bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized phase III multicenter trial of neoadjuvant docetaxel plus cisplatin and 5-fluorouracil (TPF) versus neoadjuvant PF in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN). Final analysis of EORTC 24971
Authors: Remenar E. , Van Herpen C. , Germa Lluch J. , Stewart S. , Gorlia T. , Degardin M. , Bernier J. , Spirlet C. , Vermorken J. B. 
Published: March 2020

5516 Background: So far, the Wayne State regimen combining 100 mg/m2 cisplatin on day 1 and 1000 mg/m2/d continuous infusion 5-fluorouracil over 5 days (PF), is the gold standard in advanced SCCHN. Improvement of PF induction chemotherapy by adding a taxane has been suggested from phase II studies and 2 randomized phase III trials. We now report the final analysis of EORTC 24971. Methods: Eligible were patients (pts) with unresectable stage III/IV SCCHN (no distant metastases), 18 to 70 yrs of age, PS≤1, and adequate hematologic, renal and hepatic function. Pts were stratified by primary disease site (oral cavity, oropharynx, hypopharynx, larynx) and treatment center and randomized to PF (as above) or TPF (T 75 mg/m2/1h, P 75 mg/m2/1h, both d1, F 750 mg/m2/d, d1–5) q 3 wks, for 4 cycles unless progression (PD) or unacceptable toxicity, or refusal. Thereafter (interval 4–7 wks), all pts not in PD received radiotherapy (RT: conventional [66–70 Gy], accelerated [max. 70 Gy] / hyperfractionated [max. 74 Gy]). Surgery was allowed before RT (neck) or 3 months after RT (primary, neck). Primary endpoint was progression-free survival (PFS), and 348 pts and 260 events were needed to detect a 50% increase in median PFS (10 vs 15 mo) with 85% power. Results: Between April 1999 and March 2002, 358 pts were accrued (181 PF, 177 TPF). At a median follow-up (FUP) of 32 mo, PFS was significantly improved with TPF (HR 0.72, p = 0.0071; median 8.2 vs 11.0 mo). A 51 mo median FUP showed an overall survival (OS) benefit with TPF (HR 0.71, p = 0.0052; median 14.2 vs 18.6 mo). Estimated 3-yr survival rates are 23.9% (95% CI: 17.9%;30.5%) for PF and 36.5% (29.3%;43.6%) for TPF. Response rate also favored TPF (53.6% vs 67.8%, p = 0.006). There was more severe (G3+4) leucopenia (41.6% vs 22.9%) and neutropenia (76.9% vs 52.5%) with TPF, and more severe thrombocytopenia with PF (17.9% vs 5.2%). Severe alopecia occured more with TPF (55.5% vs 11.7%); hearing loss (2.8% vs 0%) and toxic death (7.8% vs 3.7%) more with PF. Conclusions: TPF (→ RT) is superior to PF (→ RT) for PFS, OS (including long-term), response rate, and is better tolerated. [Table: see text]
Sequential evaluation of reduced radiotherapy doses in a phase II trial of induction chemotherapy (IndCT) followed by concomitant chemoradiotherapy (CTX) for advanced head and neck cancer (HNC)
Authors: Vokes E. E. , Stenson K. M. , Kistner E. , Mittal B. , Cohen E. E. , List M. A. , Brockstein B. E. , Rosen F. R. , Witt M. , Haraf D. J. 
Published: March 2020

5528 Background: CTX constitutes a standard for locoregionally advanced HNC. IndCT may decrease distant failure rates (Brockstein Ann Oncol, 2003). The combination of these approaches has resulted in favorable early survival outcomes. CTX is limited by acute mucositis and long-term functional impairment. We examined the feasibility of lowering radiotherapy doses in sequential groups of patients (pts) to maintain high antitumor activity while decreasing toxicities. Methods: This was a 3-part, nonrandomized, phase II trial. Pts with stage IV (M0) HNC received 8 weeks of IndCT with carboplatin and paclitaxel (groups A & B ); carboplatin, AUC 2, and paclitaxel 135 mg/m2 weekly x 6; group C carboplatin AUC 6 day 1, and paclitaxel 100 mg/m2 days 1, 8, and 15 with cycle 2 beginning day 28. All pts received alternating week CTX with paclitaxel, infusional fluorouracil, oral hydroxyurea, and twice daily radiotherapy (T-FHX) (Kies JCO 2001). Radiotherapy to gross disease, high risk, and low risk microscopic disease consisted of group A (n = 68): 75, 60, 45 Gy; group B (n = 64): 75, 54, 39 Gy; group C (n = 90): 72, 51, 36 Gy. We have previously reported outcome data on groups A & B (Vokes JCO 2002 & Haraf CCR 2003). Results: A total of 222 pts were treated between 11/1998 and 2/2001. 74% were male, median age was 57. Best overall response (groups A/B/C): CR: 83/93/68%. With median follow-up time of 64/53/39 months; 3-year overall survival is 72%/67%/67% (logrank p = 0.76), progression-free survival 72%/65%/59% (logrank p = 0.44), time to progression (TTP, in which deaths prior to progression are censored unless due to treatment-related toxicity) 82%/86%/67% (logrank p = 0.019), and local control92%/97%/86% (logrank p = 0.10). Acute toxicities during concurrent chemoradiotherapy included grade 3/4 mucositis 72/2%; 65/11%; 57/8%; and dermatitis 47/15%; 19/26%; 28/2%. Conclusions: This 3-stage study suggests that acute toxicity can be reduced and high overall survival rates maintained while reducing doses of radiotherapy. The lower 3 year TTP rate in cohort C suggests a dose-response curve in the CTX setting. Schedule B may represent the best therapeutic index. Functional outcomes data are presented separately. [Table: see text]
Effect of pregnancy, in the year prior and after treatment for breast carcinoma, on survival and recurrence in women with breast cancer younger than 35 years. GETNA GROUP
Authors: Largillier R. , Savignoni A. , Gligorov J. , Chollet P. , Guillaume M. , Spielmann M. , Luporsi E. , Asselain B. , Coudert B. , Namer M. 
Published: March 2020

553 Background: The goal of this study was to assess the effect of pregnancy on the subsequent risk of recurrences after treatment for breast carcinoma, adjusted on established prognostic factors Methods: Between 1990 and 1999, 908 patients aged under 35 years old were treated for a non metastatic and unilateral invasive breast carcinoma in eight french hospitals, members of the GETNA association. The median follow-up period was 87 months. Mean age was 31.4 years old. Estrogen receptor (ER) status, lymph node involvement, tumor size, histological grade and pregnancy were evaluated as potential risk factors for recurrence and death in a multivariate analysis. A modified model was constructed using the four independent variables derived from the previous multivariate Cox model and the annual risk of death and recurrences were studied. Results: Women who gave birth within one year prior to diagnosis (n=105, 11, 8%) were more likely to have axillary node positive (> N1:48%, vs 35%, p=0.009) important tumor size (>T2:75% vs 55%, p=0.0002), and ER negative (54%, vs 42%, p=0.031). In univariate analysis, pregnancy the year before carcinoma diagnosis increased the risk of death, HR=1.5 [1.05–2.20] (p=0.028) and local recurrence, HR=1.71 [1.06–2.76] (p=0.027). In multivariate analysis, only influence on local recurrence is confirmed, HR=1.75 [1.08–2.84] (p=0.006). Patients who experienced a pregnancy after diagnosis and treatment (n=118, 13.4%) did not tend to have better prognosis regarding axillary node positive (> N1:71%, vs 61%, p=0.051), tumour size (> T2:53.4% vs 59.2%, p=0.49), ER negative (ER:44.2% vs 43.6%, p=0.92) and were significantly younger (<30 years old 52.5% vs 28%, p<10−4). The overall survival after five years was 97% for women who experienced a pregnancy and only 80% for those who did not (p< 0.0001). Conclusions: In this large study population, pregnancy was not associated with poorer survival and the healthy mother effect was studied. For the purpose of advising women on the decision to go forward with pregnancy, was studied after the diagnosis and treatment of breast carcinoma, the annual risk of recurrences. Study granted by Sanofi-Aventis. Acknoledgements to OSMO for its operational support. No significant financial relationships to disclose.
Phase II study of gefitinib in patients with metastatic/recurrent squamous cell carcinoma of the skin
Authors: Glisson B. S. , Kim E. S. , Kies M. S. , Francisco M. , Blumenschein G. R. , Tsao A. S. , Clayman G. L. , Duvic M. , Weber R. S. , Lippman S. M. 
Published: March 2020

5531 Background: Interrupting the epidermal growth factor receptor (EGFR) signaling pathway has shown promise in a variety of cancers. Skin squamous cell cancer (SCC) has been increasing in incidence at the rate of 4% to 8% per year since the 1960s, with especially increased rates (up to 10% annually) in recent years. Treatment options for advanced or recurrent skin SCC are extremely limited. Patients (pts) who fail surgery, radiation and/or chemotherapy have a very poor prognosis. Because of the importance of EGFR in tumorigenesis, and its overexpression in squamous cell carcinoma of the skin, it is an interesting target for treatment intervention. Gefitinib, an EGFR tyrosine kinase inhibitor, had a 11% response rate in HNSCC. Because of the possible efficacy, we proposed to study gefitinib in advanced skin SCC. Methods: Pts were required to have pathologically confirmed skin SCC adequate performance status, measurable disease, no prior EGFR therapy, and may have received prior chemotherapy. Pts must not have been amenable for curative intenet therapy with surgery or radiation. Treatment included gefitinib 250mg orally daily for 4 weeks. Results: 18 pts have been enrolled and 17 are evaluable. Median age is 68 years (range 37–84). Median ECOG PS is 1 (range 1–2). 12 pts are men and 5 women. 15 pts are currently evaluable for response. No objective partial responses were observed per WHO criteria. 4 pts (27%) have stable disease. Clinical responses were noted in 2 pts via photographs and clinical inspection. 17 pts are evaluable for toxicity. 2 pts had grade 3 rash and 1 pt had grade 3 keratitis. The most common grade 1–2 toxicities were diarrhea and fatigue. Conclusions: Gefitinib is well tolerated and has modest activity in advanced skin SCC. These pts have very few options for therapy. Data collection for response rate, duration of response and survival is ongoing as several patients are still receiving treatment. [Table: see text]
Induction chemotherapy + gefitinib followed by concurrent chemotherapy/radiation therapy/gefitinib for patients (pts) with locally advanced squamous carcinoma of the head and neck: A phase I/II trial of the Minnie Pearl Cancer Research Network
Authors: Doss H. H. , Greco F. A. , Meluch A. A. , Gray J. R. , Spigel D. R. , Shipley D. L. , Barton J. H. , Kuzur M. E. , Ramsey S. , Lunin S. D. , Hainsworth J. D. 
Published: March 2020

5543 Background: Concurrent chemotherapy/radiation therapy (RT) improves treatment outcome in pts with locally advanced unresectable squamous cancers of the head and neck. We previously reported a 51% 3-year disease-free survival with induction paclitaxel/carboplatin/5-FU followed by concurrent paclitaxel/carboplatin/RT. In this phase II trial, we added gefitinib, an EGFR inhibitor, to a similar chemoradiation regimen. Methods: All pts had squamous carcinoma of the head and neck, with at least one of the following: N1-N3 disease, T3 or T4 primary lesion, nasopharynx primary (except T1N0M0). Additional eligibility: no previous therapy, ECOG PS 0 or 1, adequate bone marrow, kidney, liver function; informed consent. All pts received initial docetaxel 60mg/m2 D1, 22; carboplatin AUC 5.0 D1, 22; 5-FU 200mg/m2, 24-hour CI, D1–43; gefitinib 250mg PO qd, D1–43. Beginning week 8, pts received RT, 1.8Gy single daily dose to total 68.4 Gy, and concurrent docetaxel 20mg/m2 weekly × 6 doses + gefitinib 250mg PO daily. At completion of therapy, pts were reevaluated with CT scans and endoscopy. Results: 45 pts entered this trial between 8/04 and 8/05. Pertinent clinical characteristics: clinical T3/T4, 17; N2/N3, 23. 42 pts (93%) completed induction chemotherapy. 34 pts (76%) have completed combined modality therapy and have been restaged. Response to treatment: 11 CR (32%); 18 PR (53%); 5 stable/progression (15%). After median follow-up 7 months, 9 patients (20%) have developed progressive cancer. Actuarial PFS and OS at 1 year are 68% and 86%, respectively. Grade 3/4 myelosuppression was common, and grade 3/4 mucositis occurred in all pts during combined modality therapy. One pt had a treatment-related death during combined modality therapy. The addition of gefitinib did not substantially increase toxicity. Conclusions: This combined modality regimen was feasible and produced high response rates in pts with locally advanced head and neck cancer. Toxicity was consistent with other effective combined modality regimens for these pts. Further follow-up is needed to better assess the benefit of this approach. [Table: see text]
Phase I study of the EGFR tyrosine kinase inhibitor erlotinib in combination with docetaxel and radiation in locally advanced squamous cell cancer of the head and neck (SCCHN)
Authors: Savvides P. , Agarwala S. S. , Greskovich J. , Argiris A. , Bokar J. , Cooney M. , Hoppel C. , Stepnick D. W. , Lavertu P. , Remick S. 
Published: March 2020

5545 Background: EGFR is highly expressed in SCCHN, representing a promising therapeutic target. Erlotinib (E) is an EGFR tyrosine kinase inhibitor that may potentiate the efficacy of concurrent radiation (RT) and docetaxel (D). We sought to establish the MTD, toxicities and preliminary efficacy of the combination of RT, D and E in patients (pts) with SCCHN. Methods: Patients with previously untreated stage III-IVB SCCHN were enrolled in a phase I dose-escalating study with standard once-daily RT (70.2 Gy, 1.8 Gy/day), weekly D for the duration of RT and daily E for two weeks prior, during and up to two years following RT. 4 dose levels (DL) were evaluated [D (mg/m2)/E (mg): 15/50, 15/100, 20/100, 20/150]. A 3+3 escalation design was followed. Pharmacokinetic studies (PK) were performed. Results: A total of 23 patients were enrolled (6 pts at each DL 1–3, 5 pts at DL4). Primary site: oral cavity (n = 1), pharynx (n = 15) and larynx (n = 7). 20 patients (87%) had stage IV disease. Three dose-limiting toxicities were observed, 1 at each DL (1–3), including a death within 30 days from last treatment (DL1), grade 3 mucositis resulting in holding RT (>5 days) (DL2) and grade 4 mucositis (DL3). No DLT to date on DL4 with 3/5 pts evaluable. In patients enrolled at DL 1–3 (n = 18), post concurrent chemoRT, best response was CR (n = 15), not evaluable (n = 2), death on study (n = 1). 3/3 pts who underwent planned neck dissection had a pathologic CR. 9 patients are currently receiving adjuvant E and 1 has completed the 2-year course. 3 patients have relapsed. Interpatient variability of E peak plasma concentrations measured after the first dose was observed at all dose levels: 458 ± 173 ng/mL (DL1), 686 ± 364 (DL2), 1017 ± 241 (DL3), 833 ± 222 (DL4) (mean ± s.d., n = 6, 6, 6, 2 at DL1–4 respectively). Adjuvant erlotinib plasma concentration data will be presented separately. No significant PK interaction of erlotinib with docetaxel was noted. Conclusions: The combination of daily erlotinib with weekly docetaxel and RT for pts with stage III-IVB SCCHN is feasible and active. A phase II trial is planned. Supported in part by NIH grants nos. CA62502 and M01 RR-000080. No significant financial relationships to disclose.
The letrozole (L), exemestane (E), and anastrozole (A) pharmacodynamics (LEAP) trial: A direct comparison of bone biochemical measurements between aromatase inhibitors (AIs) in healthy postmenopausal women
Authors: McCloskey E. , Hannon R. , Lakner G. , Clack G. , Miyamoto A. , Eastell R. 
Published: March 2020

555 Background: The LEAP trial is an open, randomized, multicenter, Phase I pharmacodynamic study comparing the effects of the AIs L, E and A on safety parameters, such as serum markers of bone formation and resorption, lipid profiles, and adrenal function in healthy postmenopausal women with normal bone mineral density at the spine and hip. Elevated bone biochemical levels indicate high turnover of bone, and correlate with a loss in bone mineral density. It has been suggested that there are differences between the effect of the steroidal AIs (E) and non-steroidal AIs (A and L) on bone turnover, with steroidal AIs having a less negative effect. Methods: Healthy volunteersfrom the UK and Hungarywere randomized to receive A (1 mg/day), L (2.5 mg/day), or E (25 mg/day) orally, once daily for 24 weeks. Changes from baseline in log-transformed bone alkaline phosphatase (ALP), serum C-telopeptide crosslinks (CTX), parathyroid hormone (PTH) and propeptide of type I procollagen (PINP) at 24 weeks on A, were compared with those on L and E by ANCOVA, adjusting for treatment, baseline measurement, BMI, smoking status and baseline estradiol. No adjustments were made for multiple comparisons. Results: A total of 102 healthy volunteers were recruited, with 90 participants evaluable at 24 weeks (29 A, 29 L, 32 E). Participant demographics were similar between the treatment groups in terms of age, years since menopause, and history of hysterectomy and oophorectomy. Bone biochemical measurement changes are presented in the table . With the exception of PTH, where there is a greater decrease in PTH with E than with A (p=0.04), there were no statistically significant differences between the AIs. Conclusions: The steroidal and non-steroidal AIs appear to have similar effects on bone biochemical measurements, and thus bone turnover. All three licensed AIs result in increases in bone turnover. [Table: see text] [Table: see text]
Reversal of adverse effects of neoadjuvant chemotherapy on bone turnover in pre- and post-menopausal women with zoledronic acid
Authors: Aft R. , Naughton M. , Trinkuas K. , Watson M. , Weilbaecher K. 
Published: March 2020

556 Background: Ovarian failure secondary to adjuvant chemotherapy is known to have an adverse effect on bone mineral density and to increase bone turnover markers. The effects of chemotherapy with growth factor support in the absence of hormonal changes have not been described. The impact of zoledronic acid on these changes was also explored. Methods: We evaluated bone turnover markers in 82 women undergoing neoadjuvant chemotherapy for localized stage II/III breast cancer at initial diagnosis prior to treatment and after 4 cycles of epirubicin (75mg/m2)-docetaxel (75mg/m2) with pegylated G-CSF support with or without zoledronic acid. 47% of patients were post-menopausal and all groups were balanced for other variables. Women were randomized to receive zoledronic acid 4 mg IV every 3 weeks concurrently with chemotherapy (n=41) versus no bisphosphonate treatment (n=41). Bone turnover markers included: urinary N-telopeptide (NTx), serum bone specific alkaline phosphatase (BAP)and osteocalcin (OSTEO). Results: Women, regardless of menopausal status, who received no bisphosphonate had statistically significant increases in NTx, from baseline after 3 months of neoadjuvant chemotherapy using multivariable mixed repeated measures (p=0.0213). Women who received zoledronic acid concurrently with neoadjuvant chemotherapy had statistically significant decreases in NTx (p<0.0001), BAP (p<0.0001) and OSTEO (p=0.0295) from baseline. This is the first demonstration that anthracycline-taxane chemotherapy with growth factor support increased bone turnover markers in both post-menopausal and pre-menopausal women independent of hormone therapy, radiation therapy and surgery. Conclusions: Neoadjuvant chemotherapy with anthracycline- taxane and growth factor support increased bone resorption markers in both post-menopausal and pre-menopausal women. Zoledronic acid given concurrently with each cycle of chemotherapy reversed this increase in bone turnover markers. No significant financial relationships to disclose.
TPF induction chemotherapy followed by concurrent radiochemotherapy in the first line therapy of advanced carcinomas of the larynx and pharynx (phase IIb trial)
Authors: Knecht R. , Baghi M. , Hambek M. , Zamboglou N. , Tesch H. 
Published: March 2020

5562 Backround: Concurrent radiochemotherapy has become a standard procedure for the organ preservation treatment of advanced laryngeal cancer. According to the RTOG 91–11 protocol 2 years larynx preservation and disease free survival rates of 88% and 61% have been described (N Engl J Med 2003;349:2091–8). We perform a phase IIb study answering the question if the addition of triple induction therapy with docetaxel, cisplation and 5FU (TPF) to this regimen is feasible and able to enhance larynx preservation and the disease free survival. Methods: Eligibility criteria have been untreated measurable (RECIST) Stage III/IV carcinomas of the larynx and pharynx in ECOG 0–2 pts. with sufficient organ functions. Planned treatment consisted of 3 cycles induction chemotherapy (every 3 weeks) with docetaxel 75 mg/m2/d1, cisplatin 100 mg/m2/d1 and 5 Fluorouracil 1000 mg/m2/d1–4 (TPF) followed by concurrent radiochemotherapy according to the RTOG 91–11 protocol. Controls have been treated with concurrent radiochemotherapy (RTOG 91–11). One stage design, primary endpoint is recurrence free survival, planned sample size is 250 with 192 events to have a power of 80% to detect a relative risk = 1,432 using a one sided test, alfa = 0.05. Results: 103 patients have been evaluated up to know. Completion of therapy was equivalent in both groups (1/5 drop out rate). Main grade 3/4 toxicities (CTC) during induction chemotherapy were neutropenia (95%) and renal toxicity (25%) and during chemoradiation mucositis (40%) in the chemoradiation group and mucositis (43%), neutropenia (46%) and renal toxicties (24%) in the induction chemotherapy group The toxicities were reversible. After induction chemotherapy the ORR was 84% with a CR of 55%. After the completion of therapy the ORR in the induction chemotherapy group (IC) was 97% versus 93% in the chemoradiation group (RC). After a median follow up of two years the larynx preservation rates and the disease free survival rates are as follows:91% (IC) vs. 87% (CR), n.s., and 85% (IC) vs. 66% (RC), p = 0.017. Conclusion: Addition of TPF induction therapy to the RTOG 91–11 concurrent radiochemotherapy protocol may enhance the disease free survival. No significant financial relationships to disclose.