bluuebunny/crossref_metadata_2025 huggingface dataset:
Initial results from a phase II trial of motesanib diphosphate (AMG 706) in patients with differentiated thyroid cancer (DTC)
Authors: Sherman S. I. , Schlumberger M. J. , Droz J. , Hoffmann M. , Wirth L. , Bastholt L. , Martins R. G. , Licitra L. , Shi Y. , Stepan D. E.
Published: March 2020

6017

Background: This phase 2 study evaluated the safety and efficacy of AMG 706, an oral, investigational multikinase (MKI) inhibitor with antiangiogenic and direct antitumor activity achieved by selectively targeting VEGF, PDGF, and Kit receptors and RET, in pts with advanced DTC or medullary thyroid cancer (MTC). Presented here are results from the DTC stratum. Methods: This was a multicenter, phase 2, open-label, single-arm study of pts with advanced thyroid cancer stratified by DTC or MTC (planned n=80 each). The primary endpoint was objective tumor response per modified RECIST by independent central review. Secondary DTC endpoints were duration of response and progression-free survival (PFS). Pts = 18 yrs with progressive, 131I-resistant disease, ECOG 0–2, and no prior treatment with VEGFr MKIs received AMG 706 125mg QD until disease progression or unacceptable toxicity. Assessments included tumor response (q8w), pharmacokinetics (PK), and safety. Results: 93 pts with DTC were enrolled and received at least 1 dose of AMG 706. DTC subtypes were: papillary, 58%; Hürthle cell, 18%; follicular, 16%; other, 8%. Median (range) age was 62 (36–81) yrs. 20% of pts had prior chemotherapy; 96% had prior 131I therapy. With median follow-up of 32 wks, objective tumor response (CR or PR) rate (95% CI) was 12% (6.1, 20.2); SD, n=64 (69%; durable SD =24 wks, 24%); PD, n=7 (8%). Median (95% CI) time to response was 103 (53, 161) days; median PFS was 276 (221, not estimable) days. 85% of pts were alive >8 months after starting therapy. All pts (100%) had some treatment- emergent adverse events (AE): grade 3, 55%; grade 4, 10%; grade 5, 5% (all grade 5 were deemed unrelated to AMG 706). Common AEs included diarrhea (70%; 11% grade 3), fatigue (58%; 5% grade 3), hypertension (49%; 22% grade 3), headache (43%; 4% grade 3), nausea (40%; 2% grade 3), and hypothyroidism and/or increased TSH (17%; no grade 3); none of these were grade 4 or 5. 6% of pts had cholecystitis. PK results showed that AMG 706 PK at 125mg QD was comparable to data obtained in other monotherapy studies at the same dose level. Conclusions: In this study of pts with advanced 131I-resistant DTC, AMG 706 showed encouraging antitumor activity and had tolerable and manageable toxicities. Further investigation is warranted.

No significant financial relationships to disclose.
Sorafenib targets BRAF and VEGFR in metastatic thyroid carcinoma
Authors: Gupta V. , Puttaswamy K. , Lassoued W. , Redlinger M. , Ransone K. , Gold K. , Lee W. , LiVolsi V. , Fraker D. , Mandel S. , Brose M. S.
Published: March 2020

6019

Background. There is no effective therapy for patients with metastatic thyroid cancer not cured by surgery or treatment with I131. Sorafenib is a promising multi-tyrosine kinase inhibitor for patients with metastatic PTC (mPTC). Although the primary targets of sorafenib are thought to include BRAF and VEGFR, this has been the subject of debate. Whether sorafenib primarily acts on the tumor cells (TC) or endothelial cells (EC) and how BRAF mutation status (45% of PTC harbor V600E) relates to response is also unknown. Methods. Responses of patients with metastatic, iodine-refractory PTC, enrolled into our phase II study of sorafenib were monitored by PET at 4 wks and CTs every 2 mos. Sorafenib activity was studied using immunohistochemistry (IHC) for pERK, pAKT, and pVEGFR-2, while Ki-67 showed proliferating cells in tumor tissue pre- and on treatment. BRAF mutation status was determined by DNA sequencing. Results. Of 15 patients, five patients achieved a PR, three are stable (SD), two progressed, and three patients with SD withdrew due to toxicity. Target lesions decreased on average 31%. Eight of 10 PET scans showed decreased activity at 4 weeks. IHC on tissue from 2 patients (at 1 and 2 wks, both BRAFwt) showed 50% decrease in pERK (downstream of VEGFR2 and BRAF) and 30% decrease in pAKT (downstream of VEGFR2). p-ERK and p-AKT were altered in both the TC and EC. Ki-67 decreased from 10% to <1%. No change in VEGFR-2 was seen; but, pVEGFR-2 completely disappeared in one sample while the other showed a small decrease. Quantitative analysis using a multispectral imaging system confirmed the changes observed by IHC. In tissue from a patient at 17 months on sorafenib, the decrease in pERK and pAKT appeared to be the same or reversed, suggesting compensatory changes in these pathways in resistant but stable disease. Conclusions. Our study shows the early clinical and biologic activity of sorafenib in patients with mPTC and the targets of early suppression. Importantly, it also reveals compensatory changes in target molecules in cells resistant to therapy. These cells are the likely source of tumor resistance that has been seen to develop to other similar targeted agents. Sorafenib is the first viable treatment option for patients with mPTC, and these results provide key insights into the mechanisms of action and resistance of this drug.

No significant financial relationships to disclose.
Corroboration of polymorphisms in the aromatase (CYP19A1) gene with response to neoadjuvant therapy with letrozole in postmenopausal women with stages II-II ER/PgR-positive breast cancer
Authors: Lopez-Guerrero J. A. , Garcia-Casado Z. , Guerrero-Zotano A. L. , Calatrava A. , Ruiz-Sauri A. , Fernandez-Serra A. , Ruiz A. , Llombart-Bosch A. , Guillem-Porta V. , Llombart-Cussac A.
Published: March 2020

602

Background: Aromatase (CYP19A1) is the main enzyme implicated in estrogen biosynthesis. Polymorphisms in CYP19A1 can affect both aromatase expression and activity leading to changes in the estrogen levels. These changes have been previously associated with pathogenesis of estrogen-dependent diseases, including breast cancer. The purpose of this study is to evaluate whether the genotype of CYP19A1 can have an effect on the response to endocrine therapy with the aromatase inhibitor letrozole (L). Methods: We retrospectively analyzed a series of 58 postmenopausal women with stage II-III ER/PgR[+] breast cancer treated with L as neoadjuvant therapy. Response was evaluated by radiology (mammogram or ultrasound) at four months L (OMS) and data was available in 56 cases. A total of ten single nucleotide polymorphisms (SNPs) spanning the gene, a TCT insertion/deletion and a (TTTA)n repeat were evaluated. The (TTTA)n repeat was analyzed by using GeneScan to detect polymorphism length, TCT Ins/Del by direct sequencing and SNPs by allelic discrimination using TaqMan SNP Genotyping Assays (Applied Biosystems). Logistic regression analysis was used to estimate the most accurate predictive model for response to therapy. Results: Median age of our series was 77 years (range: 68 to 90). Twenty women (36%) responded to 4 months L, while 38 (67%) did not (2 PD and 36 EE). Allelic frequencies were determined for each polymorphism and the global genotype data was evaluated in a logistic regression analysis. In a first step, the analysis with the genetic information for the 12 polymorphisms resulted in a model that predicted radiological response to L with an accuracy of 80% (85% specifity, 69% sensibility). However, a reduction to 4 informative polymorphisms generated a simpler predictive model with an accuracy of 76% (76.5% specifity, 75% sensibility). Conclusions: Polymorphism analysis of CYP19A1 could predict for response to neoadjuvant therapy with L. A validation of this predictive model in an independent series is ongoing.

No significant financial relationships to disclose.
Concomitant chemoradiation versus radiotherapy in advanced squamous cell carcinoma of oropharynx and nasopharynx using weekly cisplatin: Final result of a phase III trial
Authors: Sharma A. , Mohanti B. K. , Thakar A. , Bahadur S. , Bhasker S. , Bahl A.
Published: March 2020

6030

Background: Studies have confirmed the role of concomitant chemoradiation (CTRT) in the treatment of advanced SCCHN, however, there is no large study reported from India. Consensus about type and schedule of the chemotherapy is unclear e.g. single agent Vs combination; daily/weekly/three weekly. This study was undertaken to know effectiveness of weekly Cisplatin (DDP). Methods: prospective randomized phase III study. 153 untreated stage II-IV oropharyngeal and nasopharyngeal cancer patients were randomly assigned to one of the two treatment arm; Arm (A) Radical radiotherapy 70 Gy/ 35# over 7 weeks; Arm (B) CTRT; Cisplatin 40mg/m2 weekly for 6 doses beginning day 1 of radiation treatment plus radiotherapy as in arm (A). The objective endpoints were- to know (i) the responses, (ii) toxicity profile and (iii) overall survival in the two treatment groups. Protocol was approved by local ethics committee. Study period was from June 2003 to July 2005. Results: Number of patients were 76 (A) and 77 (B) in two arms respectively. CR was 70.7 Vs 78.9% in arm A and B. Toxicity- grade III and IV toxicities were 16% and 40% respectively in 2 arms (p=<0.05). There were more frequent interruptions (9.3% Vs 28.9%) and hospitalization (20% Vs 40.8%) (p=<0.05) in CTRT arm. Survival- with median follow up of 17 months overall survival was significantly higher in CTRT arm (p=0.024); 27 months (95%CI 15.2–36.8) for RT Vs not reached (NR) for CTRT group. Three year OS was 42% Vs 62% respectively. Conclusion: This trial confirms that CTRT using single agent weekly DDP is safe and superior to RT in advanced SCCHN but treatment interruptions and toxicities are of concern for developing country’s cancer care infrastructures.

No significant financial relationships to disclose.

[Table: see text]
Long-term outcomes with concurrent carboplatin, paclitaxel, and radiation therapy in locally advanced, inoperable head and neck cancer
Authors: Ferris R. L. , Agarwala S. S. , Cano E. , Heron D. E. , Johnson J. , Myers E. , Sandulache V. , Wang Y. , Bahri S. , Argiris A.
Published: March 2020

6032

Background: Our goal was to evaluate long-term outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) treated with carboplatin, paclitaxel, and radiotherapy. Methods: We conducted a phase II trial in inoperable patients with locally advanced SCCHN. Carboplatin 100 mg/m2 and paclitaxel 40 mg/m2 were administered intravenously once a week during external beam radiotherapy (once daily, 180 cGy/fraction) for 6–7 weeks. Interstitial brachytherapy was used as a boost in selected patients with primary malignancies of the oral cavity and the oropharynx. Results: 55 patients were enrolled. 52 patients (95%) had stage IV and 51 (93%) had technically unresectable disease; 62% had an oropharyngeal primary site. 21 patients underwent brachytherapy boost. Grade 3 or 4 mucositis occurred in 30% of patients. One death occurred during treatment; it was related to complications of gastrostomy tube (G-tube) placement. Forty of 50 evaluable patients (80%) had an objective response, with a complete response rate of 52%. With a median follow-up of 69 months years for surviving patients, the 5-year progression-free survival (PFS) was 36% and the 5-year overall survival (OS) was 35%. Two of the 18 long-term survivors of >50 months were G-tube feeding dependent. Patients undergoing brachytherapy boost (n=21) had similar outcomes compared with the rest of the patients. In multivariate analysis, baseline hemoglobin levels and N stage were predictive of survival. Conclusion: Treatment with concurrent carboplatin, paclitaxel and radiation is safe and offers curative potential for poor prognosis patients with locally advanced SCCHN.

No significant financial relationships to disclose.
Randomized phase II study of concomitant chemoradiotherapy with 5-fluorouracil-hydroxyurea (FHX) compared to FHX and bevazicumab (BFHX) in intermediate stage head and neck cancer (HNC)
Authors: Choong N. W. , Haraf D. J. , Cohen E. E. , Stenson K. M. , Blair E. A. , Dekker A. , Williams R. , Karrison T. G. , Vokes E. E.
Published: March 2020

6034

Background: Preclinical data supports inhibition of vascular endothelial growth factor (VEGF) to improve tumor radiosensitivity. Phase I data demonstates that BFHX was tolerable in HNC (Seiwert, pASCO2006). Here we present preliminary toxicity data from a randomized phase II trial in pts with PS 0–2, stage II-IV (T2–4 N0–1 M0) HNC. Methods: Pts were randomized (2:1) to receive either BFHX or FHX. Planned sample size is 72pts. Chemotherapy consists of 5- FU (600 mg/m2/day continuous infusion for 120 hrs), hydroxyurea (500 mg PO q12 hours for 11 doses) with or without bevacizumab (10 mg/kg IV on day 1), concurrently with twice daily RT on a week on-week off schedule. Results: 21pts (BFHX 14pt and FHX 7pt) have completed therapy and are evaluable for toxicity. Pt characteristics in the BFHX and FHX arms are: median age 61 vs. 55 yrs, males 78% vs. 85%, stage II-III 57% vs. 86% and IV 43% vs. 14%. All pts have PS 0–1. 20 pts are evaluable for toxicity. Two episodes of gr3 leukopenia and one episode of gr 3 neutropenia were observed in the BFHX arm; whereas no gr3 hematologic toxicities were seen in the FHX arm. Mucositis (Gr3 - BFHX 85% vs. FHX 86%) and dermatitis (Gr3 - 0% vs. 14%) were observed in every pt. Other common non- hematologic toxicities were pain (100% vs. 86%), fatigue (77% vs. 86%) and anorexia (62% vs. 51%). No hemorrhagic events were observed. In the BFHX arm, one episode of deep venous thrombosis and one non-neutropenic death from sepsis were observed. Pathologic complete response rates were 92% and 100% in the BFHX and FHX arms, respectively. Conclusions: Preliminary results support the tolerability of BFHX. Toxicity appears to be similar to FHX with an apparent increase in leukopenia consistent with prior reports. Bleeding complications were not increased with BFHX.

No significant financial relationships to disclose.
Factors influencing performance of MRI in newly diagnosed breast cancer patients
Authors: Lehman C. , Gatsonis C. , Kuhl C. , Hendrick E. , Pisano E. , Hanna L. , Peacock S. , Smazal S. , Maki D. , Schnall M.
Published: March 2020

604

Background: There is wide variation in the use of breast MRI to screen the contralateral breast in patients recently diagnosed with unilateral breast cancer. Some centers routinely scan all patients with a recent diagnosis of breast cancer while others restrict breast MRI to patients with dense breast tissue, patients who are pre-menopausal, or patients with infiltrating lobular carcinoma. This international study evaluated performance measures of MRI by mammographic density, menopausal status and type of index cancer. Methods: 969 women from 21 sites with a recent diagnosis of unilateral breast cancer and a negative mammogram and CBE of the contralateral breast underwent breast MRI. Presence of breast cancer in the contralateral breast was determined by cancer positive breast biopsy within 12 months after study entry. Performance measures of breast MRI (cancer yield, sensitivity, specificity, negative predictive value, positive predictive value, biopsy rate) were compared between participant subsets defined by mammographic density (fatty vs dense), menopausal status (pre/peri menopausal vs post menopausal) and type of index cancer (invasive vs in situ and lobular vs non-lobular). Results: Performance measures of breast MRI were not influenced by breast density or index cancer histology. Cancer yield of MRI in dense breast women was 3% in both fatty and dense breasted women. Although cancer yield and sensitivity of MRI did not vary based on menopausal status, specificity was significantly higher among post-menopausal women in comparison to pre- or peri-menopausal women (p-value=0.002) as was positive biopsy rate (p-value 0.009). Conclusions: Performance of MRI in screening the contralateral breast in the newly diagnosed breast cancer patient is not influenced by breast density or index cancer histology. Specificity and positive biopsy rate are higher in post-menopausal women, which may be related to hormonal influences on breast tissue enhancement.

[Table: see text]
First safety and response results of a randomized phase III study with liposomal platin in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN)
Authors: Jehn C. F. , Siebmann S. , Pecher G. , Wernicke K. , Possinger K. , Lüftner D.
Published: March 2020

6040

Background: Cisplatin is one of the most active chemotherapeutic agents used in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN). However, its clinical efficacy is limited by its renal- and hematotoxicity profile. In a randomized, multicenter phase III trial, we replaced conventional cisplatin by a liposomal formulation of cisplatin (lipoplatin), and compared the safety and efficacy profiles of patients (pts) in the two treatment arms. Methods: Arm A: 100 mg/m2/d lipoplatin (d 1,8,15) plus 1,000 mg/m2/d 5-FU (d 1–5) q3w for 6 cycles; arm B: 100 mg/m2/d cisplatin (d 1) plus 1,000 mg/m2/d 5-FU (day 1–5) q3w for 6 cycles. Inclusion criteria: histologically confirmed SCCHN, age 18–75, renal function (creatinine clearance >50 ml/min) and primary metastatic disease or progressive SCCHN. Results: 62 pts were randomized, from which 43 pts (39 m; 4 w) were evaluable for outcome and toxicity. In the cisplatin arm hematotoxicity was more frequent (grades I/II: 28 pts, grades III/IV: 2 pts) than in the lipoplatin arm (grades I/II: 15 pts, grades III/IV: 3 pts). The rate of anemia was similar between the treatment arms. 13 pts in the lipoplatin arm experienced renal toxicity with (grade I: 3pts) and (grade II: 10 pts), as measured by a reduction of the creatinine clearance (grade I: 99–75 ml/min; grade II: 74–50 ml/min; grade III: <50 ml/min). Renal toxicity occurred in 8 patients in the cisplatin arm with 1 pt (grade I) and 3 pts (grade II), however 5 pts developed grade III. No renal toxicity grade III was developed in the lipoplatin arm until now. Outcome was as follows: lipoplatin arm: PR: 3 pts; SD: 13 pts; PD: 9 pts; cisplatin arm: PR: 8 pts; SD: 9 pts; PD: 1 pts. Thus, the non-PD pts (PR or SD) was 16/25 (64 %) in the lipoplatin arm vs 17/18 (94%) cases in the cisplatin arm. Conclusions: Liposomal platin seems to reduce both the renal and hematological toxicity as compared to conventional cisplatin to a clinically relevant extent. This reduction of side effects will influence the chance to preserve the dose density of chemotherapy, and thereby, the efficacy of treatment.

No significant financial relationships to disclose.
Cetuximab (C-mab) and chemo-radiation (CT-RT) for loco-regional advanced squamous cell carcinoma of the head and neck (HNC): A phase II study
Authors: Merlano M. C. , Numico G. , Russi E. G. , Benasso M. , Colantonio I. , Vigna Taglianti R. , Lanzilotta L. , Vigo V. , Bacigalupo A.
Published: March 2020

6043

Background: C-mab is a monoclonal antibody targeting EGFR. C-mab combined with radiotherapy (RT) improved loco- regional control and overall survival over RT alone in HNC pts (Bonner 2006). Prior data of C-mab and CT-RT (Pfister 2006) were encouraging but the trial was stopped due to an excess of severe toxicities, suggesting the need for a less toxic scheduling. For these reasons we evaluate the safety and activity of C-mab combined with alternating CT-RT in HNC pts. Methods: The primary end-point is C.R. rate. The optimal two stage design was used: the calculated sample size is 45 pts. Eligible pts have locally advanced, measurable, untreated, stage III/IV HNC (excluding nasopharynx). Chemotherapy (CT) consists of Cis-PT 20 mg/m2/day and bolus 5Fu 200 mg/m2/day from day 1 to 5, repeated on days 22 and 43. RT, 2 Gy/day, 5 days a week, is given in the pauses between the chemotherapy courses and after the last CT week, up to a total dose of 70 Gy. Results: From 10/2005 to 12/2006 24 pts were enrolled: median age 59 (49–75); median ECOG P.S. 0 (0–1); Stage IV 73%; N1–3 86%; EGFR >80% cells: 55%; EGFR 3+: 91%; most pts had hypopharynx cancer, only 1 had oral cavity tumor. Toxicity is evaluable on 20 pts (4 ongoing). Grade 3–4 toxicities included febrile neutropenia (20%), diarrhea (20%), hypomagnesaemia (10%), mucositis (60%). Unexpected skin toxicity, starting as desquamating moist dermatitis and confined at the irradiated field, occurred in 18/20 pts, usually during the second part of the treatment. Acute colon diverticulitis with perforation (1 pt), gastric perforation (1 pt), fatal myocardial infarction (1 pt) and arterial thrombosis (1 pt) also occurred. Responses, evaluated 3 months after the treatment, are available for the first 16 pts. Objective responses were observed in all them (11 CR + 5 PR). Two PRs were then rendered disease free with salvage surgery. At a maximum follow-up of 15 months, 16/20 pts are alive and 16/20 progression free. Conclusions: This trial showed a skin toxicity not previously reported in other experiences of C-mab combined with RT or CT-RT. Preliminary activity data seems to confirm the Pfister experience.

No significant financial relationships to disclose.
A randomized phase II study of concomitant CT (docetaxel±cisplatin) and (RT) in first-line treatment of locally advanced head and neck cancer (LAHNC)
Authors: Bouillet T. , Nizri D. , Zawadi A. , Herman D. , Cupissol D. , Demaux H. , Touboul E. , Cretin J. , Morere J. F.
Published: March 2020

6047

Background: 4 randomized trials demonstrated superiority of concomitant CT and radiotherapy (CRT) versus RT. Radiosensitizing effect of docetaxel showed in vitro, phase I recommended docetaxel dose as weekly 20 mg/m2 with concomitant RT. Methods: (pts) with inoperable LAHNC (T3/T4); PS < 2.RT in both arms was 70 Gy. In arm A, pts received 7 cycles of weekly Docetaxel 20 mg/m2 before RT and cisplatin 20 mg/m2 D1–3 every three weeks (3 cycles). In arm B, docetaxel alone at the same dose as in arm A.G-CSF secondary prophylaxis and ciprofloxacin recommended in both arms. Primary objective was WHO objective response rate (ORR). Statistical analysis: 2 steps according to a Simon plan authorized early interruption in case of insufficient efficacy. Results: 82 pts treated (Arms A/B:35/47); Arm A stopped in the first step. 47 pts treated in arm B. M/F (%) (83/17), median age 56.6 y, PS 0/1 (%) 54/46, T2/T3/T4 (%) 2/36/62, N0–1/N2/N3 (%) 30/55/15, primary site (%): buccal cavity (38), hypo-oropharynx (47), larynx (11). Median nbr of cycles 7 (3–7), 85% of pts completed planned CRT. ITT ORR: 89 % [75–96], median TTP 31.3 [19.3 –42.4], median OS 36.8 [21.2–49.5] months. Main grade 3–4 toxicities were mucositis (31.9%),skin toxicity (21.3%). Grade 3–4 hematological, GI and neurological toxicities were not observed. Conclusions: In this study, concomitant RT and weekly 20 mg/m2 docetaxel is effective and well tolerated in LAHNC. The docetaxel/cisplatin arm was prematurely discontinued for insufficient efficacy.

No significant financial relationships to disclose.
Phase II trial of pemetrexed (P) and bevacizumab (B) in patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC): An interim analysis
Authors: Karamouzis M. V. , Friedland D. , Johnson R. , Rajasenan K. , Branstetter B. , Argiris A.
Published: March 2020

6049

Background: P is a multi-targeted antifolate with single-agent activity in recurrent or metastatic HNSCC (RR 26%, Pivot et al. Br J Cancer 2001;85:649–55) and a preferable toxicity profile compared with cisplatin or the taxanes. B is a monoclonal antibody against the vascular endothelial growth factor that has been successfully incorporated in the treatment of other advanced solid tumors. Methods: Eligible pts had pathologically documented HNSCC, ECOG performance status 0–1, measurable disease, no history of bleeding diathesis or hemoptysis, and were not on anticoagulation. Pts had no prior systemic therapy for recurrent or metastatic HNSCC; chemotherapy as part of initial potentially curative therapy, but without P or B, was allowed if completed >6 months earlier. Treatment consisted of P 500 mg/m2 and B 15 mg/Kg, both given intravenously every 21 days, until disease progression or intolerable toxicity. All patients received folic acid, vitamin B12, and corticosteroid prophylaxis. The primary endpoint was the time to progression (TTP) with a sample size of 40 pts (one stage design) with planned interim safety analysis after the first 6 and 12 pts. Results: 14 pts have been enrolled. Median age 64 years (35–84); male/female 13/1; PS 0/1: 7/7; prior chemotherapy: 8; primary site: oropharynx (7), larynx (4), oral cavity (3). Median number of cycles 5 (1–10). With a median follow up of 5.5 months, median TTP was 6 months (95% CI, 4–8). 11 pts were evaluable for response using RECIST. Best response was CR: 2, PR: 3, SD: 6, PD: 0, with ORR 45%. There were no grade 4 toxicities in 14 evaluable pts; 2 pts had grade 3 hemorrhagic events in the first cycle (1 tumor-related and 1 due to gastric ulcer post gastrostomy tube placement), and both discontinued treatment. 3 other pts had grade 1–2 hemorrhagic events. The relationship of these events to treatment was difficult to ascertain. Other grade 3 toxicities were stomatitis, dysphagia, and fatigue (all occurred in 1 pt). Conclusions: Preliminary results show that P plus B is a novel, highly active regimen that may represent a new treatment paradigm in HNSCC. However, bleeding complications were frequent in pts with susceptibility to such events. Study accrual continues.

No significant financial relationships to disclose.
Phase II trial of docetaxel (T), cisplatin (P), and cetuximab (E) followed by concurrent radiation (RT), P, and E in locally advanced head and neck squamous cell carcinoma (HNSCC)
Authors: Argiris A. , Karamouzis M. V. , Heron D. E. , Smith R. , Ferris R. , Lai S. , Kim S. , Branstetter B. , Johnson J. , Grandis J.
Published: March 2020

6051

Background: E is a chimeric IgG1 monoclonal antibody against the external domain of the epidermal growth factor receptor that may enhance the efficacy of RT and chemotherapy. Our goal was to incorporate E in the induction and subsequent chemoradiotherapy of HNSCC. We report our preliminary results with TPE induction. Methods: Patients (pts) had pathologically documented HNSCC stage III/IV or selected stage II (base of tongue, hypopharynx, or nasopharynx), no prior therapy, ECOG PS 0–1, and adequate hematologic, kidney and liver laboratory parameters. Induction consisted of T 75 mg/m2 day 1, P 75 mg/m2 day 1, and E 250 mg/m2 days 1,8, and 15 (after an initial dose of 400 mg/m2 on cycle 1, day 1), repeated every 21 days × 3 cycles. Subsequently, pts received RT 70 Gy (2 Gy/day) with concurrent P 30 mg/m2 and E 250 mg/m2 weekly, followed by maintenance E for 6 months. Prophylactic antibiotics were given on days 5–14 of each TPE cycle. Tumor assessment was performed after induction (primary endpoint) and 8 weeks after RT. Sample size was 39; one-stage design; target overall response rate (ORR): 80%. Results: 21 pts have been enrolled to date: median age 55 (39–74); Male/Female: 18/3; primary site: oropharynx (n=13), larynx (n=5), and other (n=3); stage III/IV: 4/17. In 16 evaluable pts, ORR to TPE was 15/16 (94%), CR: 2, PR 13, SD 1. For the primary site (12 evaluable): CR 6, PR 5, SD 1; for the lymph nodes (14 evaluable): CR 1, PR: 12, SD 1. The pt with SD discontinued E in the first cycle due to recurring infusion reaction. Another patient had a grade (G) 3 infusion reaction on the first E administration and was removed from study. Other serious toxicities during TPE (n=20): grade (G) 3/4 neutropenia (n=4/n=7) without incidence of neutropenic fever, G 3 anemia (n=1), G 3 thrombocytopenia (n=1), G 3/4 hypomagnesemia (n=2/n=1), G 3 rash (n=1), G 3 fatigue (n=4), and G 3 diarrhea (n=1). 1 pt had sudden death due to myocardial infarction (autopsy) after the third cycle of TPE. Subsequent RT plus P and E was feasible. 10 pts completed RT and all remain progression-free. Conclusions: Preliminary results suggest that TPE has predictable and manageable toxicities and high activity in HNSCC. Accrual is ongoing and updated data will be available.

No significant financial relationships to disclose.
Impact of chemoradiotherapy for locally advanced head and neck cancer on swallowing function
Authors: Burke E. , Goguen L. , Tishler R. , Wirth L. , Posner M. , Hempel E. , Allen A. , Costello R. , Haddad R.
Published: March 2020

6054

Background: We examined the impact of chemoradiotherapy (CRT) on swallowing function in a group of patients treated for locally advanced head and neck cancer in an ongoing randomized phase II study with concurrent CRT, with or without Ethyol. Methods: Chemotherapy consisted of weekly carboplatin AUC 1.5 and paclitaxel at 45 /m2 for 4 weeks. Radiation was delivered using a 3 field technique with a concomitant boost schedule to a total dose of 72 Gy. Patients were randomized to receive or not receive daily subcutaneous Ethyol. Patients had video swallow studies at the start of radiation and 8, 12, 24 and 52 weeks post chemoradiotherapy. Dysphagia and weight loss were monitored. Video swallow study reports were collected and the incidence of penetration, aspiration, pharyngeal residue and upper esophageal narrowing analyzed. Results: Baseline data were available for 31 patients out of 43 enrolled. 29% of the patients penetrated, 6.4% aspirated and 29% had pharyngeal residue. Patients on both arms of the study had a steady decline in swallowing function from onset until 24 weeks post radiation. Penetration, aspiration and pharyngeal residue were consistently noted at all time points and improvements in deglutition were seen on the 52-week post radiation video swallow. Forty percent of the patients (17/43) had narrowing in the upper esophagus. On average, a third of the patients examined required dilations. The remaining patients with esophageal narrowing were able to advance their diet and have their feeding tubes removed without dilations. The average time from the end of the treatment to PEG removal was 219 days. Conclusion: Based on the video swallow studies that were conducted, patients had a gradual decline in swallowing function from initiation of CRT until 24 weeks post. Esophageal narrowing was common, often requiring dilation. Given that it takes 7 months on average for the feeding tubes to come out, we recommend that these patients undergo intensive swallowing therapy and continuous long term follow up and assessment at two and possibly three years post CRT. Study is ongoing.

No significant financial relationships to disclose.
Clinical significance of ERCC1 expression in advanced squamous cell carcinoma of the head and neck treated with cisplatin- based concurrent chemoradiation
Authors: Jun H. , Ahn M. , Kim H. , Park B. , Han J. , Ahn Y. , Jeong H. , Son Y. , Baek J. , Park K.
Published: March 2020

6061

Background: The cytotoxic effect of cisplatin is based on the DNA cross linking. Nucleotide excision repair is associated with resistant to platinum-based chemotherapy. The excision repair cross-complementation group 1 (ERCC1) enzyme plays a rate-limiting role in nucleotide excision repair pathway. We evaluated the expression of ERCC1 as a predictive factor for survival in patients of squamous cell carcinoma of the head and neck (SCCHN) treated with cisplatin-based concurrent chemoradiotherapy (CCRT). Methods: We reviewed the clinical records and pathologic specimens of locally advanced SCCHN patients who had been treated with cisplatin-based definitive CCRT between 1995 and 2005. ERCC1 expression of the biopsy specimen was assessed by immunohistochemical (IHC) staining and a semi- quantitative grading system (H-score) was used for the evaluation. The median value of the H-score was chosen as the cutoff point for positive ERCC1 expression. Results: A total of 44 specimens and clinical data of the patients were reviewed. The median age was 59 years (range; 27–75), and 81.8% were male; 94.2% had ECOG performance status 0–1. The positive ERCC1 expression rate was 54.5% of all specimens (N=24/44). Overall tumor response rate for CCRT was 90.9% (CR=65.9%; PR=25.0%). With a median follow-up of 45.9 months (range; 5.4–133.0), 5-year progression free survival (PFS) rate was 58.0% and 5-year overall survival (OS) rate was 57.2%. Patients in group of positive ERCC1 expression showed poor survival in terms of PFS and OS (p=0.04; p=0.05), compared with negative ERCC1 expression group. Conclusions: The positive ERCC1 expression might be a predictive factor for poor survival and early progression in patients with locally advanced SCCHN treated with cisplatin-based CCRT.

No significant financial relationships to disclose.
Influence of preoperative MRI on the surgical management of patients with operable breast cancer
Authors: Braun M. W. , Pölcher M. , Schrading S. , Zivanovic O. , Kowalski T. , Flucke U. , Leutner C. , Park - Simon T. , Rudlowski C. , Kuhn W. , Kuhl C. K. Christiane
Published: March 2020

613

Background:
To evaluate the impact of preoperative magnetic resonance imaging (MRI) of the breast on the clinical management of patients with operable breast cancer (BC).
Methods:
Retrospective analysis of 160 patients with operable breast cancer (stages Tis, through T4), who were treated from 2002 through 2004. All patients underwent a full mammographic assessment, high frequency breast ultrasound, and breast MRI. The impact of preoperative MRI was evaluated for each patient with regard to changes in the therapeutic procedure. Patient and tumor characteristics were analysed to identify possible patient subgroups that predominantly benefit from preoperative MRI.
Results:
Preoperative MRI affected the clinical management in 44 of 160 patients (27.5%). In 30 cases (18.75%) additional in-situ or invasive cancers or a more widespread tumor extent were diagnosed correctly which went undetected by clinical palpation, mammography, and breast ultrasound. In 14 cases (8.75%) additional, surgical procedures were performed based on suspicious MRI findings with benign pathology. Age, menopausal status, breast density, tumor characteristics (type, tumor size, grading), ER-, PR- and HER2- receptor features did not significantly differ between patients in which breast MRI affected the clinical management and patients that experienced no additional information from MRI.
Conclusions:
Preoperative breast MRI changes surgical management in a considerable amount of patients with operable breast cancer. MRI detects additional invasive carcinoma and proves to be a meaningful supplement to the conventional work-up in the clinical management of breast cancer. This benefit is independent from patients and tumor characteristics.

No significant financial relationships to disclose.
Deriving valid utilities for comparing treatments in clinical trials using standard quality-of-life (QoL) questionnaires
Authors: Grimison P. S. , Simes R. J. , Stockler M. R.
Published: March 2020

6500

Background: Treatments for cancer have a myriad of beneficial and harmful effects. Benefits include prolonging survival and relieving cancer symptoms. Harms include side effects, inconvenience and costs. Assessing the overall impact of treatments requires a single, precise measure of net benefit, which combines information about health-related QoL, disease control and survival. Our aim is to develop a system for converting data from a QoL questionnaire into valid utilities, which allows comparison of treatments tested in clinical trials using utility measures and quality-adjusted survival analysis. Methods: 200 cancer patients previously completed the Utility-Based Questionnaire-Cancer (UBQ-C), a validated cancer-specific QoL measure which includes scales of health status (1 item), overall QoL (1 item), disabilities (12 items) and distresses (20 items); and were interviewed to elicit utilities using time trade-off (TTO) techniques. Scores were standardized to a scale bounded by 0 (worst outcome or death) and 1 (best possible health). A global QoL measure was derived from a weighted combination of the UBQ-C scales. Linear regression of overall health status on scales determined the weights. An equation to convert global QoL into utility was derived. Results: The global QoL measure as derived from the UBQ-C scales was more precise than the single- item scales. Median scores (IQR) were much lower for the global QoL measure: 0.77 (0.65–0.85) than for the direct measure of utility: TTO 0.98 (0.85 to 1.0). The best model to predict utility from derived global QoL was a power transformation: TTO=1-(1-global QoL)2.1. The mean absolute error in predicting utilities was 0.02. Conclusions: QoL measures underestimate utilities. A global QoL measure based on a weighted combination of the single item scales is more precise than single-item QoL scales. Our work enables QoL data obtained with a simple questionnaire to be converted into valid utilities that can be used in clinical trials to (i) describe the effects of cancer treatments on QoL (accounting for trade-offs between disparate aspects), (ii) evaluate trade-offs between quality and quantity of life, and (iii) do cost- effectiveness analysis.

No significant financial relationships to disclose.
Risk-based care in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS)
Authors: Nathan P. C. , Greenberg M. L. , Ness K. K. , Mahoney M. C. , Gurney J. G. , Hudson M. M. , Donaldson S. S. , Leisenring W. M. , Robison L. L. , Oeffinger K. C.
Published: March 2020

6502

Background: Childhood cancer survivors are at significant risk of morbidity as a result of their therapy. Thus, they require regular medical follow-up focused on their specific long-term risks. We examined the frequency and type of care received by a cohort of adult survivors of childhood cancer and examined the predictors of the receipt of appropriate risk-based care. Methods: Eligible subjects were members of the CCSS, a multi-institutional study of patients who have survived at least 5 years after being diagnosed with childhood cancer between 1970 and 1986. Participants completed a baseline survey and a subsequent survey on health care contact within the preceding 2 years. Contact was classified hierarchically as general care, cancer-related care, basic risk-based care and optimal risk-based care. Optimal risk-based care was assessed only in patients whose therapy is associated with a substantial risk of cardiac disease (=300 mg/m2 of an anthracycline, or any anthracycline plus chest radiation) or breast cancer (females who received chest radiation who are =27 years). Univariate and multivariable analyses were performed to assess associations between demographic/treatment variables and health care outcomes using logistic regression models. Results: The health care questionnaire was completed by 8,448 survivors. Median age (range) at diagnosis was 6.8 (0–21.0) years and at assessment was 31.4 (17.5–54.1) years. 87% reported general medical contact, 31% cancer- related care and 12% basic risk-based cancer care. Amongst patients at increased risk of cardiac disease (N=1,798) or breast cancer (N=852), only 28% reported receiving an echocardiogram and 49% a mammogram, respectively. Patients without health insurance (odds ratio [OR]=2.22, 95% confidence interval [CI]=1.56–3.13, p<0.0001 by Wald statistic), males (OR=1.19, 95% CI=1.03–1.37, p=0.02), younger patients (OR=1.03, 95% CI=1.02–1.04, p<0.0001) and those who perceived their health as good/excellent (OR=1.37, 95% CI=1.13–1.65, p=0.001) were at increased risk of not having received basic risk-based care. Conclusions: Despite a significant risk of late effects after cancer therapy, the majority of adult survivors of childhood cancer do not receive appropriate risk-based health care.

No significant financial relationships to disclose.
Hope and prognostic disclosure
Authors: Mack J. W. , Cook E. F. , Wolfe J. , Grier H. E. , Cleary P. D. , Weeks J. C.
Published: March 2020

6510

Background: Physicians sometimes selectively convey prognostic information to support patients’ hopes. However, the relationship between prognostic disclosure and hope is not known. Methods: We surveyed 194 parents of children with cancer (overall response rate 70%) in their first year of cancer treatment at the Dana-Farber Cancer Institute and Children’s Hospital, Boston, Mass, and the children’s physicians. We evaluated relationships between parents’ recall of prognostic disclosure by the physician and the extent to which physician communications “always” made them feel hopeful. A five-item index of prognostic disclosure assessed whether prognostic information was provided in any form, in quantitative terms, and in written form, whether the physician gave prognostic information before the parent asked, and whether parents wanted additional prognostic information beyond what they had already received. Results: Parents were less likely to report hopeful communication when the child’s likelihood of cure was low (OR .70 per category of decreasing likelihood of cure, P=.0003). However, parents who reported having received more extensive prognostic information were more likely to report hopeful communication, even when the prognosis was poor. In a multivariable model, parental report that physician communication “always” made them feel hopeful was associated with increased prognostic disclosure (OR 1.67 per element of disclosure, P=.009) and higher perceived communication quality (OR 5.39, P<.0001). In contrast, communication-related hope was inversely associated with the child’s likelihood of cure (OR .67, P=.006). Conclusions: Although physicians sometimes selectively convey prognostic information to preserve hope, we found no evidence that prognostic disclosure makes parents less hopeful. Instead, disclosure of prognosis by the physician can support hope for parents of children with cancer, even when the child’s prognosis is poor.

No significant financial relationships to disclose.

[Table: see text]
Randomized trials in oncology stopped early for benefit: A systematic review
Authors: Wilcox R. A. , Guyatt G. H. , Montori V. M.
Published: March 2020

6513

Background: Investigators finding a large treatment effect in an interim analysis may terminate a randomized trial (RCT) earlier than planned. A systematic review (Montori et. al., JAMA 2005; 294: 2203–2209) found that RCTs stopped early for benefit are poorly reported and may overestimate the true treatment affect. The extent to which RCTs in oncology stopped early for benefit share similar concerns remains unclear. Methods: We selected RCTs in oncology which had been reported in the original systematic review and reviewed the study characteristics, features related to the decision to monitor and stop the study early (sample size, interim analyses, monitoring and stopping rules), and the number of events and the estimated treatment effects. Results: We found 29 RCTs in malignant hematology (n=6) and oncology (n=23), 52% published in 2000–2004 and 41% in 3 high-impact medical journals (New England Journal of Medicine, Lancet, JAMA). The majority (79%) of trials reported a planned sample size and, on average, recruited 67% of the planned sample size (SD 31%). RCTs reported (1) the planned sample size (n=20), (2) the interim analysis at which the study was terminated (n=16), and (3) whether the decision to stop the study prematurely was informed by a stopping rule (n=16); only 13 reported all three. There was a highly significant correlation between the number of events and the treatment effect (r=0.68, p=0.0007). The odds of finding a large treatment effect (a relative risk < median of 0.54, IQR 0.3–0.7) when studies stopped after a few events (no. events < median of 54 events, IQR 22–125) was 6.2 times greater than when studies stopped later. Conclusions: RCTs in oncology stopped early for benefit tend to report large treatment effects that may overestimate the true treatment effect, particularly when the number of events driving study termination is small. Also, information pertinent to the decision to stop early was inconsistently reported. Clinicians and policymakers should interpret such studies with caution, especially when information about the decision to stop early is not provided and few events occurred.

No significant financial relationships to disclose.
Source of funding, conflict of interest (COI), and the interpretation of cancer clinical trials
Authors: Riechelmann R. P. , Dounaevskaia V. , Taback N. , O′Carroll A. , Krzyzanowska M. K.
Published: March 2020

6530

Background: Concern exists that industry sponsorship and financial relationships between investigators and drug companies may bias clinical cancer research. Our objective was to determine whether funding or authors' COI are associated with interpreting cancer clinical trials in more positive light. Methods: We reviewed phase II and randomized clinical trials (RCT) of anticancer and supportive care drugs published in 5 clinical cancer journals in a one-year period. We collected information on study design, source of funding, COI disclosure and results of primary endpoints (EP). Each concluding statement in the articles′s abstracts were independently rated by two reviewers (blinded to other study information) with respect to level of enthusiasm for the experimental agent using a 5-point scale ( Table 1 ). Summary statistics and logistic regression were used to describe the results. Results: 213 articles met inclusion criteria: 124 phase II and 89 RCT. Approximately 40% were funded by industry, at least one COI was declared in 35% of articles. Among 130/213 (61%) articles with clearly positive conclusions, the proportion of articles with highly positive conclusions was 61% in articles that declared COI vs. 40% in articles with no COI (p=0.017, CMH, adjusted for study result). In a stepwise logistic regression with journal, funding, study type, study result, and COI only COI remained significant (OR=2.4, 95%CI 1.2–5.0, P=0.017). While all articles with a negative conclusion had a negative primary EP, 21 articles with clearly positive conclusions had a negative primary EP. The most common reasons for such finding were: positive secondary EP (6 studies), experimental agent had better toxicity profile (5), non-statistically significant difference in favour of experimental agent (4). Conclusion: COI is associated with highly positive conclusions that use superlatives to promote the experimental arm

No significant financial relationships to disclose.

[Table: see text]