Addition Of Docetaxel Research Articles

New aspects of induction chemotherapy for head and neck cancer: POSTASCO 2011

Treatment options of patients with advanced head and neck cancer developed in the last years. Surgical approaches with or without radiotherapy used to be the standard therapy for a long time. Calls for organ preservation, poor overall survival and unsatisfactory quality of life made changes in this therapy regime necessary. Systemical approaches were evaluated, first concepts of platinum-based chemotherapy paired with 5-fluorouracil (PF) made up the basis of induction chemotherapy (ICT). Hypothesized advantage of this regime was improvement in local and distant tumor responsiveness with an acceptable toxicity profile. Further investigations proved the addition of docetaxel (TPF) superior to PF, which presents the gold standard of current induction chemotherapy regimes. Long-term results underlining well-known aspects of this regime as well as new approaches of induction chemotherapy were published at ASCO 2011, including the addition of bioimmunotherapy to radiotherapy, adding nanoparticle-bound albumin to chemotherapy and investigations in toxicity reduction. Further investigations are still made not only to increase survival outcomes and local control but also to improve quality of life by reducing acute and late toxicities.

Long-term results from EORTC24971/TAX323: Comparing TPF to PF in patients with unresectable squamous cell carcinoma of the head and neck (SCCHN).

5530 Background: At a median follow-up (FU) of 32.5 months, the original EORTC24971/TAX323 study showed that compared with standard cisplatin/infusional fluorouracil (PF), induction chemotherapy (ICT) with the addition of docetaxel (TPF) prior to radiotherapy significantly improved progression-free survival (PFS) and overall survival (OS) with less toxicity and an improved quality of life in patients with unresectable SCCHN (NEJM 2007; 357: 1695; BJC 2010; 103: 1173). The present report describes survival data after a median FU of 8.6 years and long-term side effects (feeding tube dependency, tracheostomy, gastrostomy and second malignancies). Methods: Data were collected in a long-term FU form and analyzed in the intent-to-treatment population, using a Cox PH model adjusted for treatment, tumor site, T&N stage and performance status. The two treatment arms were also compared with an unstratified logrank test at a 2-sided 5% significance level. The clinical database was locked on January 10, 2011. Results: FU forms were obtained from 308 (86%) of the 358 randomized patients (156 TPF, 152 PF). PFS remained significantly better with TPF compared with PF (hazard ratio [HR] unadjusted 0.71 (95% CI, 0.57-0.89), p=0.003, medians of 12.7 vs 8.6 months, and 5-years PFS 22.9% vs 13.5%, mainly due to less locoregional progression). A similar picture was observed for OS (HR unadjusted 0.74 (95% CI, 0.59-0.94), p=0.011, medians of 18.8 vs 14.5 months, 5-years OS 27.5 vs 18.6%). These data were confirmed in the Cox PH model. Long-term side effects in TPF/ PF arms were: tracheostomy 13/9 ; feeding tube dependency 6/10; gastrostomy 19/19; second malignancy 14/6 (of which lung 42.9%/50%; H&N 42.9%/33.3%, and GI 14.3%/16.7%). Conclusions: This long-term update supports the conclusions of the final analysis that TPF is superior to PF as ICT for patients with unresectable SCCHN.

Evaluation of the prognostic and predictive value of tumor-infiltrating lymphocytes (TILs) in a phase III randomized adjuvant breast cancer (BC) trial (BIG 2-98) of node-positive (N+) BC comparing the addition of docetaxel to doxorubicin (A-T) with doxorubicin (A)-only chemotherapy (CT).

556 Background: Previous clinical and preclinical data suggest a contribution of the immune system to prognosis and response to anthracycline CT, however clinical utility is yet to be established in BC. We hypothesized that TILs would be associated with prognosis and would predict increased benefit from A-based over A-T CT regimens in the triple negative (TN) and HER2+BC. Methods: We investigated the relationship between percentage of TILs (both intratumoral and peristromal) at diagnosis in 2016 N+ BC samples from the BIG 2-98 adjuvant phase III trial and clinical outcome from A-based (AC-CMF;A-CMF) or combination A-T (AT-CMF; A-T-CMF) CT (Francis et al., 2008). TILs were independently evaluated by two pathologists. Disease-free and overall survival (DFS, OS) associations were studied in a multivariate Cox model adjusted for other prognostic markers. Median FU is 93.6 months. Results: Correlation between pathologists was 0.67, p<0.001. There was no significant prognostic association in ER+/HER2- disease o...

Development of targeted therapy for squamous cell carcinomas of the head and neck

Targeted therapy is a very exciting era in the treatment of squamous cell carcinomas of the head and neck. After adding cetuximab to conventional chemotherapy and radiation therapy, we are strongly considering the role of induction chemotherapy with the addition of docetaxel. At the same time, other new treatments, especially targeted agents and novel combined regimens, are being evaluated in ongoing clinical trials. For example, several trials are attempting to combine docetaxel and cetuximab in chemoradiation or induction settings. However, in the near future we are likely to see a strong presence of targeted agents that have been found to be not only effective, but also less toxic than conventional chemotherapeutic agents. Their toxicity profiles make them eligible for addition to radiation treatment strategies, as well as other chemotherapy agents, or even for replacing these chemotherapy agents. In this article, we are going to review the indications and current role of cetuximab, tyrosine kinase inhibitors (gefitinib and erlotinib), dual inhibitors, IGF receptor inhibitors, as well as other agents that are in development for treatment of head and neck squamous cell carcinomas.

A phase II trial of docetaxel, cisplatin, and 5-fluorouracil (TPF) in locally advanced and metastatic carcinoma of the penis (CRUK/09/001).

TPS240 Background: Chemotherapy for penile cancer is used mainly as palliation of metastatic disease. It also has a role as treatment for locally advanced disease but the rarity of the disease has hampered attempts to define an evidence base for its use. Combined cisplatin (P) and 5-fluororacil (F) has been used for treatment of squamous cell carcinoma (SCC) of the penis since 1990. Pathological similarities to head and neck SCC suggest that addition of docetaxel (T) to an established platinum-based regimen may lead to improved therapeutic benefits. The purpose of the trial is to determine the activity ofTPF chemotherapy in penile cancer Methods: This single stage phase II trial is the only UK-wide trial for penile cancer. Eligible patients (pts) have histologically proven SCC of the penis staged M1; M0, T4 any N; M0, any T, N3 or inoperable N2; or M0, any T, N1 where chemotherapy is to be offered as first-line therapy. Pts must have measurable disease and be fit to receive TPF as palliative or definitive treatment or as treatment for relapse. All pts receive three 21 day cycles of: T 75mg/m2 day 1, P 60mg/m2 day 1, F 750mg/m2/day (days 1-5). Fourteen or more responses in 26 pts are required to conclude a response rate of 60% or more (p0=0.35, p1=0.60, α=0.1, β=0.2; Fleming-A'Hern exact methods). The primary endpoint is overall response rate (RECIST) assessed by MRI/CT scan at completion/discontinuation of trial treatment. The proportion of pts with inoperable locoregional disease rendered operable following TPF, safety, tolerability, and progression-free and overall survival are secondary endpoints. The trial opened in September 2009. To end 2009, 4 pts have been recruited of which two have completed trial treatment and remain on follow-up. The National Cancer Research Institute's Penile Cancer Studies Group plans further studies. If results suggest a high response rate, they are likely to lead to an expanded phase II TPF programme in two settings: as neoadjuvant therapy (in operable and inoperable disease); and as palliation of metastatic disease. The trial also takes the first steps to defining a standard of care for synchronous chemoradiotherapy as consolidation for inoperable locoregional disease. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline, Pfizer, Roche, sanofi-aventis sanofi-aventis

Safety results of a phase III trial evaluating ADT+ docetaxel versus ADT alone in hormone-naïve metastatic prostate cancer patients (GETUG-AFU 15/0403).

4681 Background: Androgen deprivation therapy (ADT) is the standard treatment of hormone naïve metastatic prostate cancer (HNMPC). We decided to initiate a phase III multicentre trial to evaluate the additional docetaxel (D) chemotherapy in these populations. Methods: Patients (pts) with HNMPC were randomly assigned to either arm A (ADT plus D: 75mg/m2 q3w, 9 cycles) or arm B (ADT alone). Primary endpoint was overall survival. Secondary endpoints included the toxicity profile of D. Results: From 10/2004 to 12/2008, 385 pts were accrued. Median age was 63 years (43-84), median PSA 26.6 ng/ml (0.1-11900), Gleason score >8: 57%. Median number of applied cycles was 9. Pts were classified according to Glass et al. risk groups as good (48%), intermediate (29%), and poor prognosis (22%). Among the 385 pts, neutropenia grade ≥ 3 was observed in 33%, febrile neutropenia: 7%. After accrual of 215 patients, 3 toxic deaths occurred in arm A, 2 due to neutropenia, 1 due to general impairment. After a safety interim analysis, the independent data monitoring committee recommended systematic use of G-CSF from day 5 to day 10 after each D administration. No subsequent toxic death was observed. Furthermore, in arm A rates of toxicity were observed: G ≧ 3 sexual dysfunction 15%, G ≧ 3 fatigue 7%, G ≧ 3 hot flushes 4%, G ≧ 3 nail changes 3%, G ≧ 3 anemia 2% and G ≧ 3 dyspnea 2%. Other toxicities with ≤1% grade ≥3 toxicity were: alopecia 54%, nausea/vomiting 35%, diarrhea 30%, sensory neuropathy 29%, mucositis 29% and peripheral oedema 29%.In arm B: hot flushes 62% (2% G≥ 3), sexual dysfunction 29% (8% G ≥ 3), anemia 22%, and fatigue 19%. Conclusions: Relative to ADT alone D chemotherapy is associated with a significant increase of toxicity. However, apart from a higher incidence of febrile neutropenia, overall toxicity was comparable to toxicity rates observed in previous studies in metastatic castration resistant prostate cancer patients. Systematic use of G-CSF is recommended in this setting. No significant financial relationships to disclose.

EGFR Mutations Detected in Plasma Are Associated with Patient Outcomes in Erlotinib Plus Docetaxel-Treated Non-small Cell Lung Cancer

Activating mutations in the epidermal growth factor receptor (EGFR) are associated with enhanced response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC), whereas KRAS mutations translate into poor patient outcomes. We hypothesized that analysis of plasma for EGFR and KRAS mutations from shed tumor DNA would have clinical utility. An allele-specific polymerase chain reaction assay using Scorpion-amplification refractory mutation system (DxS, Ltd) was used to detect mutations in plasma DNA from patients with advanced stage NSCLC treated as second- or third-line therapy on a phase I/II trial of docetaxel plus intercalated erlotinib. EGFR mutations were detected in 10 of 49 patients (20%). Six (12%) had single activating mutations in EGFR, associated with improved progression-free survival (median, 18.3 months), compared with all other patients (median, 3.9 months; p = 0.008), or those with wild-type EGFR (median, 4.0 months; p = 0.012). Four of 49 patients harbored a de novo T790M resistance mutation (median progression-free survival, 3.9 months). EGFR mutational status was associated with clinical response (45 assessable, p = 0.0001); in the six patients with activating mutations, all achieved complete (33%) or partial (67%) response. All CR patients had E19del detectable in both tumor and plasma. KRAS mutations were detected in two of 49 (4%) patients, both of whom had rapid progressive disease. Activating EGFR mutations detected in shed DNA in plasma are significantly associated with favorable outcomes in patients with advanced NSCLC receiving docetaxel plus intercalated erlotinib. The addition of docetaxel in this schedule did not diminish the efficacy of erlotinib against patients with EGFR activating mutations.

Phase I study of gemcitabine, docetaxel, and imatinib in refractory and relapsed solid tumors

e13538 Background: The combination of the tyrosine kinase inhibitor imatinib with cytotoxic chemotherapy targets multiple pathways of tumor progression. In a previous phase I study, the combination of gemcitabine and imatinib was tolerable and had broad activity. The maximally tolerated dose (MTD) was gemcitabine 1500 mg/m2/150 minute and imatinib 400 mg days 1–5, 8–12, and 15–19. Given the activity seen when combining gemcitabine and docetaxel in some solid tumors, this phase I trial studied the addition of docetaxel to gemcitabine/imatinib. Methods: Twenty patients with relapsed/refractory solid tumors were enrolled in this IRB-approved study at the Cancer Institute of New Jersey and University of Michigan. The mean age was 64, mean ECOG PS 1. Five patients had lung cancer; 5, sarcoma; 3 ampullary-biliary tumors; 2 mesothelioma and bladder, 3, other. Imatinib was administered at 400 mg daily on days 1–5, 8–12 and 15–19. Gemcitabine was started at 600 mg/m2 at the fixed dose infusion of 10 mg/min on days 3 and 10 and docetaxel at 30 mg/m2 on day 10. Results: Because of unexpectedly severe hematological toxicities seen with escalating either gemcitabine or docetaxel, the protocol was amended to eliminate days 15–19 of imatinib. The MTD is gemcitabine 600 mg/m2, on days 3 and 10, docetaxel 30 mg/m2 on day 10, and imatinib 400 mg PO given on days 1–5 and 8–12. The dose limiting toxicities were neutropenic fever, pleural and pericardial effusion after cycle 1 of chemotherapy. The best response achieved was stable disease at 6 cycles in one patient each with mesothelioma and non small cell lung cancer (NSCLC) at the MTD. Two other patients with NSCLC had stable disease at 4 cycles. Discussion: An unexpectedly low MTD for this triplet was identified, an outcome different from prior experience with the doublets gemcitabine/imatinib or gemcitabine/docetaxel where much higher dosages are tolerated. Our results suggest possible drug-drug interactions that amplify toxicities with little initial evidence of improved tumor control. Given the unexpectedly high toxicity of the combination of gemcitabine, docetaxel and imatinib at low dosages, further development of this regimen is not indicated. [Table: see text]

Feasibility and toxicity of docetaxel before or after fluorouracil, epirubicin, and cyclophosphamide as adjuvant chemotherapy for early-stage breast cancer

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.

Human Melanoma Cells under Endoplasmic Reticulum Stress Acquire Resistance to Microtubule-Targeting Drugs through XBP-1-Mediated Activation of Akt

Past studies have shown that melanoma cells have largely adapted to endoplasmic reticulum (ER) stress. In this study, we report that melanoma cells under ER stress are more resistant to apoptosis induced by the microtubule-targeting chemotherapeutic drugs, docetaxel and vincristine, and this is, at least in part, due to activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway mediated by the X-box-binding protein 1 (XBP-1) axis of the unfolded protein response. Treatment with the ER stress-inducer tunicamycin (TM) or thapsigargin before the addition of docetaxel or vincristine reduced the levels of apoptosis induced by the drugs. This was associated with inhibition of mitochondrial release of apoptogenic proteins and activation of Bax and Bak. Induction of ER stress resulted in the rapid activation of the PI3K/Akt pathway that seemed to be important in antagonizing docetaxel and vincristine, in that inhibition of Akt blocked the effect of pretreatment with TM on apoptosis induced by the drugs. Neither docetaxel nor vincristine triggered ER stress in melanoma cells, but the basal activity of XBP-1 signaling seemed to play a role in the protection against the drugs because small interfering RNA knockdown of XBP-1 enhanced docetaxel- and vincristine-induced apoptosis. In addition, inhibition of XBP-1 decreased the constitutive levels of activation of Akt and blocked the activation of Akt induced by TM. Taken together, these results identify activation of the PI3K/Akt pathway by XBP-1-mediated signaling of the unfolded protein response as a resistance mechanism against docetaxel and vincristine in melanoma cells under ER stress.

RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

mTOR activity is increased in advanced prostate cancer (CaP) as a result of a high rate of PTEN mutations. RAD001 (Everolimus) is a new orally available mTOR inhibitor. The objective of our study was to evaluate the effects of RAD001 on the growth of CaP in the bone, both alone and in combination with docetaxel and zoledronic acid. C4-2 CaP cells were injected into tibiae of mice and the animals were treated with RAD001, docetaxel, and zoledronic acid alone or in combination. Histomorphometrical analysis, serum PSA measurements, bone mineral density (BMD), and microCT were used to determine the effects of treatment on tumor and bone. All three agents alone decreased tumor volume, and RAD001 and docetaxel also decreased levels of serum PSA by 68% and 65%, respectively (both P < 0.01). Combinations of the agents were more effective in decreasing tumor volume than single agents. Three-drug treatment showed the greatest effect: 64% inhibition versus control (P < 0.01). Treatment with RAD001 interfered with the weight loss associated with growth of this tumor in the bone (non-RAD001 groups: 4.0% decrease in body weight, P = 0.0014; RAD001 groups: increase of 3.6% in body weight, P = 0.0037). RAD001 inhibited growth of C4-2 cells in bone, an effect augmented by addition of docetaxel and zoledronic acid. Moreover RAD001 had a significant impact on maintenance of body weight. RAD001 may hold promise for its effects on both metastatic CaP and the important syndrome of tumor cachexia.

Preferences for adjuvant chemotherapy (ACT) in early breast cancer: The benefits needed to make extended treatment with docetaxel, doxorubicin, and CMF worthwhile

6528 Background: Small benefits are judged sufficient to make ACT worthwhile by women who have had either 6 cycles of CMF or 4 cycles of AC. We sought to determine the benefits needed to make longer and more intensive regimens worthwhile. Methods: 293 women who completed ACT 3 to 39 months earlier were presented 4 hypothetical scenarios based on known survival times (5 and 15 years) and rates (65% and 85% at 5 years) without ACT using validated, standardised interviews. 179 were in a randomized trial (BIG 02–98) testing addition of docetaxel (T) to a standard regimen including doxorubicin (A) and classical CMF; 114 were treated outside of the trial at the same centres. Women also rated their recollections of health-related quality of life during ACT. Results: The median age was 55 (range 25 to 78), 36% had a college or university degree, and 62% had dependants. The regimens (and their duration) in the trial were: 4 cycles of A or AC then 3 cycles of CMF (24w) in 31% of the women; 4 cycles of AT followed by 4 cycles of CMF (24w) in 29%; and 3 cycles of A then 3 cycles of T then 3 cycles of CMF (30w) in 40%. The regimens outside of the trial were: 4 cycles of AC (12w) in 52%; 6 cycles of CMF (24w) in 20%; and 4 cycles of AC then 3 cycles of CMF (24w) in 23%. A 2% gain in 5-year survival rates or a 6-month gain in survival duration was judged sufficient to make ACT worthwhile by 62–67% of women. Gains of more than 5% in 5-year survival rates or more than 2 years in survival duration were judged necessary to make ACT worthwhile by 10–20% of women. Women's preferences were strongly associated with the aversiveness of their treatment. Women who had more problems with physical well-being, coping with treatment, and nausea or vomiting judged larger benefits necessary to make their ACT worthwhile (p&lt;.0001). Preferences were unaffected by chemotherapy regimen, duration, context in a trial, age, time between treatment and interview, and social circumstances (p&gt;.2). Conclusions: As in previous studies, small benefits were judged sufficient to make ACT worthwhile, even if it lasted 6–7 months, and included docetaxel, doxorubicin and CMF. No significant financial relationships to disclose.

A clinical phase II study of combination Cisplatinum and Vinorelbine followed by Docetaxel as first-line chemotherapy in metastatic breast cancer

10683 Background: Many chemotherapeutic options exist for metastatic breast cancer (MBC) but there is no standard regimen. We tested a sequential combination regimen using Cisplatinum and Vinorelbine (PVn) followed by Docetaxel as first-line chemotherapy in a phase II clinical trial. This is the first study using a non-anthracycline sequential combination chemotherapy of PVn with Docetaxelin MBC. Methods: Thirty-five patients were enrolled. Cisplatin 80 mg/m2, which was given on day 1 and Vinorelbine 30 mg/m2 on days 1 and 8 q3 weeks for 4 cycles. After the 4th cycle, responding patients received Docetaxel 75 mg/m2 every 21 days for a maximum of 4 cycles. Patients were evaluated every two cycles and those who had no response were offered other therapy. Patients who showed progression after 2 cycles of PVn were offered Docetaxel but were considered off protocol. Three patients were excluded from analysis because of death unrelated to treatment. Results: After a median follow up of 14 months (range 1–36), 32 patients (91.4%) completed the study. Overall response rate was 53.1%. Complete remission was seen in 5 pts (15.6%), partial response in 12 patients (37.5%), stable disease in 6 patients (18.75%), and progressive disease in 9 patients (28.1%). 20 patients (62.5%) were alive at 12 months. Median time to disease progression was 8 months (range 1–24). At 24 months 37.5% (12 patients) were alive. Response rates to PVn were not significantly improved by sequential addition of Docetaxel. A total of 183 cycles were administered with a median of 6 cycles per patient. Delay of chemotherapy because of Grade II neutropenia occurred in 41/183 cycles (22.4%). Febrile neutropenia was observed in 4 patients (2.2%). Grade II anemia was observed in 40/183 cycles (21.8%) and Grade III in 24/183 cycles (13.1%). Grade II nephrotoxicity occurred in 12 cycles (6.5%) and Grade III vomiting was observed in 31/183 cycles (16.9%). No treatment-related mortality has been reported. Conclusions: Sequential PVn-Docetaxel is a feasible and effective non-anthracycline option as first-line chemotherapy in patients with MBC. More effective Docetaxel may be better used upfront and followed by PVn. This regimen has acceptable toxicity as well. No significant financial relationships to disclose.

Impact on quality of life (QoL) of the addition of docetaxel (T) to neoadjuvant cisplatin plus 5-fluorouracil treatment in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN): EORTC study 24971

5522 Background: The EORTC 24971 trial compared the efficacy and safety of two neoadjuvant regimens in the treatment of stage III or IV, M0 SCCHN. Eligible patients (pts) with primary tumor sites in the oral cavity, oropharynx, hypopharynx, and larynx and WHO performance status (PS) ≤1) were randomized to 2–4 cycles of cisplatin (P) 100 mg/m2 day 1, followed by a continuous infusion of 5-fluorouracil (F) 1000 mg/m2/day from days 1- 5 (PF), or T 75 mg/m2 + P 75 mg/m2 day 1 then F 750 mg/m2/day from days 1 - 5 (TPF), followed by locoregional radiation therapy (RT). The impact of the two regimens on QoL was a secondary endpoint. Methods: QoL was assessed at baseline, at cycles 2 and 4, and 6 and 9 months after RT using the EORTC QLQ-C30 questionnaire to obtain the Global Health Status/Quality of Life (GHS/QoL) score, and the Head and Neck Performance Status Scale (PSS-HN) to assesses the normality of diet, eating in public, and understandability of speech on a scale of 0 to 100. The EORTC QLQ-HN35 questionnaire was also administered at those time-points. Results: 358 pts were randomized to PF (181 pts) or TPF (177 pts). Baseline (BL) characteristics of the pts were well balanced between groups. TPF was superior to PF in terms of response rate, progression-free survival (primary endpoint), overall survival, and tolerability. Compliance with the QLQ-C30 questionnaire was good ranging from 96% at BL to 41% at 9 months post RT, and was similar between the treatment arms. GHS/QoL scores were comparable at BL between the two arms (p = 0.54) and improved in both arms on starting treatment. Over time this score remained stable with TPF, but decreased after RT with PF (treatment-time interaction: p = 0.009). Evolution of the PSS-H&amp;N score was better on TPF (normality of diet p= 0.0064; eating in public p = 0.0004; understandability of speech p = 0.0003). Moreover, TPF was associated with a 30% reduction in the risk of WHO PS deterioration (p = 0.0158) Conclusions: The use of docetaxel in neoadjuvant treatment of SCCHN improves efficacy without deleterious effects on QoL and functional outcomes. [Table: see text]

Incidence of reversible amenorrhea in women with early-stage breast cancer undergoing adjuvant anthracyclin-based chemotherapy with or without docetaxel

10517 Background: The objective of this study was to determine the incidence of reversible amenorrhea in women with early-stage breast cancer undergoing adjuvant anthracyclin-based chemotherapy with or without docetaxel. Methods: We studied the amenorrhea duration induced by 2 chemotherapy regimens. The first arm (6FEC) consisted in the administration of 6 cycles of FEC100 (5-Fluorouracil 500 mg/m2, Epirubicin 100 mg/m2, Cyclophosphamide 500 mg/m2, day 1, every 3 weeks) and the second arm (3FEC/3D) in the administration of 3 cycles of FEC100 followed by 3 cycles of Docetaxel (100 mg/m2, day 1, every 3 weeks). Some of these patients (N = 121, 78%) were treated in the PACS01 trial that was designed to evaluate the impact of the sequential addition of docetaxel to FEC100 on disease-free survival for patients with node positive, operable breast cancer. Other patients (N = 33.22%) were patients treated with the same regimens after the inclusion period of PACS01. Reversible amenorrhea was defined as a recovery of regular menses and -when available (101 patients)- premenopausal hormonal values (minimum 2 tests at 3 months interval) in the year following the end of chemotherapy infusion. Results: 154 pre-menopausal patients were included: 84 were treated in the 6FEC and 70 in the 3FEC/3D. Median age was 43.5 (28–58) and 44 (29–53), respectively. The incidence of chemotherapy-induced amenorrhea at the end of chemotherapy was not different between the two groups, 6FEC: 93% and 3FEC/3D: 92.5%. In the year following the end of chemotherapy, more patients recovered regular menses in the 3FEC/3D arm compared to the 6FEC arm: 35.5% (25/70) versus 23.7% (20/84) (p = 0.019). For the 101 for which hormonal values were available, more patients recovered premenopausal hormonal values in the 3FEC/3D arm: 42% (18/42) versus 29% (17/59) (p &lt; 0.01). Conclusions: Our study suggests that it could be interesting to record the menopausal status at different time points after the end of chemotherapy. In addition, the survival advantage in the PACS01 trial in favor of the 3FEC/3D arm was observed only for women over the age of 50 and not for women younger than 50. In this context, the clinical relevance of reversible amenorrhea warrants further investigation. No significant financial relationships to disclose.

Five years update of sequential high dose doxorubicin, cyclophosphamide and docetaxel in inflammatory breast cancer; PEGAGE05 trial on behalf of FNLCC

10773 Background: Inflammatory breast carcinoma is a distinct clinicopathologic entity with poor survival outcome. Early response to initial chemotherapy was reported as predictive for survival and complete pathological response is considered as a major prognostic factor. This study was conducted to determine the safety and to estimate the efficacy of sequential high dose chemotherapy with doxorubicine (D) + cyclophosphamide (CPM) and docetaxel (Doc), in terms of pathological response, disease-free and overall survival Methods: Fifty-four patients entered into the trial from July 1997 to March 1999; treatment consisted in four 3 weekly cycles of D75 mg/m2 + CPM 6 g/m2 in C1 and C2; Doc 100 mg/m2 q 2w in C3, C4 and C6; D75 mg/m2 + CPM3 g/m2 in C6 and C7. Mastectomy with axillary dissection was performed for responding patients, followed by radiotherapy. Results: An interim analysis showed the same efficacy reported in previous high dose chemotherapy trial Pegase 02, without Docetaxel, and unexpected toxicity with 2 toxic deaths that warranted an early closure of the trial The overall 35% [22.5%–47.9%] grade 1 or 2 pathological response according to Chevallier as compared to the 32% reported in the Pagase 02 trial, suggest no greater efficacy for additionel Docetaxel to high dose D + CPM Five-year disease-free survival and overall survival showed a better tendency in Pegase 05 trial, with respectively 42% and 62% as compared to Pegase 02 trial with 33% and 50% Conclusions: these results suggest some benefit from dose intensified CT in terms of complete pathological response rate with improvment of the disease- free and survival outcome. The positive impact of additional docetaxel will be assessed in the last randomized multicenter Pegase 07 trial. No significant financial relationships to disclose.

Docetaxel as adjuvant and neoadjuvant treatment for patients with breast cancer

Developments in the role of adjuvant and neoadjuvant chemotherapy for the treatment of patients with breast cancer have focused on the taxes, in particular, docetaxel. This paper discusses the rationale for the introduction of docetaxel into the management of patients following surgery and also its role in those patients with locally-advanced disease, focussing on key clinical trials. The addition of docetaxel to standard adjuvant chemotherapeutic regimens does seem to result in an increased survival in some patients with early-stage disease. In the neoadjuvant setting, the addition of docetaxel to standard regimens does increase pathological response rates, which is a surrogate marker of eventual outcome.

Dose-intensified chemotherapy and additional Docetaxel may improve inflammatory breast cancer patients outcome over two decades: Results from Institut Curie protocols 1977–1987 and two consecutive French multicenter trials Pegase 02 (1995–96) and Pegase 05 (1997–99)

848 Background: Standard anthracycline based chemotherapy had improved survival of inflammatory breast cancer. New modalities have been developed over the past 10 years including sequential high dose chemotherapy and newer drugs such as taxanes. Methods: We analyzed a first (G1) of patients uniformly treated with conventional chemotherapy in our institution and compared to a second group (G2) receiving sequential HDC and a third group (G3) with HDC + docetacel G1: 223 pts (1977–1987) were treated at the Institut Curie on 3 consecutive protocoles with conventional doxorubicine based CT G2: 95 pts (1995–96) were enrolled onto the multicenter trial Pegase 02 consisting in four 3 weekly cycles of doxorubicine 75mg/m2 associated with CPM (6g/m2 at C1; 3g/m2 atC2) and 5FU 3g/m2 at C3 and C4 G3: 54 pts (1997–99) accrued in Pegase 05 multicenter trial received four 3 weekly cycles of D75mg/m2 + CPM 6g/m2 at C1; CPM 3g/m2 at C2, C6 and C7; docetaxel 100mg/m2 q 2W was administred at C3, C4 and C5 Median survival 3 year OS and DFS were compared between the 3 groups. Conclusions: These results suggest some benefit from dose intensified CT in term of MSV, 3Y OS and DFS. Additional docetaxel seems to inprove 3Y OS and DFS Statistical significance in survival curves will be shown at the ASCO meeting. The impact of Taxotere is currently assessed in the randomized multicenter trial Pegase 07. No significant financial relationships to disclose.

Dose-intensified chemotherapy and additional Docetaxel may improve inflammatory breast cancer patients outcome over two decades: Results from Institut Curie protocols 1977–1987 and two consecutive French multicenter trials Pegase 02 (1995–96) and Pegase 05 (1997–99)

Dose-intensified chemotherapy and additional Docetaxel may improve inflammatory breast cancer patients outcome over two decades: Results from Institut Curie protocols 1977–1987 and two consecutive French multicenter trials Pegase 02 (1995–96) and Pegase 05 (1997–99)

Promising combination therapies with gemcitabine

Because treatment regimens for breast cancer commonly include gemcitabine, we evaluated two promising combinations in preclinical studies: gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) with either ionizing radiation or docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ). In breast cancer cell lines that expressed either wild-type p53 (MCF-7) or mutant p53 (MCF-7/Adr), sensitivity to the cytotoxic effects of gemcitabine during a 24-hour incubation was similar (IC 50 values 80 and 60 nmol/L in MCF-7 and MCF-7/Adr, respectively). Both cell lines were well radiosensitized by gemcitabine at the corresponding IC 50, with radiation enhancement ratios of 1.6 to 1.7. Although the MCF-7 cells accumulated nearly twice as much gemcitabine triphosphate compared with the MCF-7/Adr cells, a similar reduction in 2′-deoxyadenosine 5′-triphosphate pools was observed. While the number of dying cells, as measured by sub-G1 DNA content or S-phase cells unable to replicate DNA, differed between the wild-type p53 or mutant p53-expressing cell lines, neither parameter correlated with radiosensitization. Docetaxel was a more potent cytotoxic agent than gemcitabine in MCF-7 cells (IC 50 = 1 nmol/L). Strong synergistic cytotoxicity was observed in cells treated with gemcitabine (24 hours) followed by docetaxel (24 hours) or the reverse sequence. However, simultaneous addition of the two drugs was antagonistic. To determine whether synergy with radiation or docetaxel was mediated by increased DNA damage, DNA double-strand breaks (double-strand breaks) were measured by immunostaining for phosphorylated H2AX. Ionizing radiation produced more double-strand breaks than gemcitabine alone, while no significant double-strand breaks formed with docetaxel alone. The addition of docetaxel or ionizing radiation to gemcitabine-treated cells did not increase H2AX foci formation. These results show that the combination of gemcitabine with ionizing radiation or docetaxel produces strong, schedule-dependent synergy in breast cancer cells that is not mediated through increasing DNA double-strand breaks.