was well tolerated, with main toxicity consisting in neutropenia (31% G3–4). Response rate was 87%. RT dose ranged from 64 Gy to 70 Gy (median 70 Gy). Main toxicities during cCTRT were: neutropenia (38% G3, 4% G4), febrile neutropenia (11% G3), thrombocytopenia (7% G3–4) and mucositis (40% G3, 4% G4). Nasogastric tube was placed in 33% of pts and maintained for a median of 40 days. During cCTRT, platinum compounds mean dose delivery was 75%, with 6 pts shifting to carboplatin for renal function impairment. Observed late toxicities were xerostomia (G3 in 38% of cases) and peripheral neurotoxicity (G1 in 27%, G2 in 7% and G3 in 2% of the pts). After treatment completion, complete and partial response were recorded in 78% and 20% of the pts respectively, while 1 pt showed stable disease. With a median follow up of 22 months (range 7 to 47), 9 pts showed recurrence or progressive disease (7 at local and/or regional level, 2 distant metastases and 1 at both sites), with a 2-years event free survival of 78% and an overall survival of 85%. Conclusions: TPF followed by cCTRT is feasible in LANPC. In this high-stage nonendemic population local-regional disease control still remains the main therapeutic goal. Supported in part by AIRC.

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A phase II trial evaluating weekly docetaxel and capacitabine in patients with metastatic or advanced, locally, recurrent head and neck cancer
Authors: Zhang J. , Lee J. S. , Urba S. , Worden F.
Published: August 2020

6051

Background: Docetaxel has documented clinical efficacy in head and neck cancer and the synergy between docetaxel and capacitabine has been shown in preclinical studies. Phase I studies combining docetaxel and capacitabine demonstrated anti-tumor effects in breast, colon, and bladder cancers. We therefore test this combination in patients with metastatic or locally advanced head and neck cancer. Methods: To be eligible for this single arm safety/efficacy phase II study, patients must have documented measurable advanced, locally recurrent or metastatic head and neck cancers, which were untreatable by surgical resection or radiation therapy, a Zubrob performance status of 0–2, adequate marrow, hepatic and kidney functions. Prior chemotherapy with non-docetaxel containing regimen was allowed. Docetaxel 30 mg/m2 was given on day 1, 8 and 15, while capecitabine 1,000 mg bid was given on days 5–18 of the 28 days cycle. Response to treatment was assessed after every 2 cycles. Patients with complete response (CR) received 2 additional cycles of therapy. Patients with partial response (PR) or stable disease (SD) continued to receive the therapy until they developed CR or progressive disease (PD). Patients with PD or unacceptable toxicity will be off the study. Results: 39 patients (33 male, 6 female) with a median age of 58.4 years were enrolled between September 2003 and April 2008. At baseline, 14/39 patients (36%) had local regional disease, 17/39 (44%) had distant metastasis, and 7/39 (18%) had both. 31/39 (79%) of the patients had prior chemotherapy. Responses at 4 months were analyzed on 36 patients: 5 patients (13%) had confirmed responses (2 CR, 3 PR) and 8 patients (20%) had stable diseases. Progression-free survival at 6 month was 34% (95% CI 19% - 49%). Major grade 3 and 4 toxicities were lymphopenia (8/39, 20%), infection without neutropenia (5/39, 13%) and fatigue (4/39, 10%). Conclusions: Weekly docetaxel and capacitabine are well tolerated and the disease control rate (33%) is comparable with the historical controls in patients with metastatic or advanced, locally, recurrent head and neck cancers.

No significant financial relationships to disclose.
Neoadjuvant chemotherapy followed by radiotherapy or chemoradiation for locally advanced nasal and paranasal sinus tumors
Authors: Hameed S. , Jamshed A. , Hussain R. , Ali M. , Iqbal H. , Majeed U. , Shah M. A.
Published: August 2020

6055

Background: The treatment of locally advanced nasal and paranasal sinus tumors is controversial. The disease is chemosensitive and there is increasing interest in the use of chemotherapy with radiation in this group of patients. Our aim was to determine survival in patients with locally advanced nasal and paranasal sinus tumors treated with neoadjuvant chemotherapy followed by radiotherapy or chemoradiation (RT/CRT). Methods: Between August 2005 and August 2008, 21 patients with AJCC stage III or IV nasal and paranasal sinus tumors were treated with neoadjuvant chemotherapy followed by RT/CRT in our institution. There were 15 males and 6 females (M 71%:F 29%) with a median age of 49 years (range 19 - 70 years). Site of disease was nasal cavity 33% (7), ethamoid sinus 43% (9), maxillary antrum 19% (4), and frontal sinus in 5% (1) of patients. Histopathological diagnosis was squamous cell carcinoma 43% (9), undifferentiated carcinoma 29% (6), adenocarcinoma 19% (4), esthesioneuroblastoma in 9% (2) of patients. Induction chemotherapy consisted of cisplatin 75 mg / metre2 day 1 and gemcitabine 1 gm / metre2 day 1 and 8 every three weeks. Eighty-five percent (18/21) received 2 cycles of neoadjuvant chemotherapy (range 1–4 cycles) prior to radiotherapy. Radiotherapy dose was 54 Gy - 70 Gy (median radiation dose 66 Gy). Fifty-seven percent (12/21) received concomitant cisplatin with radiotherapy. Results: Response to neoadjuvant chemotherapy; complete in 19% (4), partial in 67% (14), no response/progression 14% (3). Following RT/CRT 86% (18/21) had complete regression of disease. Thirty-three percent (7/21) have failed treatment (local 3, regional 2, and distant metastasis in 2 patients). Among treatment failures 2 patients were successfully salvaged; surgery for local recurrence in one patient and in the other case radiation was given for regional recurrence. Disease free and overall survival at 40 months was 52% and 63%, respectively. Conclusions: Gemcitabine cisplatin chemotherapy has good activity in nasal and paranasal sinus tumors. In combination with RT/CRT survival rates are encouraging and the approach merits further investigations in clinical trials.

No significant financial relationships to disclose.
A prospective, open-label, randomized phase II trial to evaluate the changes of bone resorption marker after administration of zoledronic acid (ZOL) in nasopharyngeal cancer (NPC) patients with bone metastases (BM)
Authors: Zhao Y. , Liao H. , Hou X. , Sun J. , Guo Y. , Li S. , Zhang L.
Published: August 2020

6063

Background: ZOL is the only bisphosphonate that has demonstrated efficacy for the prevention of skeletal-related events (SREs) in patients with BM in a wide range of tumor types. Recent retrospective analyses also showed that normalization of N-telopeptide of type I collagen (NTX) over 3 months by the treatment of ZOL provided a continuum of SRE risk reduction and survival benefit in patients with BM (Lipton et al. ASCO 2007). Therefore, we conducted the prospective open-label randomized phase II trial to evaluate the changes of NTX after administration of ZOL in NPC patients with BM. Methods: Newly diagnosed NPC patients with BM were randomized to receive chemotherapy of cisplatin (20mg/m2 IV, D1–5) plus FU (500mg/m2 IV, D1–5) (CF regimen, q3wks) and intravenous ZOL (4mg, q4wks, for 3months, CF+ZOL Group) or the same chemotherapy alone (CF Group). Urinary NTX was measured by ELISA method (Coleman et al. JCO 2005) at baseline and 1, 2, 3 months after administration of ZOL in all patients. Results: Sixty patients were enrolled into the study, 30 patients in each group. The median chemotherapy cycles was the same (4 and 4, respectively) in two groups. The median baseline NTX level had no difference between the two groups (75.4 vs. 95.6 nM BCE/mM creatinine, respectively p>0.05). The NTX decreased 65.9% within 1 month in CF+ZOL group, whereas NTX increased 2.61 % in CF group (p<0.01). The median NTX decrease percentage in 2,3 months after treatment were 70.8%, 86.5% in CF+ZOL Group and 15.9%, 34.5% in CF Group respectively (p<0.01, p<0.01). Conclusions: ZOL administered with chemotherapy (CF) consistently reduced NTX levels in NPC patients with BM, indicating potential benefit of ZOL may exist in this group of patients. The value of NTX reduction in NPC patients with BM need to be further studied in larger prospective randomized trials.

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Synchronous and metachronous bilateral breast cancer: Are the risks greater in women with a history of radiation for Hodgkin lymphoma?
Authors: Elkin E. B. , Gonzales A. R. , Ishill N. M. , Klem M. L. , Hodgson D. , Ng A. K. , Marks L. B. , Weidhaas J. , Freedman G. M. , Miller R. C. , Yahalom J.
Published: August 2020

607

Background: Women with a history of radiation therapy (RT) for Hodgkin lymphoma (HL) have an elevated risk of breast cancer (BC). The characteristics, treatment and outcomes of these cancers, compared with sporadic breast cancers, are not well described. In particular, rates of synchronous and metachronous bilateral BC may be greater in patients with a history of RT for HL. Methods: Women diagnosed with BC between 1980 and 2006 following RT for HL were identified retrospectively from 8 institutions in North America. Each patient in this cohort was matched with 3 BC patients with no history of HL, from the same institution, by age at BC diagnosis, year of BC diagnosis and race. Information on patient and tumor characteristics, disease recurrence and new contralateral tumors was obtained from medical records. Analysis of metachronous contralateral breast cancer (CBC) was limited to women with a breast at risk, and adjusted hazard ratios (HRs) for CBC were estimated using Cox proportional hazards regression. Results: 253 BC patients with a history of RT for HL were matched with 741 patients with sporadic BC. The median interval between HL and first BC diagnosis was 19 years. Median age at BC diagnosis was 44 years and median follow-up was 5 years from BC diagnosis. Synchronous bilateral BC was diagnosed in 6% of the HL survivors and 2% of the matched patients with sporadic BC. Among women with unilateral disease, 21% of HL survivors and 3% of sporadic BC patients had a bilateral mastectomy. Overall 64 women with a breast at risk developed metachronous CBC. BC patients with a history of RT for HL had a greater rate of metachronous CBC (adjusted hazard ratio 3.3, 95% CI 2.1–5.8), controlling for patient, tumor and treatment characteristics. In addition, those who received chemotherapy for BC were less likely to develop CBC (adjusted HR 0.51, 95% CI 0.31–0.85), and those with a family history of BC in a 1st degree relative were more likely to develop CBC (adjusted HR 1.8, 95% CI 1.1–3.0). Conclusions: Women who develop BC after RT for HL have more than 3 times the risk of CBC than similar women with sporadic BC. Our findings support close follow-up for CBC in BC patients with a history of RT for HL and may inform decisions about prophylactic mastectomy in this population.

No significant financial relationships to disclose.
A pan-European survey to gauge public awareness and understanding of head and neck cancer and associated risk factors
Authors: Leemans C. R. , Lefebvre J. , Vermorken J. B.
Published: August 2020

6073

Background: Head and neck cancer is the sixth most frequently occurring cancer worldwide yet there appears to be little awareness of this disease amongst the general public in Europe. As part of an ongoing program to fully understand the patient perspective, the ‘About Face’ survey was planned and conducted in collaboration with the European Head and Neck Society to gauge current awareness and understanding of head and neck cancer and its associated risk factors. Methods: A total of 7,520 Omnibus internet interviews were conducted in 7 European countries (FR, DE, IT, NL, SP, SW, UK) in September 2008. Results: Only 23% of respondents overall were aware of the term ‘head and neck cancer.’ While most symptoms of head and neck cancer were recognized; the majority were cited correctly by fewer than half of respondents; 60% believed that ‘head and neck cancer’ includes tumors of the brain. Sixty-one percent of those surveyed underestimated the incidence of head and neck cancer in Europe by at least a factor of 10. While the majority recognized the link between head and neck cancer and smoking or high alcohol intake, far fewer were aware of the role of excessive sun exposure or HPV infection in disease etiology. One in four respondents felt that the consequences of surgery would cause the most distress to a person diagnosed with the disease. Conclusions: There is a general lack of knowledge amongst the general public in Europe of the risk factors and symptoms of head and neck cancer. This is a significant issue that should be addressed as these data suggest that patients may be more likely to delay consulting a physician and therefore be diagnosed with this difficult-to-treat disease at a late stage. Further education of the public on head and neck cancer is warranted.

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