Maintenance Gemcitabine Research Articles

The observation of single-agent gemcitabine maintenance therapy in patients with metastatic breast cancer

Objective The aim of the study was to evaluate the efficacy and tolerability of single-agent gemcitabine in the maintenance treatment of histologically confirmed metastatic breast cancer cases.

Randomized Phase II trial of paclitaxel and carboplatin followed by gemcitabine switch-maintenance therapy versus gemcitabine and carboplatin followed by gemcitabine continuation-maintenance therapy in previously untreated advanced non-small cell lung cancer

BackgroundIn recent years, maintenance chemotherapy is increasingly being recognized as a new treatment strategy to improve the outcome of advanced non-small cell lung cancer (NSCLC). However, the optimal maintenance strategy is still controversial. Gemcitabine is a promising candidate for single-agent maintenance therapy because of little toxicity and good tolerability. We have conducted a randomized phase II study to evaluate the validity of single-agent maintenance chemotherapy of gemcitabine and to compare continuation- and switch-maintenance.MethodsChemonaïve patients with stage IIIB/IV NSCLC were randomly assigned 1:1 to either arm A or B. Patients received paclitaxel (200 mg/m2, day 1) plus carboplatin (AUC 6 mg/mL/min, day 1) every 3 weeks in arm A, or gemcitabine (1000 mg/m2, days 1 and 8) plus carboplatin (AUC 5 mg/mL/min, day1) every 3 weeks in arm B. Non-progressive patients following 3 cycles of induction chemotherapy received maintenance gemcitabine (1000 mg/m2, days 1 and 8) every 3 weeks. (Trial registration: UMIN000008252)ResultsThe study was stopped because of delayed accrual at interim analysis. Of the randomly assigned 50 patients, 49 except for one in arm B were evaluable. Median progression-free survival (PFS) was 4.6 months for arm A vs. 3.5 months for arm B (HR = 1.03; 95% CI, 0.45–2.27; p = 0.95) and median overall survival (OS) was 15.0 months for arm A vs. 14.8 months for arm B (HR = 0.79; 95% CI, 0.40–1.51; p = 0.60), showing no difference between the two arms. The response rate, disease control rate, and the transit rate to maintenance phase were 36.0% (9/25), 64.0% (16/25), and 48% (12/25) for arm A vs. 16.7% (4/24), 50.0% (12/24), and 33% (8/24) for arm B, which were also statistically similar between the two arms (p = 0.13, p = 0.32, and p = 0.30, respectively). Both induction regimens were tolerable, except that more patients experienced peripheral neuropathy in arm A. Toxicities during the maintenance phase were also minimal.ConclusionSurvival and overall response were not significantly different between the two arms. Gemcitabine may be well-tolerable and feasible for maintenance therapy.

FDG-PET/CT-based restaging may alter initial management decisions and clinical outcomes in patients with locally advanced pancreatic carcinoma planned to undergo chemoradiotherapy

The impact of [18F]fluorodeoxyglucose-positron emission tomography (PET)/computed tomography (CT) restaging on management decisions and outcomes in patients with locally advanced pancreatic carcinoma (LAPC) scheduled for concurrent chemoradiotherapy (CRT) is examined. Seventy-one consecutive patients with conventionally staged LAPC were restaged with PET/CT before CRT, and were categorized into non-metastatic (M0) and metastatic (M1) groups. M0 patients received 50.4 Gy CRT with 5-fluorouracil followed by maintenance gemcitabine, whereas M1 patients received chemotherapy immediately or after palliative radiotherapy. In 19 patients (26.8%), PET/CT restaging showed distant metastases not detected by conventional staging. PET/CT restaging of M0 patients showed additional regional lymph nodes in 3 patients and tumors larger than CT-defined borders in 4. PET/CT therefore altered or revised initial management decisions in 26 (36.6%) patients. At median follow-up times of 11.3, 14.5, and 6.2 months for the entire cohort and the M0 and M1 cohorts, respectively, median overall survival was 16.1, 11.4, and 6.2 months, respectively; median locoregional progression-free survival was 9.9, 7.8, and 3.4 months, respectively; and median progression-free survival was 7.4, 5.1, and 2.5 months, respectively (P < 0.05 each). These findings suggest that PET/CT-based restaging may help select patients suitable for CRT, sparing those with metastases from futile radical protocols, and increasing the accuracy of estimated survival.

Our Panel of Experts Highlight the most Important Articles Across the Spectrum of Topics Relevant to the field of Lung Cancer Management

Perol et al. performed a randomized Phase III trial for patients with advanced non-smallcell lung cancer (NSCLC) in which two maintenance strategies were investigated: continuation maintenance with gemcitabine or switch maintenance with erlotinib. A total of 464 NSCLC patients who did not progress after four cycles of induction chemotherapy with cisplatin plus gemcitabine were randomly assigned to observation, gemcitabine or erlotinib study arms until disease progression, unacceptable toxicity or death. On disease progression, patients in all three arms received pemetrexed as the predefined second-line therapy. A significant improvement in progression-free survival, the primary end point of the trial, with gemcitabine (3.8 vs 1.9 months; hazard ratio [HR]: 0.56; 95% CI: 0.44–0.72; p < 0.001) and erlotinib (2.9 vs 1.9 months; HR: 0.69; 95% CI: 0.54–0.88; p < 0.003) versus observation alone was observed. This benefit was consistent across all clinical subgroups. Progression-free survival improvement did not translate into a significant overall survival (OS) advantage in both gemcitabine versus observation (median OS: 12.1 vs 10.8 months; HR: 0.89; 95% CI: 0.69–1.15; p = 0.3867) and erlotinib versus observation (median OS: 11.4 vs 10.8 months; HR: 0.87; 95% CI: 0.68–1.13; p = 0.3043). The exploratory subgroup analysis suggested that patients who received second-line pemetrexed or with a performance status of 0 appeared to derive greater benefit in both maintenance arms, while the response to induction chemotherapy may affect the OS benefit as a result of gemcitabine maintenance. Maintenance gemcitabine and erlotinib were well tolerated, with no unexpected adverse events. This is the first study simultaneously exploring both continuous and switch maintenance therapy. This trial confirms that the maintenance strategy significantly improves duration of disease control in patients with advanced NSCLC. The lack of an OS benefit could be related to the standardization of second-line treatment with pemetrexed, which was also administered in all histology subgroups (~35% of patients in the three arms were affected by squamous or unknown NSCLC) because the study was designed and conducted before the labeling restriction of pemetrexed to nonsquamous NSCLC. Ongoing Phase III randomized trials exploring the two maintenance approaches might further help in defining the most appropriate strategy to employ in this setting.

Randomized, Phase III Study of Gemcitabine or Erlotinib Maintenance Therapy Versus Observation, With Predefined Second-Line Treatment, After Cisplatin-Gemcitabine Induction Chemotherapy in Advanced Non–Small-Cell Lung Cancer

This phase III study investigated whether continuation maintenance with gemcitabine or switch maintenance with erlotinib improves clinical outcome compared with observation in patients with advanced non-small-cell lung cancer (NSCLC) whose disease was controlled after cisplatin-gemcitabine induction chemotherapy. Four hundred sixty-four patients with stage IIIB/IV NSCLC without tumor progression after four cycles of cisplatin-gemcitabine were randomly assigned to observation or to gemcitabine (1,250 mg/m(2) days 1 and 8 of a 3-week cycle) or daily erlotinib (150 mg/day) study arms. On disease progression, patients in all three arms received pemetrexed (500 mg/m(2) once every 21 days) as predefined second-line therapy. The primary end point was progression-free survival (PFS). PFS was significantly prolonged by gemcitabine (median, 3.8 v 1.9 months; hazard ratio [HR], 0.56; 95% CI, 0.44 to 0.72; log-rank P < .001) and erlotinib (median, 2.9 v 1.9 months; HR, 0.69; 95% CI, 0.54 to 0.88; log-rank P = .003) versus observation; this benefit was consistent across all clinical subgroups. Both maintenance strategies resulted in a nonsignificant improvement in overall survival (OS); patients who received second-line pemetrexed or with a performance status of 0 appeared to derive greater benefit. Exploratory analysis showed that magnitude of response to induction chemotherapy may affect the OS benefit as a result of gemcitabine maintenance. Maintenance gemcitabine and erlotinib were well tolerated with no unexpected adverse events. Gemcitabine continuation maintenance or erlotinib switch maintenance significantly reduces disease progression in patients with advanced NSCLC treated with cisplatin-gemcitabine as first-line chemotherapy. Response to induction chemotherapy may affect OS only for continuation maintenance.

711P - Does FDG-PET-CT based Re-Staging Influences Initial Management Decision and Clinical Outcome in Patients with locally advanced Pancreatic Carcinoma Planned to Undergo Chemoradiotherapy?

ABSTRACT Background Impact of re-staging with 18F-fluoro-deoxy-glucose positron emission tomography (PET-CT) on management decision and clinical outcomes in patients with locally-advanced pancreatic carcinoma (LAPC) initially planned to undergo concurrent chemoradiotherapy (CRT) was investigated. Materials and methods Seventy-one consecutive patients with conventionally staged LAPC were re-staged with PET-CT before CRT. Patients were categorized into non-metastatic (M0) and metastatic (M1) groups according to PET-CT findings. M0patients underwent 50.4 Gy (1.8 Gy/fr) of radiotherapy and concurrent 5-FU followed by maintenance gemcitabine. Results Re-staging PET-CT revealed conventional imaging occult distant metastases in 19 cases (26.8%). Of 52 patients with LAPC confirmed by PET-CT, additional regional lymph nodes were identified to be involved in 7 (13.4%), mandating enlargement of radiation field. Taken together, PET-CT results changed or revised initial management decision in 37.2% patients. Median follow-up times for the whole, M0 and M1 cohorts were 11.3, 14.5, and 6.2 months, respectively. Median overall, locoregional progression-free, and progression-free survivals for the same cohorts were 11.4, 7.8, and 5.1 months,16.1, 9.9, and 7.4 months, and 6.2, 3.4, and 2.5 months, respectively. Survival differences between M0 and M1 cohorts were statistically significant (p Conclusions Current results demonstrated the importance of PET-CT based re-staging of LAPC in selection of suitable patients for CRT, prevention of useless aggressive treatment in metastatic cases, and precise estimation of survival outcomes of LAPC patients following radical CRT. Disclosure All authors have declared no conflicts of interest.

715P - Timing and Patterns of Disease Progression Following Concurrent Radiochemotherapy in Patients with Unresectable Locally-Advanced Pancreas Cancer

ABSTRACT Background Timing and patterns of disease progression in patients with unresectable locally-advanced pancreas carcinoma (LAPC) treated with definitive concurrent radiochemotherapy (C-RCT) was analyzed. Materials and method Fifty-two patients with histologic proof of LAPC underwent 50.4 Gy (1.8 Gy per fraction) of C-RCT with 5-FU followed by maintenance gemcitabine. Disease was considered to be unresectable if contrast-enhanced CT or staging laparoscopy/laparotomy revealed a low likelihood of complete resection and/or any of the following: involvement of superior mesenteric artery/cealiac trunk, encasement of 180 degrees or more of the circumference of superior mesenteric/portal vein, and/or evidence of narrowing of or thrombus within the superior mesenteric/portal vein. Elective nodal irradiation was not adopted. Primary aim was to assess timing and patterns of disease progression. Results Treatment was well tolerated and all patients were able to receive intended C-RCT regimen. At median 17.4 months of follow-up 38 (73.1%) were dead. Median, 1- and 2-year overall- and progression-free survival estimates were 16.1 months, 61.2% and 22.6%, and 7.4 months, 27% and 12.3% respectively. Analysis for timing of disease progression revealed that 7 (13.5%), 15 (28.8%), 20 (38.5%), and 22 (42.3%) patients experienced disease progression at 3, 4, 5, and 6 months, respectively, since initiation of R-RCT. Interestingly, although there were no isolated local or regional failures during this early follow-up period, all failures were presented as distant metastases with/without local/regional disease progression. Conclusion Results of this study demonstrated that, despite aggressive staging and treatment strategies, early distant disease progression are common source of treatment failures in unresectable LAPC. Present findings impact the urgent need for more efficacious chemotherapeutic agents for control of distant metastatatic tumor deposits and better treatment strategies, such as induction chemotherapy followed by C-RCT, to eliminate early treatment failures and unnecessary and futile C-RCT in metastatic disease state. Disclosure All authors have declared no conflicts of interest.

1219 - Cost-Utility Analysis of Maintenance Therapy with Either Gemcitabine or Erlotinib versus Observation with Predefined Second-Line Treatment after Cisplatin-Gemcitabine Induction Chemotherapy in Advanced Nsclc: Ifct-Gfpc 0502-ECO Phase III Study

ABSTRACT Rationale The IFCT–GFPC 0502 phase III reported prolongation of progression-free survival with maintenance with either gemcitabine or erlotinib versus observation after cisplatin-gemcitabine chemotherapy in advanced NSCLC. Their incremental cost-effectiveness ratio (ICER) was assessed in global population and in pre specified sub-groups. Methods A cost-utility analysis was performed to evaluate ICER of maintenance therapy with either gemcitabine or erlotinib, compared to observation. Direct medical costs (drugs costs, hospitalization, examinations, second-line treatments and palliative costs) were prospectively collected per patient alongside the trial, until death, from the third party payer perspective. Utility were extracted from literature. Sensitivity analyses were performed. Results ICER for maintenance therapy with gemcitabine and erlotinib were respectively 76 625 and 184 733 €/quality-adjusted life years (QALY). Gemcitabine maintenance therapy had favourable ICER in patients with PS = 0 (52 213 €/QALY), in responders to induction chemotherapy (64 296 €/QALY) and in patients with adenocarcinoma (62 292 €/QALY); erlotinib had favourable ICER if PS = 0 (94 908 €/QALY), in patients with adenocarcinoma (97 160 €/QALY) and objective response to induction (101,186 €/QALY), but it is not cost-effective in patients with PS = 1, other histology or if stable disease. Conclusion Gemcitabine and erlotinib maintenance therapy have acceptable ICER but with wide variation, function of histology, PS and response to the first line chemotherapy. Disclosure I. Borget: Honoraria from Roche for set up a class in health economy (no relation with the present study). M. Perol: consultant or advisory board with Roche, Lilly (myself) Honoraria from Lilly, Roche, Pfizer, Boehringer Ingelheim (myself) Research funding from Lilly, Roche (myself). D. Perol: Honoraria : Roche (myself). G. Zalcman: Honoraria from Lilly, Roche Research funding from Lilly, Roche. A. Vergnenegre: honoraria and research funding from Roche. C. Chouaid: Honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffman la Roche, Astra Zeneka, Sanofi Aventis, Lilly, Novartis and Amgen Research funding from AstraZeneca, Lilly, Novartis and Amgen. All other authors have declared no conflicts of interest.

Impact of omission of elective nodal irradiation on treatment outcomes in locally advanced pancreatic adenocarcinoma patients treated with definitive concurrent chemoradiotherapy

BackgroundWe evaluated influence of limited-field radiotherapy with no elective nodal irradiation (ENI) on outcomes and toxicity profile in patients with locally advanced pancreatic adenocarcinoma (LAPAC), treated with definitive concurrent chemoradiotherapy (C-CRT). MethodsThirty-five patients with histological proof of LAPAC underwent 50.4Gy of C-CRT with 5-FU followed by maintenance gemcitabine. Target volume included primary tumor and lymph nodes that appeared to be involved on either contrast-enhanced computerized tomography or 18F-fluoro-deoxyglucose positron emission tomography. ResultsNo grade 4/5 acute/late toxicity was reported at median 15.7 months. Acute hematologic plus non-hematologic grade 3 toxicity was noted in 10 (28.6%) patients. At long-term, 2 patients (5.7%) experienced grade 3 gastric outlet obstructions at 8.7 and 10.9 months, respectively. No isolated regional relapses were noted. Median overall-survival (OS), progression-free survival (PFS), and locoregional-PFS (LRPFS) were 15.2, 9.1 and 7.3 months, respectively. Corresponding 1- and 2-year survival estimates were 60.0% and 20.0% for OS, 41.9% and 17.4% for LRPFS, and 34.0% and 12.7% for PFS, respectively. ConclusionsCompared to ENI literature, first report of a limited-field C-CRT study carried out in Turkey showed that omission of ENI was relatively well tolerated without compromising survival and locoregional control rates in patients with LAPAC.

Phase II clinical trial of induction chemotherapy with fixed dose rate gemcitabine and cisplatin followed by concurrent chemoradiotherapy with capecitabine for locally advanced pancreatic cancer

5-FU-based concurrent chemoradiotherapy (CRT) has been the mainstay of treatment for locally advanced pancreatic cancer (LAPC) for the past decades, but the prognosis remains dismal. Patients with pathologically confirmed LAPC of the pancreas, an ECOG PS of 0-2 and no prior chemo- or radiotherapy were eligible. The treatment consisted of induction (IND) chemotherapy with a fixed dose rate gemcitabine 1,000 mg/m(2) on days 1 and 8 and CDDP 60 mg/m(2) on day 1 every 3 weeks for 3 cycles. Subsequently, the patients without progression received CRT of 55.8 Gy/31 fractions with capecitabine 650 mg/m(2) twice daily. Gemcitabine was given for 3 cycles after CRT. The primary endpoint was time to progression. Thirty-seven patients with LAPC were enrolled. Median age was 55 years, there were 20 males and 17 females, and ECOG PS was 0 in 6 and 1 in 31. Three patients (9.7 %) achieved partial responses after IND chemotherapy. Twenty-five patients received CRT with a mean radiation dose of 54.0 Gy, with one additional patient achieving a partial response. The median time to progression was 7.2 months (95 % CI, 4.4-10), and the median overall survival was 16.8 months (95 % CI, 12.9-20.7). The grade 3/4 toxicities included neutropenia (29 %/6.5 %), thrombocytopenia (3.2 %/0 %) and anemia (9.7 %/0 %) during the IND phase and grade 3 neutropenia and diarrhea occurring in one and two patients during CRT phase. IND chemotherapy with gemcitabine and cisplatin followed by CRT with capecitabine and maintenance gemcitabine was well tolerated and exhibited promising efficacy for the treatment of LAPC.

P-0120 Prognostic Value of Gross Tumor Volume Delineated by Fdg-Pet-Ct-Based Radiotherapy Treatment Planning Locally Advanced Pancreatic cancer Treated with Chemoradiotherapy

IntroductionWe aimed to assess whether gross tumor volume (GTV) determined by fusion of contrast-enhanced computerized tomography (CT) and 18F-fluoro-deoxy-D-glucose positron emission tomography-CT (FDG-PET-CT) based radiotherapy planning could predict outcomes, namely overall survival (OS), local-regional progression-free survival (LRPFS), and progression-free survival (PFS) in cases with locally advanced pancreas cancer (LAPC) treated with definitive concurrent chemoradiotherapy. MethodsA total of 30 patients with histological proof of LAPC underwent 50.4 Gy (1.8 Gy/28 fractions) of radiotherapy concurrent with continuously infused 5-FU followed by 4 to 6 courses of maintenance gemcitabine. Target volume delineations were performed on FDG-PET-CT-based RTP. Patients were stratified into 2 groups: GTV lesser (GTVL) versus greater (GTVG) than cut off value determined by receiver operating characteristic (ROC) analysis, and compared in terms of OS, LRPFS and PFS. ResultsMedian GTV delineated according to the FDG-PET-CT data was 100.0 cm3. Cut off GTV value determined from ROC curves was 91.1cm3. At a median follow up of 11.2 months, median OS, LRPFS and PFS for the entire population were 10.3, 7.8 and 5.7 months, respectively. Median OS, LRPFS and PFS for GTVL and GTVG cohorts were 16.3 vs. 9.5 (p=0.005), 11.0 vs. 6.0 (p=0.013), and 9.0 vs. 4.8 months (p=0.008), respectively. ConclusionThe superior OS, LRPFS and PFS observed in GTV L patients over GTVG ones suggests a potential for FDG-PET-CT-defined GTV size in predicting outcomes of LAPC patients treated with definitive C-CRT, which needs to be validated by further studies with larger cohorts.

Cost-utility analysis of maintenance therapy with either gemcitabine or erlotinib versus observation with predefined second-line treatment after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC: IFCT-GFPC 0502-eco phase III study.

e16560 Background: The IFCT–GFPC 0502 phase III study reported a prolongation of progression-free survival with maintenance with either gemcitabine or erlotinib versus observation after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC. The aim of this analysis is to assess the incremental cost-effectiveness ratio (ICER) of these strategies in the global population and in pre specified sub-groups. Methods: A cost-utility analysis was performed to evaluate ICER of maintenance therapy with either gemcitabine or erlotinib, compared to observation, from randomization until end of follow up. Direct medical costs (including drugs costs, hospitalization, follow-up examinations, second-line treatment and palliative costs) were prospectively collected per patient alongside the trial, until death, from the third party payer perspective. Utility data were extracted from literature. Sensitivity analyses were performed. Results: The ICER for maintenance therapy with gemcitabine and erlotinib were respectively 84,011 and 183,261 euros per quality-adjusted life years (QALY). Gemcitabine maintenance therapy had a favourable ICER in patients with PS = 0 (51,168 €/Qaly), in responders to induction chemotherapy (65,554€/Qaly) and in patients with squamous cell carcinoma (44,884€/Qaly); erlotinib had a favourable ICER in patients with PS = 0 (162,371 €/Qaly) and objective response to induction (101,569 €/Qaly ). Conclusions: Gemcitabine and erlotinib maintenance therapy have acceptable ICER but with a wide variation function of histology, PS and response to the first line chemotherapy.

Efficacy of pemetrexed as second-line therapy in advanced NSCLC after either treatment-free interval or maintenance therapy with gemcitabine or erlotinib in IFCT-GFPC 05-02 phase III study.

7574 Background: Continuous exposure of tumor cells to maintenance therapy in advanced NSCLC might lead to resistance to subsequent treatments. IFCT–GFPC 0502 study showed a progression-free survival (PFS) benefit with gemcitabine (G) or erlotinib (E) maintenance compared to observation (O) after cisplatin-G induction chemotherapy. The trial included a pre-defined second-line therapy with pemetrexed (P), allowing post-hoc assessment of its efficacy according to previous maintenance treatment or treatment-free interval. Methods: Stage IIIB/IV NSCLC patients (pts) with a PS of 0-1 were randomized after 4 cycles of cisplatin-G chemotherapy to O or to receive maintenance therapy with G or E until disease progression. P was given as second-line treatment on disease progression in all arms. PFS and OS were assessed from the beginning of P therapy according to randomization arm. Tumor response to P and tolerance were also analyzed. Results: Of the 464 pts randomized to either O (155), G (154) or E (155), 360 pts (78 %) received P as second-line therapy, i.e. 130 (84%), 114 (74%) and 116 (75%) in O, G and E arm, respectively. Baseline characteristics remained well balanced between arms (overall median age of 58 years, 28% female, 91% stage IV, 41% PS 0, 65/19/16%, adenocarcinoma/squamous/other, 10% non-smokers and 56% responders to induction CT). Median number of delivered P cycles was 3 (1-40) in all arms. Response rate was 19%, 7% and 15% for non-squamous pts in O, G and E, respectively. Median PFS did not significantly differ between G and O (4.2 vs 3.9 months, HR [95% CI] 0.81 [0.62-1.06]) or E and O (4.2 vs 3.9 months, HR 0.83 [0.64-1.09]). OS data showed a non-significant improvement with G vs O (HR 0.81 [0.61-1.07]) or E vs O (HR 0.80 [0.61-1.05]), with a median of 7.5, 8.3 and 9.1 months for O, G and E, respectively. Results were similar when analysis was restricted to non-squamous pts. Grade 3-4 treatment-related AEs were similar in O (33.1%), G (31.6%) and E (25%). Conclusions: Maintenance therapy with continuation of G or switch to E does not impair the efficacy of second-line P by comparison with administration after a treatment-free interval.

1666 SWOG S0353 PHASE II TRIAL OF INTRAVESICAL GEMCITABINE IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER WHO RECURRED FOLLOWING AT LEAST TWO PRIOR COURSES OF BCG

INTRODUCTION AND OBJECTIVES: The optimal treatment for patients with intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) who have recurred following intravesical BCG therapy is unclear. Gemcitabine has good activity against urothelial cancer when used systemically, and prior Phase I & II studies have shown it to be active and well tolerated when used intravesically. However, durable responses following a single 6-week induction course have been observed in 30% of high-risk patients. SWOG performed a multi-institutional phase II study to evaluate the potential role of gemcitabine induction plus maintenance therapy in this setting. METHODS: Eligible patients had recurrent NMIBC, stage Tis, T1, Ta high-grade (HG), or Ta low-grade (LG) with 2 lesions, following a minimum of 2 prior courses of intravesical BCG therapy (6 6 weeks or 6 3 weeks, with or without maintenance). Prior single dose peri-operative chemotherapy and up to 1 course of weekly intravesical chemotherapy within the prior year were allowed. All visible lesions were resected and patients were treated with 2gm gemcitabine in 100cc NS weekly x6 and then monthly to 12 months. Patients had bladder biopsy at the initial 3-month evaluation following induction, and then were followed with cystoscopy and cytology every 3 months with further biopsies as clinically indicated. Initial response required negative cystoscopy, cytology and biopsy at 3 months. RESULTS: 58 patients were enrolled; 9 were ineligible and 2 received no treatment. Of 47 evaluable patients, 41 (87%) had high-risk disease, with HGTa in 11 (23%), HGT1 in 2 (4%), and Tis in 28 (8 with and 20 without associated papillary lesions). All patients have been followed a minimum of 12 months. Thirty patients had G1-2 toxicity, mostly dysuria and urinary frequency, while 3 had G3 toxicity (dysuria, frequency and neutropenia). At the initial 3-month evaluation, 21 (45%) patients were free of disease while 13 patients were continuously disease free at 12 months (28% of evaluable patients and 62% of the initial responders). CONCLUSIONS: Intravesical gemcitabine has activity in high risk BCG refractory NMIBC. However, only a minority of patients with intermediate to high-risk disease who have recurred after 2 prior courses of intravesical BCG will attain a durable response to this treatment, even with the addition of monthly maintenance treatments.

Prognostic value of gross tumor volume delineated by FDG-PET-CT based radiotherapy treatment planning in patients with locally advanced pancreatic cancer treated with chemoradiotherapy

BackgroundWe aimed to assess whether gross tumor volume (GTV) determined by fusion of contrast-enhanced computerized tomography (CT) and 18F-fluoro-deoxy-D-glucose positron emission tomography-CT (FDG-PET-CT) based radiotherapy planning could predict outcomes, namely overall survival (OS), local-regional progression-free survival (LRPFS), and progression-free survival (PFS) in cases with locally advanced pancreas cancer (LAPC) treated with definitive concurrent chemoradiotherapy.MethodsA total of 30 patients with histological proof of LAPC underwent 50.4 Gy (1.8 Gy/28 fractions) of radiotherapy concurrent with continuously infused 5-FU followed by 4 to 6 courses of maintenance gemcitabine. Target volume delineations were performed on FDG-PET-CT-based RTP. Patients were stratified into 2 groups: GTV lesser (GTVL) versus greater (GTVG) than cut off value determined by receiver operating characteristic (ROC) analysis, and compared in terms of OS, LRPFS and PFS.ResultsMedian GTV delineated according to the FDG-PET-CT data was 100.0 cm3. Cut off GTV value determined from ROC curves was 91.1 cm3. At a median follow up of 11.2 months, median OS, LRPFS and PFS for the entire population were 10.3, 7.8 and 5.7 months, respectively. Median OS, LRPFS and PFS for GTVL and GTVG cohorts were 16.3 vs. 9.5 (p = 0.005), 11.0 vs. 6.0 (p = 0.013), and 9.0 vs. 4.8 months (p = 0.008), respectively.ConclusionsThe superior OS, LRPFS and PFS observed in GTVL patients over GTVG ones suggests a potential for FDG-PET-CT-defined GTV size in predicting outcomes of LAPC patients treated with definitive C-CRT, which needs to be validated by further studies with larger cohorts.

Phase II Trial of Full-Dose Gemcitabine and Bevacizumab in Combination With Attenuated Three-Dimensional Conformal Radiotherapy in Patients With Localized Pancreatic Cancer

To evaluate response rate, survival, and toxicity in patients with nonmetastatic pancreatic cancer treated with gemcitabine, bevacizumab, and radiotherapy. Patients received three cycles of therapy over 10 weeks. In total, treatment consisted of intravenous (IV) gemcitabine, 1,000 mg/m(2), every 1 to 2 weeks (7 doses), IV bevacizumab, 10 mg/kg every 2 weeks (5 doses), and 36 Gy of radiotherapy (2.4-Gy fractions during cycle two). Response was assessed by cross-sectional imaging and carbohydrate antigen 19-9 (CA 19-9) levels. Patients with resectable tumors underwent surgery 6 to 8 weeks after the last dose of bevacizumab. Maintenance gemcitabine and bevacizumab doses were delivered to patients who had unresected tumors and no progression. Twenty-eight of the 32 enrolled patients completed all three cycles. The median follow-up was 11.07 months. Most grade 3 or 4 toxicities occurred in the initial treatment phase; the most frequent toxicities were leukopenia (21%), neutropenia (17%), and nausea (17%). At week 10, 1 patient (4%) had a complete response, 2 patients (7%) had partial responses, 21 patients (75%) had stable disease, and 4 patients (14%) had progressive disease. The median pretreatment and posttreatment CA 19-9 levels (25 patients) were 184.3 and 57.9 U/ml, respectively (p = 0.0006). One of 10 patients proceeding to surgery experienced a major complication. Two of 6 patients undergoing resection had complete pathologic responses. The median progression-free and overall survival durations were 9.9 months and 11.8 months, respectively. The combination of full-dose gemcitabine, bevacizumab, and radiotherapy was active and was not associated with a high rate of major surgical complications.

Successful Treatment with GEMOX in Patient with Metastatic Pancreatic Adenosquamous Carcinoma

Pancreatic adenosquamous carcinoma (PASC) is a rare subtype of pancreatic cancer characterized by a dual histological component and aggressive behavior. This form is not well known, its histogenesis is uncertain, and there are different opinions on the diagnostic histopathological criteria. The differential diagnosis with more common ductal adenocarcinoma, squamous cell carcinoma, squamous or adenosquamous metastases is complex. The available therapies do not improve the poor prognosis and it is difficult to find long-term survivors (more than 1 year), even after demolitive surgery with complementary therapies. We report a case of advanced PASC with excellent progression-free survival and overall survival, 20 months and 29 months, respectively. Furthermore, an almost complete response was obtained to first-line chemotherapy with gemcitabine/oxaliplatin (GEMOX) followed by maintenance gemcitabine. GEMOX followed by gemcitabine as maintenance could be an effective treatment for this pancreatic entity. Further reports are needed to confirm this outcome.

Cancer du pancréas localement évolué non resécable : chimioradiothérapie d’induction suivie de chimiothérapie par gemcitabine contre chimiothérapie exclusive par gemcitabine : résultats définitifs de l’étude de phase III 2000–2001de la FFCD et de la SFRO

Purpose To compare chemoradiation with systemic chemotherapy to chemotherapy alone in locally advanced pancreatic cancer. Patients and methods One hundred and nineteen patients with locally advanced pancreatic cancer, with World Health Organization performance status of zero to two were randomly assigned to either the induction chemoradiation group (60 Gy, 2 Gy/fraction; concomitant 5-fluoro-uracil infusion, 300 mg/m 2 per day, days 1–5 for 6 weeks; cisplatin, 20 mg/m 2 per day, days 1–5 during weeks 1 and 5) or the induction gemcitabine group (GEM: 1000 mg/m 2 weekly for 7 weeks). Maintenance gemcitabine (1000 mg/m 2 weekly, 3/4 weeks) was given in both arms until disease progression or toxicity. Results Overall survival was shorter in the chemoradiation than in the gemcitabine arm (median survival 8.6 [99% confidence interval 7.1–11.4] and 13 months [8,9,9–18], p = 0.03). One-year survival was, respectively, 32 and 53%. These results were confirmed in a per-protocol analysis for patients who received 75% or more of the planned dose of radiotherapy. More overall grades 3–4 toxic effects were recorded in the chemoradiation arm, both during induction (36 versus 22%) and maintenance (32 versus 18%). Conclusion This intensive induction schedule of chemoradiation was more toxic and less effective than gemcitabine alone.

Maintenance with either gemcitabine or erlotinib versus observation with predefined second-line treatment after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC: IFCT-GFPC 0502 phase III study.

7507 Background: NSCLC patients (pts) whose tumors have not progressed following platinum-based chemotherapy (CT) obtain PFS and OS benefits with maintenance CT or erlotinib (E). We investigated maintenance gemcitabine (G) or E vs observation (O), following induction CT. Unlike previous maintenance trials, we included a predefined second-line therapy in all arms (pemetrexed [P]). Methods: Stage IIIB/IV pts with an ECOG PS of 0-1 whose tumors did not progress following four cycles of cisplatin-gemcitabine were randomized (stratified by center, gender, histology, response to induction CT and smoking status) to O, or to receive as maintenance therapy either G (1,250 mg/m2, days 1 and 8 of a 3 week cycle) or E 150 mg/day until disease progression. The primary endpoint was PFS by independent review with an 80% power to detect a 50% improvement in the median PFS (HR 0.66) for each comparison (G vs O and E vs O) at a two-sided 5% alpha level. Results: Of the 834 pts who received induction CT, 464 were randomized from November 06-September 09 to either O (155), G (154) or E (155). Baseline characteristics were well balanced between arms (overall 27% female, 91% stage IV, 50% ECOG PS 0, 65/20/15% adenocarcinoma/squamous/other, 38% non-smokers and 53% responders to induction CT). Median PFS by investigator assessment was 2.1, 3.7 and 2.8 months for O, G and E respectively. PFS by independent review (83% pts assessed) was significantly prolonged by G (HR [95% CI] 0.51 [0.39-0.66]) and E (HR 0.83 [0.73-0.94]) vs O. Second--line P was received by 72/55/60% of pts, respectively. Grade 3-4 treatment-related AEs were more common with G (27%) and E (14%) than with O (2%). Final results of the independent review will be available for the meeting, and will include mature OS data, subgroup analyses by stratification factors and EGFR mutation status. Conclusions: Maintenance with G or E significantly delays disease progression after cisplatin-gemcitabine induction. The impact on OS with a predefined second-line therapy will be discussed in the May 2010 update. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, GlaxoSmithKline, Lilly, Merck Serono, Pfizer, Roche Amgen, AstraZeneca, GlaxoSmithKline, Lilly, Merck, Merck Serono, Novartis, Roche Amgen, Lilly, Pfizer, Roche Lilly, Roche

Phase III study of maintenance gemcitabine (G) and best supportive care (BSC) versus BSC, following standard combination therapy with gemcitabine-carboplatin (G-Cb) for patients with advanced non-small cell lung cancer (NSCLC).

7506 Background: The use of single agent cytotoxic or targeted agent as maintenance following combination therapyrepresents a useful strategy to improve patient outcomes in advanced stage NSCLC. An earlier study with gemcitabine as maintenance therapy demonstrated improved time to progression (TTP) compared to BSC (6.6 mos. vs 5.0 mos., p < 0.001) (Brodowicz et al, Lung Cancer, 2006; 52:155-163). Based on this, we conducted a randomized phase III study to compare G + BSC versus BSC as maintenance therapy for patients with advanced NSCLC. Methods: Patients with stage IIIB (wet)/IV NSCLC were initially treated with gemcitabine (1,000 mg/m2 on day 1 and 8) and carboplatin (AUC = 5 mg/mL.min on d 1) every 3 weeks for 4 cycles. Subsequently, patients with CR/PR or SD were randomized 1:1 to receive maintenance G (1,000 mg/m2 on d 1 and 8), every 3 weeks with BSC or BSC alone until disease progression. The primary endpoint was the comparison of overall survivalbetween the two arms and the secondary endpoint was progression free survival (PFS). Results: 519 patients were enrolled (median age-67 years, stage IV disease- 86%, ECOG performance status 0/1-75%). With G-Cb, the RR was 28% (CR-1.2%, PR-26.8%), and 37% had SD. Following 4 cycles of G-Cb, 255 non- progressors were randomized to receive G + BSC (n = 128) or BSC (n = 127). The median PFS was 3.9 m (95% CI:3.3, 5.6) for G + BSC and 3.8 m (95% CI: 2.6, 5.5) for BSC. Median survival was 8.0 m (95% CI: 6.0, 10.2) for G+ BSC and 9.3 m (95% CI: 7.7, 12.7) for BSC. The differences in survival between the two arms were not statistically significant (HR = 0.97 [95% CI: 0.72, 1.30], p = 0.84). Maintenance therapy was tolerated well despite a higher incidence of grade 3/4 toxicity (anemia 9.4% vs. 2.4%; neutropenia 13.3% vs. 1.6%; thrombocytopenia 9.4% vs. 1.4%; and fatigue 3.9% vs. 1.6%). Conclusions: The use of gemcitabine as maintenance therapy failed to improve survival following G-Cb in patients with advanced NSCLC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly