Median Time To Disease Progression Research Articles

A phase 2 study of a fixed combination of uracil and ftorafur and leucovorin given orally in a twice‐daily regimen to treat patients with recurrent metastatic breast cancer

UFT, a combination of uracil and ftorafur, was developed to combine the cytotoxic effects of 5-fluorouracil (5-FU) with convenient oral dosing. Leucovorin is combined with UFT to further potentiate the effect of 5-FU on tumor cells. Orally administered UFT and leucovorin provide higher peak plasma concentrations of 5-FU and prolonged therapeutic 5-FU concentrations compared with continuous infusion of 5-FU. Ninety-four patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35-day cycle. The total daily dose of UFT was 300 mg/m(2), which was given in 2 divided doses every 12 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (OR = complete response [CR] + partial response [PR]) and overall survival (OS). Of the 94 patients enrolled, 68 were evaluable for efficacy. Although no CRs were observed, 9 patients achieved PRs, for an OR of 13.2% in the evaluable population. The median TTP for the evaluable population was 10.3 weeks, and the proportion of patients free of disease progression at 6 months was 17%. The median OS was 61.6 weeks for all patients enrolled. The most common drug-related >or= grade 3 adverse events (graded using the National Cancer Institute Common Toxicity Criteria version 2) were diarrhea, asthenia, nausea, and dehydration. The combination of UFT and leucovorin administered orally in a twice-daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes.

A phase 2 study of a fixed combination of uracil and ftorafur (UFT) and leucovorin given orally in a 3‐times‐daily regimen to treat patients with recurrent metastatic breast cancer

A combination of uracil and ftorafur (UFT) was developed to combine the cytotoxic effects of 5-fluorouracil (5-FU) with convenient oral dosing. Leucovorin was combined with UFT to further potentiate the effect of 5-FU on tumor cells. Orally administered UFT and leucovorin provided higher peak plasma concentrations of 5-FU and prolonged therapeutic 5-FU concentrations compared with continuous infusion of 5-FU. Ninety-one patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35-day cycle. The total daily dose of UFT was 300 mg/m(2), administered in 3 doses of 100 mg/m(2) each every 8 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (overall response equals complete response plus partial response) and overall survival. Of the 91 patients enrolled, 70 were evaluable for efficacy. Although no complete responses were observed, 7 patients had partial responses, for an overall response rate of 10% in the evaluable population. The median TTP for the evaluable population was 10 weeks, and the proportion of patients who were free of disease progression at 6 months was 23%. The median overall survival was 59.4 weeks for all patients enrolled. Common, drug-related > or = grade 3 adverse events (graded according to National Cancer Institute Common Toxicity Criteria, version 2) included diarrhea, vomiting, abdominal pain, and nausea. The combination of UFT and leucovorin administered orally in a 3-times-daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes.

Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer

BackgroundThe purpose of this study was to compare docetaxel plus epirubicin versus docetaxel plus capecitabine combinations as front-line treatment in women with advanced breast cancer (ABC). Patients and MethodsPreviously untreated patients with ABC were randomly assigned to receive docetaxel 75 mg/m2 plus epirubicin 75 mg/m2 (DE) on day 1 or docetaxel 75 mg/m2 on day 1 plus capecitabine 950 mg/m2 orally twice daily on days 1–14 (DC) in 21-day cycles. Previous anthracycline-based (neo)-adjuvant chemotherapy was allowed if completed >1 year before enrollment. The primary objective of the study was to compare time to disease progression (TTP). ResultsOne hundred and thirty-six women were treated on each arm and median TTP was 10.6 versus 11.0 months (P = 0.7), for DE and DC, respectively. According to RECIST criteria we observed 15 (11%) versus 11 (8%) complete responses and 55 (40%) versus 61 (45%) partial responses (P = 0.8), with DE and DC, respectively. Severe toxicity included grade 3–4 neutropenia (57% versus 46%; P = 0.07), febrile neutropenia (11% versus 8%; P = 0.4), hand–foot syndrome (0% versus 4%; P = 0.02), grade 2–3 anemia (20% versus 7%; P = 0.001) and asthenia (12% versus 6%; P = 0.09) with DE and DC, respectively. ConclusionsThe DE and DC regimens have similar efficacy but different toxicity. Either regimen can be used as front-line treatment of ABC.

The Analysis of Erlotinib on Brain Metastases in Patients with Non-small-cell Lung Cancer.

Brain metastases are common in non-small-cell lung cancer (NSCLC) and the prognosis is poor. Erlotinib is a specific inhibitor of the epidermal growth factor receptor-associated tyrosine kinase (EGFRTKI), which has been gradually used in the treatment for advanced NSCLC. The aim of this study is to evaluate the antitumor efficacy and its relevant factors of erlotinib in NSCLC patients with brain metastases. The clinical data of 30 NSCLC patients with brain metastases were reviewed retrospectively. All of them were treated with erlotinib, given orally 150mg daily. These patients discontinued administration of erlotinib until disease progression, death or intolerable side effects. In terms of intracranial lesions, partial response (PR) was observed in 2 patients (6.7%), with stable disease (SD) in 17 patients (56.7%), for overall disease control rate (DCR) of 63.4%. As for systemic disease, PR was observed in 2 patients (6.7%), with SD in 5 patients (16.7%), for overall DCR of 23.4%. There was no statistical difference in DCR among different subtypes of age, gender, smoking history, histology, PS score, the number of brain metastases, the onset of brain metastases, chemotherapy, brain radiotherapy and side effects. The median time to disease progression (MTTP) and median survival time (MST) was 2.4 months and 7.7 months respectively. The 1 and 2 year survival rate was 38.4% and 15.2%. The univariate analysis showed that the survival time was related to the patients' PS score, smoking history, brain radiotherapy and chemotherapy. The multivariate analysis indicated that brain radiotherapy was the independent prognostic factor and the relationship between the survival time and smoking history was near to statistical significance. The patients receiving brain radiotherapy may have better survival benefit. Non-smokers have a trend to survive longer than smokers. Erlotinib may be effective on brain metastases in NSCLC patients and appears to be a possible new treatment option.

Pemetrexed plus Cetuximab in Patients with Recurrent Non-small Cell Lung Cancer (NSCLC): A Phase I/II Study from the Hoosier Oncology Group

Pemetrexed is a standard treatment against recurrent non-small cell lung cancer (NSCLC), and cetuximab has single-agent activity against NSCLC. This study evaluates the safety and efficacy of the combination of these agents in patients with advanced NSCLC. Patients with recurrent NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1 were entered. Patients on the phase I portion of the study received cetuximab 400 mg/m2 intravenously (IV) on day -7 followed by weekly doses of cetuximab at 250 mg/m2 IV with escalating doses of pemetrexed every 3 weeks (dose levels: 500, 600, 750, 900 mg/m2) in a standard 3 + 3 design. Once the maximum tolerated dose (MTD) of the combination was determined, patients were enrolled on the phase II portion. The primary end point was to determine the median time to disease progression (TTP) (null hypothesis 12 weeks, alternative hypothesis 24 weeks). Thirty-six patients were enrolled (phase I: n = 13, phase II: n = 23). Patient characteristics included 60.6% men, median age 64 years (range, 37-80 years), 57.6% had performance status 0 and 54.6% had adenocarcinoma histology. The median number of previous regimens was 2 (range, 1-6). The maximum tolerated dose of pemetrexed in combination with cetuximab was determined to be 750 mg/m2. The median TTP was 14.6 weeks. The median survival time was 42 weeks and 1-year survival was 38.5%. The combination of pemetrexed at 750 mg/m2 every 21 days with weekly cetuximab at 250 mg/m2 was feasible; however, in this unselected patient population, the combination regimen does not seem to improve TTP compared with historical controls of either single agent.

Multicenter, randomized, phase 2 study of zoledronic acid in combination with docetaxel and carboplatin in patients with unresectable stage IIIB or stage IV non-small cell lung cancer

This study was designed to evaluate the efficacy and safety of combined zoledronic acid and docetaxel/carboplatin in patients with non-small cell lung cancer (NSCLC) as preclinical studies showed synergistic antitumoral activity with bisphosphonates and docetaxel. Patients with inoperable stage IIIB or stage IV NSCLC were randomized 2:1 to receive docetaxel 75 mg/m 2 and carboplatin area under the concentration time curve 6 with (Arm A) or without (Arm B) zoledronic acid 4 mg every 3 weeks for 6 cycles. Patients responding in Arm A were rerandomized to receive monthly zoledronic acid (maximum: 12 months [Arm A1] or no zoledronic acid [Arm A2]). Patients responding in Arm B entered Arm B1 for follow-up evaluation only. The primary endpoint was the proportion of patients without disease progression; secondary endpoints were time to disease progression (TTP), TTP in bone, best overall response rate, 1-year overall survival (OS) time, and safety; study not powered to detect endpoint differences. Of 150 patients, 98 were randomized to Arm A and 52 to Arm B. In the treatment phase, results were similar between groups in the proportion of patients without disease progression (40.9% vs 38.8%; P = .8096) and median TTP (132 d vs 132 d; P = .9622). One-year OS times and best overall response rates were 266 d vs 206 d ( P = .4855) and 64.1% vs 72% ( P = .3423), respectively; the study was not powered to detect differences. In the follow-up phase, TTP and OS time were similar. Adding zoledronic acid to docetaxel/carboplatin in advanced stage NSCLC patients was well tolerated, but provided little to no effect on disease progression endpoints.

Effect of sorafenib on chemotherapy resistance and refractoriness in castration-resistant prostate cancer (CRPC)

e16105 Background: There is no standard for CRPC once chemotherapy fails. In studies employing docetaxel (D), 35–39% of pts did not complete therapy due to progression and only 45–50% had a PSA response. This implies that many pts develop resistance to D. Sorafenib is a multi kinase inhibitor with antiangiogenesis properties. We hypothesized that sorafenib could overcome chemotherapy resistance in these pts. Methods: Eligible pts must have progressed while on either D or mitoxantrone (M). They received sorafenib at 400 mg orally twice/daily in addition to the chemotherapy agent they were on. Sorefinib/chemotherapy combination was given for a maximum of 6 cycles followed by sorafenib monotherapy until progression. Primary end point was safety of the sorafenib/chemotherapy combination. Secondary end points included the overall clinical benefit calculated as the sum of complete response (CR), partial response (PR), and stable disease (SD), toxicity, and time to disease progression (TTP). Results: To date, 15 pts have been enrolled; 14 are evaluable. Eleven pts were on D and 4 on M. Median age was 68 (range 61–83), median PSA was 111.2 ng/ml (13.6–1703.9). Nine pts (60%) had visceral and bone disease. Median PSA-DT pre-study was 2 months (0.5–6) and median time from last chemotherapy to starting study was 4 weeks. Median number of given cycles was 6.5 (2–12). Six pts did not require dose reduction, 2 others were re-escalated to the full dose. Sorafenib was safely combined with chemotherapy with 6 pts experiencing grade 3 fatigue, 3 developing grade 3 hand/foot syndrome, and 1 experiening grade 3 diarrhea. Eleven pts (73%) had SD radiographically that lasted a median of 6.7 months. In all, 6 out of 14 pts (42%) had a PSA decline after adding sorafenib and 3 (21%) had stable PSA. Of these 9 pts (PR+SD), 2 never doubled their PSA. Two pts had PSA decline after withdrawing sorafenib. Median TTP for PSA was 3.75 months. PSA responses did not correlate with radiographic changes or clinical benefit. With a median follow-up of 8 months, 5 pts (33%) remain alive with 1 continuing on therapy without progression. Conclusions: Sorafenib overcomes chemotherapy-refractoriness and failures in CRPC. [Table: see text]

Phase 1/2 study of intravenous paclitaxel and oral cyclophosphamide in pretreated metastatic urothelial bladder cancer patients

To the authors' knowledge, no previous studies have been reported with the combination of paclitaxel and oral cyclophosphamide in patients with metastatic bladder cancer. A phase 1/2 study was conducted of paclitaxel in combination with oral cyclophosphamide for patients with advanced urothelial bladder cancer who had been previously treated with gemcitabine/cisplatin chemotherapy as first-line metastatic treatment. This was a single-arm phase 1/2 study. Patients were treated with paclitaxel and oral cyclophosphamide at 3-week intervals until disease progression or irreversible toxicity occurred. Primary endpoints were to determine the maximum tolerated doses (MTD) and objective response rate; secondary endpoints were safety, time to disease progression (TTP), and overall survival (OS). Forty-four patients were enrolled. Dose levels of paclitaxel of 175 mg/m(2) (Day 1) and cyclophosphamide of 50 mg (Days 1-7 orally) (dose level I) of a 21-day cycle were tolerated without dose-limiting toxicities (DLTs). At a cyclophosphamide dose of 100 mg (dose level II) the MTD was exceeded; 3 of 6 patients experienced a DLT (grade 3 constipation and grade 4 neutropenia and thrombocytopenia [toxicities were graded using National Cancer Institute Common Toxicity Criteria (version 3.0)]). Dose level I was expanded and determined to be the MTD. A total of 32 patients were treated at dose level I in the phase 2 portion. Partial responses were observed in 31% of patients (10 of 32 patients; 95% confidence interval [95% CI], 17%-45%). Grade 1/2 vomiting, peripheral neuropathy, and neutropenia were the most common side effects, noted in 11 (34%), 8 (25%), and 10 (31%) patients, respectively. The median TTP was 5 months (95% CI, 2 months-7.5 months) and the median OS was 8 months (95% CI, 4 months-14 months). The combination of paclitaxel and cyclophosphamide is well tolerated and associated with promising efficacy. Further trials are needed to confirm these preliminary results.

Incorporating Marrow Plasma Cell Infiltration at Diagnosis and Cytogenetic Features into Prognostic Scoring at Point of Autologous Stem Cell Transplantation for Multiple Myeloma

240 patients (152 male, 88 female) with a median age of 59 years (27ys–73ys), referred to Hammersmith Hospital, London, for high dose therapy (HDT) and autologous stem cell transplantation (ASCT) between 1994 and 2007 were treated in a uniform fashion with myeloablative doses of Melfalan. The median OS post HDT/ASCT of all patients was 53 months with a median time to disease progression (TTP) of 20 months. In univariate analysis (194 pts) a > 60% plasmacell infiltration of trephine biopsy at presentation was associated with a significantly shorter median TTP (15 months) following HDT/ASCT compared to patients with a lesser degree of marrow plasmocytosis, whose median TTP was 20 months (p=0.003). Studies of chromosomal aberrations were undertaken by metaphase cytogenetics and interphase FISH in 142 pts at the time of ASCT and yielded interpretable results in 96 (67%) pts. Failure of conventional G –banding and FISH was universally due to low plasma cell content of the marrow aspirate below 5% of nucleated cells. 59 pts (42%) did not show any chromosomal abnormalities at point of transplantation; 37 pts (26%) had chromosomal aberrations, involving the IgH gene locus on chromosome 14q32 and/or deletions of the long arm of chromosome 13 (del 13q) in 33 cases. Deletion of the short arm of Chromosome 17 (del 17p) was only seen in one patient. In multivariate analysis (92 pts), independent risk factors for early relapse post ASCT were progressive disease/minimal treatment response at time of transplantation (RR 5.95, 95%CI 2.86–12.57), a plasma cell infiltrate of more than 60% on marrow trephine at diagnosis (RR 3.4, 95% CI 1.68–6.88) and presence of cytogenetic abnormalities other than sole t(11;14) or del 13q (RR 2.04, 95% CI 1.0–4.17) at time of ASCT. An additive scoring model based on these predictive factors (Table 1) identifies a low risk group of 49 pts (score 0) with a median progression free survival (PFS) of 33 months, an intermediate risk group of 34 pts (scores 1–2) with a median PFS of 15.7 months and a high risk group of 9 pts (scores 3–4), whose median PFS is 4.6 months (p<0.0001).Table 1: Prognostic scoring modelRisk FactorScorePlasmacells >60% on diagnosis trephine biopsy1Plasmacells <60%0Progressive disease/minimal response at time of ASCT2Complete response/partial response0Normal Cytogenetics or t (11.14)/del 13q as sole abnormalities at time of ASCT0All other chromosomal aberrations1 [Display omitted]

Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone‐refractory prostate cancer

Atrasentan is a potent, oral, selective endothelin-A (ET(A)) receptor antagonist that has clinical activity in patients with hormone-refractory prostate cancer (HRPC). In this article, the authors report the results from a phase 3, randomized, double-blind, placebo-controlled trial of atrasentan in patients with nonmetastatic HRPC. Of 941 patients who had adequate androgen suppression and no radiographic evidence of metastases but rising prostate-specific antigen (PSA) levels, 467 patients were randomized to receive atrasentan at a dose of 10 mg, and 474 patients were randomized to receive placebo daily. The primary endpoint was the time to disease progression (TTP), which was defined as the onset of metastases. Secondary endpoints were the time to PSA progression, change in bone alkaline phosphatase (BALP) levels, PSA doubling time, and overall survival. There was a 93-day delay in the median TTP with atrasentan, but the difference from placebo in TTP was not statistically significant (P= .288). Large geographic differences in the median TTP were noted: in the US: The difference was 81 days longer with placebo; whereas, in non-US sites, the difference was 180 days longer with atrasentan. Atrasentan lengthened the PSA doubling time (P= .031) and slowed the increase in BALP (P< .001). The median survival was 1477 days with atrasentan and 1403 days with placebo. The most common adverse events associated with atrasentan were peripheral edema, nasal congestion, and headache, consistent with the vasodilatory properties of ET(A) receptor antagonists. Although the primary endpoint was not achieved, large regional differences in TTP were noted, suggesting that trial conduct may have influenced the results. The biologic activity was consistent with findings from other clinical trials of atrasentan in HRPC.

Paclitaxel- and Platinum-Based Postoperative Chemotherapy for Primary Fallopian Tube Carcinoma: A Single Institution Experience

Background: Primary fallopian tube carcinoma (PFTC) is a rare gynecologic malignancy with very few data existing on the activity of the combination of paclitaxel with a platinum analogue as adjuvant chemotherapy. Methods: We retrospectively analyzed 41 consecutive patients with PFTC who were treated postoperatively with paclitaxel- and platinum-containing chemotherapy regimens. Results: We observed 12 (63.2%) complete and 6 (31.6%) partial responses among 19 patients with measurable disease. The median time to disease progression (TTP) for all patients was 68 months. The median overall survival (OS) for all patients has not been reached yet. The median TTP was 84 months for patients with stage I/II disease and 34 months for patients with advanced disease (p = 0.017). Median OS has not been reached yet for patients with stage I/II PFTC, while it was 63.8 months for patients with stage III/IV disease (p = 0.002). Furthermore, OS has not been reached yet for patients with optimally debulked tumors, while it was 34.1 months for patients with residual disease >2 cm (p < 0.0001). Conclusion: Adjuvant platinum- and paclitaxel-based chemotherapy should be regarded as the standard treatment in patients with PFTC. Early stage disease and optimal debulking are associated with improved TTP and OS.

Phase III Study of Valspodar (PSC 833) Combined With Paclitaxel and Carboplatin Compared With Paclitaxel and Carboplatin Alone in Patients With Stage IV or Suboptimally Debulked Stage III Epithelial Ovarian Cancer or Primary Peritoneal Cancer

To compare the safety and efficacy of carboplatin and paclitaxel administered with or without the multidrug resistance modulator valspodar (PSC 833) in untreated patients with advanced ovarian or primary peritoneal cancer. Seven hundred sixty-two patients with stage IV or suboptimally debulked stage III ovarian or primary peritoneal cancer were randomly assigned to receive either valspodar 5 mg/kg every 6 hours for 12 doses, paclitaxel 80 mg/m(2), and carboplatin area under the curve (AUC) 6 (PC-PSC; n = 381) or paclitaxel 175 mg/m(2) and carboplatin AUC 6 (PC; n = 381). Time to disease progression (TTP) was the primary end point. Secondary end points were overall survival time (OS), response rate (RR), safety, and tolerability. With a median follow-up of 736 days (range, 1 to 2,280 days), the median TTP was 13.2 and 13.5 months in the PC-PSC and PC groups, respectively (P = .67); the median OS was 32 and 28.9 months, respectively (P = .94). The overall RR was higher in the PC group (41.5% v 33.6%; P = .02). Central and peripheral nervous system and GI toxicities were more common in the PC-PSC group. Ataxia occurred in 53.5% and 3.2% of PC-PSC-and PC-treated patients, respectively. Febrile neutropenia occurred more frequently in the PC-PSC group. More PC-PSC-treated patients discontinued therapy because of adverse events (AEs), experienced serious AEs, and required paclitaxel dose reductions. The addition of valspodar to PC did not improve TTP or OS and was more toxic compared with PC in untreated patients with advanced ovarian or primary peritoneal cancer.

A phase II study with single agent erlotinib in chemotherapy-naïve androgen independent prostate cancer (AIPC)

16104 Background: Mechanisms of hormone resistance in AIPC are variable. One mechanism is the epidermal growth factor receptor (EGFR) stimulating cell proliferation. We investigated an oral anti-EGFR inhibitor (Erlotinib) in chemotherapy-naïve AIPC patients (pts). The primary endpoint was the overall clinical benefit defined as the sum of complete response (CR), partial response (PR), and stable disease (SD). Secondary endpoints were time to disease progression (TTP) and toxicities. Methods: Between January 2006 and December 2007, 29 pts were enrolled onto this phase II study. Median age was 78 years (61–96). Median PSA at enrollment was 64.1 ng/dl (9.2- 914.2). Median time from initial diagnosis to starting Erlotinib was 8 years (1–14). Erlotinib was given at 150 mg daily during 4-week cycles until disease progression or intolerability. Response assessment occurred every 2 cycles, including computed tomography of measurable disease areas, bone scans, and serum PSAs. Pts who progressed radiographically but maintained a PSA response or those who progressed biochemically but maintained a radiographic response were considered stable and continued on study. Results: The study has completed accrual. Nineteen pts are currently evaluable. 4 are early in their therapy, 4 withdrew consent, and 2 progressed before completing 2 cycles. Erlotinib was well-tolerated and most toxicities were grade 1 or 2. Hematuria occurred in 3 pts but was deemed unrelated to erlotinib. Grade 3 diarrhea and dehydration occurred in 2 pts (8%). One patient (3.4%) developed grade 3 rash. One pt developed a venothromboemblic event and another developed cord compression early in his therapy. One pt (3.4%) required a dose reduction secondary to grade 3 hand/foot syndrome. One pt (3.4%) was unable to tolerate therapy even at the reduced dose because of grade 3 fatigue. With a median follow up of 10 months (1–23), 20 pts (72%) remain alive. Two pts achieved PR and 3 pts demonstrated SD. The calculated overall clinical benefit was 26% (5 responses out of 19 patients). Although median TTP was 2 months (2–20), the 2 PR patients responded for 20 and 13 months respectively. Conclusions: Erlotinib is safe and has modest single-agent activity in AIPC. Further studies are warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology Genentech™ BioOncology

Concomitant docetaxel plus gemcitabine versus sequential docetaxel followed by gemcitabine

1106 Background: Docetaxel plus Gemcitabine represent an active combination in anthracycline pretreated advanced breast cancer patients (pts.). Impact of sequential administration of these drugs is unclear. This trial aimed to compare concomitant DG with sequential D->G in anthracycline pretreated advanced breast cancer patients. Methods: Pts. pretreated with anthracyclines in the (neo)adjuvant or metastatic setting were randomized to receive either: 8 cycles Gemcitabine 1,000 mg/m2 on days 1 and 8, plus Docetaxel 75 mg/m2 on day 8 (DG), or 4 cycles Docetaxel 100 mg/m2 on day 1, followed by four cycles Gemcitabine 1,250 mg/m2 on days 1 and 8 (D->G), in a 21-day schedule. The primary endpoint was time to disease progression (TTDP), secondary endpoints were overall response rate (ORR), response duration (RD), overall survival (OS) and toxicity. Sample size was calculated to be 430. Due to poor recruitment the trial was closed after randomization of 100 pts. Results: Between September 2002 and March 2006, 100 pts. at 14 centers in 7 countries were randomly assigned to DG (n=46) or D->G (n=54). The median age was 53 vs 55 years in DG and D->G arms, 52%/50% vs 55/47 were ER/PR positive, 23% vs 17 were HER2 positive, 52%/44% vs 42/47% had liver/lung metastases at baseline. Grade 3/4 adverse events encompassed leukopenia (29% in DG; 68% in D->G), neutropenia (49 vs 83%) (p<0.001 for both) and febrile neutropenia (4 vs 9%). One treatment-related death due to enterocolitis was reported in the DG arm. ORR, RD, TTDP and OS were similar in both arms. Conclusions: The present data suggest that sequential D->G treatment produced significantly more episodes of hematologic toxicity. Regarding efficacy no trend in favor of any regimen was observed. Efficacy Parameters DG (n=45) D->G (n=53) ORR (%) 31% 28% RD (months) 5.4 7.8 Median TTDP (months) 7.0 6.7 Median OS (months) 15.5 15.9 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly

Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy

Recently, the authors reported improved time to disease progression (TTP) with a combination of pegylated liposomal doxorubicin (PLD) and bortezomib compared with bortezomib alone in a phase 3 randomized trial in patients with recurrent/refractory multiple myeloma (MM). In the current analysis, they determined 1) the efficacy of PLD plus bortezomib versus bortezomib alone in patients with MM who had failed on prior thalidomide/lenalidomide (immunomodulatory drug [IMiD]) treatment and 2) the efficacy and safety profile of PLD plus bortezomib in IMiD-exposed and IMiD-naive patients. This prespecified analysis included 646 patients who were randomized to receive either PLD with bortezomib (n=324; 194 IMiD-naive patients and 130 IMiD-exposed patients) or bortezomib alone (n=322; 184 IMiD-naive patients and 138 IMiD-exposed patients). The primary efficacy endpoint was TTP, and secondary endpoints included overall survival, response rate, and safety. The median TTP was significantly longer with PLD plus bortezomib compared with bortezomib alone in IMiD-exposed patients (270 days vs 205 days). No statistical difference was noted with respect to TTP between IMiD-naive (295 days) versus IMiD-exposed (270 days) subgroups who received PLD plus bortezomib. A sustained trend favoring combination therapy was observed in analyses of overall survival. In patients who achieved a response, the response duration was comparable for IMiD-naive patients and IMiD-exposed patients in the combination treatment group and lasted a median of 310 days and 319 days, respectively. The incidence of grade 3/4 adverse events was similar with PLD plus bortezomib regardless of prior IMiD exposure. A significantly prolonged TTP was observed with combined PLD plus bortezomib combination therapy compared with bortezomib alone despite prior IMiD exposure. For the combination treatment arm in the IMiD-naive and IMiD-exposed subgroups, TTP was comparable. Similarly, the safety profile of the PLD plus bortezomib combination was unaltered by prior IMiD exposure.

High‐dose chemotherapy with autologous stem cell transplantation in adults with recurrent embryonal tumors of the central nervous system

Embryonal central nervous system (CNS) tumors (medulloblastoma, cerebral neuroblastoma, pineoblastoma, and primitive neuroectodermal tumors) are rare in adults. Recurrent disease has an extremely poor outcome. The use of high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has demonstrated promising results in children with recurrent disease, but there are only limited data regarding its role in adults. The purpose of the current study was to evaluate adult patients with embryonal CNS tumors who were treated with HDC with ASCT and compare their outcomes with those of patients who received conventional-dose chemotherapy. The authors reviewed the medical records of 23 adult patients (age >or= 18 years) who were treated at the Mayo Clinic for recurrent embryonal CNS tumors between 1976 and 2004. The authors compared treatment with HDC with ASCT (10 patients) with an historic control of patients treated with conventional-dose chemotherapy (nitrosourea based, cisplatin based, or both) (13 patients). HDC with ASCT was associated with increased survival (P= .044) and a longer time to disease progression (TTP) (P= .028). The conventional-dose chemotherapy group had a median TTP of 0.58 years and a median survival of 2.00 years. The HDC with ASCT group had a median TTP of 1.25 years and a median survival of 3.47 years. When restricted to patients receiving ASCT after first disease recurrence, the median TTP was 2.5 years and the median survival was 4.16 years. Toxicities were similar in both groups. Improvements in the median TTP and survival noted with the administration of HDC with ASCT, as well as the acceptable toxicity of this regimen, supports consideration of its use in adults with recurrent embryonal CNS tumors.

Effect of mucin production on survival in colorectal cancer: a case-control study.

To investigate the impact of mucin production on prognosis in colorectal cancer, in terms of overall survival (OS) and time to disease progression (TTP) in patients with mucinous compared to those with non-mucinous colorectal cancer (NMCRC), matched for age, gender, and tumor stage. Thirty five patients with mucinous colorectal cancer (MCRC) were matched for age, gender, and tumor stage with 35 controls having NMCRC. OS and TTP were compared among 4 groups divided according to mucin content: group A (50%-75% mucin), group B (75%-100% mucin), group C or controls (<50% mucin). Group D consisted of all patients with tumors having <75% mucin (controls and groups A together). Median survival in MCRC and NMCRC groups was 46.2 and 112.9 mo, respectively (P=0.26). OS in groups A and B was 70.1 and 32.8 mo (P=0.46), and in groups B and D was 32.8 and 70.1 mo, respectively (P=0.143). TTP in MCRC and NMCRC was 50.17 and 44.77 mo, respectively (P=0.795). TTP in groups A, B, and D was 70.1, 24.8, and 65.5 mo, respectively. Twenty-eight percent of patients with MCRC had poorly differentiated adenocarcinoma versus 8.6% in NMCRC patients (P=0.028). MCRC is associated with a non-significant decrease in median survival and TTP, particularly when mucin content is >75% of tumor volume. However, it tends to be more poorly differentiated. A larger study matching for stage and grade is needed.

Clinical report of combined chemotherapy with gemcitabine plus cisplatin as first-line treatment to 79 cases of advanced non-small cell lung cancer

Chemotherapy is the main treatment measure of advanced non-small cell lung cancer(NSCLC).The aim of this study is to explore the efficacy,toxicity,time to disease progression(TTP) and overall survival under the combined chemotherapy with gemcitabine(GEM) plus cisplatin(DDP) in the treatment of advanced NSCLC. Retrospective review was conducted on 79 chemotherapy-naive cases of advanced NSCLC treated with GEM and DDP from October 1999 to November 2005.Among 79 patients,51 were male and 28 female;the median age was 53 years old(ranged from 21 to 74);there were 17 cases of squamous cell carcinoma,53 cases of adenocarcinoma,3 cases of large cell carcinoma,1 case of adeno-sqamous cell carcinoma,5 unidentified cases;there were 26 cases in IIIB stage and 53 cases in IV stage according to AJCC 1997 standard.All patients received GEM 800-1250 mg/m² on days 1 and 8 and DDP 75-80 mg/m² on day 1 or 30 mg/m² for three days by intravenous administration,with 21 days as one cycle.Each patient received 2-4 cycles chemotherapy. The total clinical reponse rate(complete and partial response) was 31.6%,and clinical benefit rate(complete and partial response and stable disease) was 73.4%.1-year survival rate was 64.9%,2-year survival rate was 32%.After median follow-up of 2.33 years,median TTP was 5.06 months.The main toxicities were nausea,vomitting and hematological toxicities.The rates of grade III to IV leukopenia and thrombocytopenia were 25.4% and 31.6% respectively.Other toxicities were slight and tolerable. Combined chemotherapy with GEM plus DDP as first-line treatment to advanced NSCLC is an effective and feasible regimen,which is one of the standard regimens.For old patients,this regimen is a good choice.The fit dosage of GEM for Chinese is 1000 mg/m².

Phase II Study of Irinotecan plus Leucovorin and Bolus 5-Fluorouracil as First- or Second-Line Chemotherapy in Patients with Advanced Gastric or Esophageal-Gastric Junction Adenocarcinoma

The aim of this study was to evaluate the activity and safety of 5-fluorouracil (5-FU) / leucovorin (LV) and irinotecan as first- or second-line treatment in patients with advanced gastric adenocarcinoma. Treatment consisted of irinotecan 80 mg/m2 intravenously (i.v.), followed by LV 200 mg/m2 (i.v.) and 5-FU 450 mg/m2 as an i.v. bolus, administered weekly for 6 weeks, followed by a 2-week rest period. Thirty-one patients (23 chemo-naïve, 8 chemo-exposed) were enrolled. The overall response rate was 22.6% and the disease control rate was 38.7%. Among the patients who received the regimen as first-line treatment, objective response rate was 30.4% and the disease control rate was 52.1%. However, progression of the disease was recorded in all the patients receiving the combination as second-line chemotherapy. The median time to disease progression (TTP) was 4 months and the median duration of survival was 7 months. The median TTP was 6 months for patients treated with first-line chemotherapy and 2.5 for those who received study treatment as second line. Furthermore, the median survival duration was 8 months and 6 months, respectively. The most frequent grade 3 toxicity was febrile neutropenia. Grade 3 non-hematological toxicities were rare. There were no treatmentrelated deaths.The combination of 5-FU/LV and irinotecan as first-line treatment was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation would be worthwhile, particularly in elderly or debilitated patients who cannot tolerate aggressive chemotherapy.

BCIRG 007: First overall survival analysis of randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin as first line therapy in HER2 amplified metastatic breast cancer (MBC)

LBA1008 Background: Based on preclinical synergism between docetaxel (T), carboplatin (C) and trastuzumab (H), BCIRG conducted a phase III trial in HER2-positive MBC to evaluate efficacy and safety of H in combination with T or TC. Methods: 263 patients (pts) with HER2 FISH+ MBC were randomized to TH (H with T 100mg/m2) or TCH (H with T 75mg/m2 and C AUC=6). Chemotherapy was given every 3 weeks (q3w) for 8 cycles with weekly H at 2mg/kg (loading dose of 4 mg/kg) followed by H q3w at 6 mg/kg until progression. Pts were stratified by centre and prior (neo) adjuvant taxane chemotherapy. Primary endpoint was Time To disease Progression (TTP). Secondary endpoints include overall survival, response rate, duration of response (DR), clinical benefit (CB) and safety. Results: 131 pts were treated in each arm Pt characteristics were well balanced in both groups. A first efficacy analysis was conducted at 204 events. There was no significant difference between TH and TCH in median TTP (11.1 vs 10.4 mos, p=0.57), ORR (73% in both arms), DR (10.7 vs 9.4 mos) and CB (67% in both arms). At 39 months of median follow-up, median overall survival was 36.40 and 36.57 months in TH and TCH arms respectively. More patients on TCH received the max number of chemotherapy cycles, and numerically fewer patients on TCH discontinued treatment as a result of non hematological toxicity. The most common gr 3/4 toxicities were: Neutropenic infection that was 16.8% vs 9.2% respectively for TH and TCH, thrombocytopenia (2% vs 15%), asthenia (5% vs 12%), anemia (5% vs 11%), and diarrhea (2% vs 10%). Two pts died (1.5%) due to sepsis in TCH. Absolute LVEF decline &gt; 15 % were seen in 5.5 % vs 6.7 % of pts. One pt (0.8%) had a symptomatic CHF in TH arm. Conclusion: Both TH (T 100) and TCH (T 75) were highly effective treatment regimens in women having HER2-positive MBC, demonstrating high response rates, median TTP &gt; 10 months, and median overall survival &gt; 36 months in both TH and TCH. Cardiac toxicity was no significant problem with either treatment. [Table: see text]