Annals of Oncology Advance Access originally published online on November 22, 2005
Annals of Oncology 2006 17(2):226-231; doi:10.1093/annonc/mdj054
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2005 European Society for Medical Oncology
A phase II trial of a combination of pemetrexed and gemcitabine in patients with metastatic breast cancer: an NCCTG study
1 Mayo Clinic and Foundation, Department of Oncology and Medicine, Rochester, MN; 2 Roger Maris Cancer Center, Fargo, ND; 3 Carle Clinic Association, Champaign, IL; 4 Duluth Clinic, Duluth, MN; 5 Scottsdale CCOP, Scottsdale, AZ; 6 Oncology Hematology Association, Peoria, IL; 7 Mayo Clinic Jacksonville, Jacksonville, FL, USA
* Correspondence to: Dr A. A. Adjei, Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1-507-538-0548; Fax: +1-507-284-1803; E-mail: adjei.alex{at}mayo.edu
 |
Abstract |
|---|
 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
|---|
Purpose: This phase II study was undertaken to define the efficacy and toxicity of pemetrexed in combination with gemcitabine in patients with metastatic breast cancer.
Patients and methods: Patients with measurable metastatic breast cancer who had previously received an anthracycline and a taxane in either the adjuvant or metastatic setting were treated with gemcitabine 1250 mg/m2 (intravenous; days 1 and 8) and pemetrexed 500 mg/m2 (intravenous; day 8) every 21 days.
Results: Fifty-nine patients received a median of five cycles (range one to 22) of treatment and were followed until death or for a median of 28 months (range 19.4–36.6) among living patients. Fourteen partial responses for an overall response rate of 24% [95% confidence interval (CI) 16% to 39%] were documented. Nine (15%; CI 5% to 32%) patients had stable disease for >6 months. The median survival time was 10.3 months (95% CI 8.3–18.9) and the 1 year survival rate was 49% (95% CI 38% to 64%). The median time to progression was estimated to be 3.7 months (95% CI 2.3–5.3). The most common grade 3 or 4 toxicities were neutropenia and thrombocytopenia in 83% and 27% of patients, respectively. Fourteen percent of patients experienced febrile neutropenia. Other common grade 3 or 4 non-hematological toxicities included fatigue (17%), dyspnea (15%), rash (7%) and anorexia (5%).
Conclusions: The combination of pemetrexed and gemcitabine is clinically active, with an overall response rate of 24% in patients with metastatic breast cancer who have previously been treated with an anthracycline and a taxane. Myelosuppression (66% grade 4 neutropenia and 14% febrile neutropenia) was the major treatment-related toxicity observed for this combination.
Key words: clinical trial, gemcitabine, metastatic breast cancer, pemetrexed
|
introduction |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
Pemetrexed is a novel folate antimetabolite [1
]. It inhibits a number of folate-dependent enzymes, including thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase, involved in de novo purine and pyrimidine synthesis [2]. Single-agent pemetrexed has demonstrated activity in a variety of tumor types in phase II studies [3–15]. A response rate of 10–28% has been observed in patients with advanced breast cancer, including those with prior treatment with an anthracycline and paclitaxel [6, 15–19]. The major toxicities of pemetrexed are myelosupppression, skin rash and mucositis, with neutropenia being the primary dose-limiting toxicity. Transient grade 3 and 4 elevations of liver transaminases are common but not dose-limiting. An elevated level of plasma homocysteine was found to be a significant risk factor for treatment-related toxicities. Supplementation with vitamin B12 and folic acid has been shown to lower plasma homocysteine level, and ameliorate the toxicity of pemetrexed [3, 16].
Gemcitabine (difluorodeoxycytidine) is a novel pyrimidine antimetabolite [20], which has broad activity in a variety of solid tumors [21]. In several phase II studies, the response rate of patients with metastatic breast cancer treated with gemcitabine has ranged from 29% (second-line therapy) to 38% (first-line therapy) [22, 23]. Using HCT-8 colon carcinoma cells for clonogenic studies, sequence-dependent cytotoxic synergy was demonstrated between gemcitabine and pemetrexed [24, 25]. A subsequent phase I study of the combination of gemcitabine and pemetrexed was undertaken [24–26]. The most common toxicity was neutropenia, which was dose-limiting. The recommended dose and schedule of this combination for subsequent phase II testing was gemcitabine 1250 mg/m2 given on days 1 and 8 with pemetrexed 500 mg/m2 given on day 8, 90 min after completion of the gemcitabine infusion.
Based on the antitumor activity of gemcitabine and pemetrexed as single agents in metastatic breast cancer, as well as the synergic cytotoxic effect of these two agents observed in preclinical studies, a phase II study was performed to evaluate the combination of these two agents in metastatic breast cancer. The goals of this study were to assess the efficacy and toxicity of this combination in patients with metastatic breast cancer who had received an anthracycline and a taxane in either the adjuvant or metastatic setting, and to describe the overall survival and time to disease progression.
|
patients and methods |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
patient selection
Women with histological or cytologic confirmed bidimensionally measurable breast cancer with clinical evidence of metastatic disease were eligible for this study if they met the following criteria: they must have previously received an anthracycline and a taxane or a combination of both, in the adjuvant or metastatic setting; they must not have received more than one chemotherapy regimen for metastatic disease (unless these were a taxane and anthracycline); age
18 years; Eastern Cooperative Oncology Group performance status 
2; adequate bone marrow (platelets 100 x 109 cells/l, absolute neutrophil count 1.5 x 109 cells/l), hepatic (total bilirubin 2x the upper limit of normal; aspartate transaminase 3x the upper limit of normal or 5x the upper limit of normal if metastatic disease was present in the liver) and renal functions (estimated creatinine clearance 45 ml/min); albumin 3 g/dl; and a life expectancy of 3 months.
Exclusion criteria included: diagnosis of another malignancy within the past 5 years (except basal cell or squamous cell skin cancer and adequately treated non-invasive carcinomas); prior treatment with gemcitabine, pemetrexed or strontium 89; uncontrolled infection or any chronic debilitating disease; clinically significant effusions (pericardial, pleural, ascites) unless these could be drained; body surface area >3 m2; aspirin or NSAIDs 2 days prior to pemetrexed administration; major surgery or any immunologic, genetic, radiation or chemotherapy <4 weeks prior to randomization; more than three prior chemotherapy regimens; radiation therapy to >25% of the bone marrow; and known brain metastasis. Written informed consent was obtained according to federal and institutional guidelines.
experimental treatment
Pemetrexed and gemcitabine were supplied as lyophilized powder forms by Eli Lilly & Company through the NCCTG Coordinating Center Pharmacy. These agents were then reconstituted in sodium chloride solution prior to use. Gemcitabine 1250 mg/m2 was given intravenously in 250 ml of normal saline over 30 min on days 1 and 8 and pemetrexed 500 mg/m2 was given intravenously in 100 ml of normal saline over 10 min, 90 min after the end of gemcitabine infusion on day 8 of a 3-week cycle; 350–600 µg of folic acid was given orally daily and 1000 µg of vitamin B12 was given intramuscularly every 9 weeks starting 7 days prior to the first dose and until 3 weeks after the last dose of pemetrexed; 4 mg of dexamethasone was given orally every 12 h on the day before, day of and day after all doses of pemetrexed. Antiemetics were given before chemotherapy on days 1 and 8 according to institutional guidelines. Colony-stimulating factors were not used prophylactically to prevent granulocytopenia. Treatment continued until disease progression, unacceptable toxicity or two cycles beyond identification of a complete response (CR). All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0).
clinical care of patients
Complete patient histories, physical examinations, complete blood cell counts, chemistries (aspartate aminotransferase, total bilirubin, creatinine, albumin), calculated creatinine clearance, homocysteine level and chest X-ray were performed at baseline and, with the exception of chest X-ray, prior to each course of treatment. Complete blood cell count was repeated weekly while patients were on study. Radiological studies (roentgenograms, computed axial tomographic scans or magnetic resonance imaging) were performed at baseline and after every two cycles of therapy to assess tumor response. A CR was defined as complete disappearance of all measurable disease. Partial response (PR) was defined as at least 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. Progression was defined as 50% increase or an increase of 10 cm2 (whichever is smaller) in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) or appearance of any new lesion, or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). Stable disease (SD) was documented when there was persistence of disease without meeting the criteria for progression, PR or CR.
statistical design
This was a single-stage phase II study with an interim analysis, conducted to assess the efficacy and toxicity of pemetrexed in combination with gemcitabine. A treatment success was defined as either a CR or PR observed on two consecutive evaluations at least 4 weeks apart.
The trial was designed to test the null hypothesis that the true treatment success rate is at most 0.15. The smallest treatment success proportion that would imply this regimen warrants further study was 0.30. The planned accrual for this Simon design [27] was 55 evaluable patients. An interim analysis was conducted after the first 19 patients had been followed for 6 months. Accrual was not suspended while the first 19 patients were followed for 6 months. If three or fewer responses were observed during the interim analysis, the study was to be closed permanently. If four or more confirmed responses were observed during the interim analysis, accrual was to continue. At the time of the final analysis, a confirmed response among 13 or more of the 55 evaluable patients would suggest that this regimen merits further investigation.
Time to progression was defined as the time from registration to the date of progression. Patients who died without disease progression were censored at the date of their last evaluation. If a patient died without documentation of disease progression, the patient was considered to have had tumor progression at the time of death, unless there was sufficient documented evidence to conclude that progression did not occur prior to death. Survival was defined as the time from registration to death due to any cause. The distribution of time to progression and survival time was estimated using the Kaplan–Meier method [28]. Confidence intervals (CI) for the true treatment success rate were constructed according to the method of Duffy and Santner [29].
|
results |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
patient demographics
A total of 59 patients were enrolled between December 2000 and January 2003. The characteristics of these patients are presented in Table 1. The majority of women were postmenopausal (78%) and had visceral metastasis (86%). The number of prior adjuvant chemotherapy regimens was 0 (five patients, 8%) or 1 (54 patients, 92%). The number of prior metastatic chemotherapy regimens was 0 (23 patients, 39%), one (35 patients, 59%) or two (one patient, 2%). Among those who received gemcitabine/pemetrexed as the first-line therapy for metastatic disease, 35% were within 6 months of completing the adjuvant chemotherapy. Twenty-eight (48%) had received prior hormonal therapy. Three hundred and sixty-two doses of treatment were administered throughout the study with a median of five cycles per patient (range one to 22). All 59 patients have discontinued study treatment. The reasons for discontinuing treatment include disease progression (37 patients, 63%), toxicity (nine patients, 15%), patient refusal (eight patients, 14%), alternate treatment (one patient, 2%), physician discretion (three patients, 5%) and death (one patient, 2%). The death on treatment was due to disease progression.
|
toxicities
Any adverse event deemed at least possibly related to treatment was defined as a toxicity and is included in these analyses. Toxicity data were available for all patients. The frequency and severity of the grade 3 and 4 toxicities (occurring in at least 5% of all patients) are shown in Table 2.
|
hematological toxicity
Neutropenia was the most common and severe hematological toxicity. Without prophylactic colony-stimulating factors support, 17% of patients had absolute neutrophil count nadir values constituting grade 3 toxicity, 66% had grade 4 toxicity and 14% had febrile neutropenia. Thrombocytopenia was also common, with 24% grade 3 and 3% grade 4 observed. Severe anemia occurred less frequently, with incidences of 2% grade 3 and 0% grade 4. Only 5% of patients required packed red blood cell transfusion.
non-hematological toxicity
Among the grade 3 and 4 non-hematological toxicities, fatigue (17%) and dyspnea (15%) were most common, followed by rash (7%) and anorexia (5%). Other grade 3 and 4 non-hematological toxicities were edema (3%), nausea (3%), stomatitis (2%) and vomiting (2%).
correlation between homocysteine level and toxicity
Homocysteine levels were available for 56 patients at baseline (pretherapy) and 27 patients at cycle 2. No significant difference was observed between the median homocysteine levels of 8 µM (range 3–17) at base line and 8 µM (range 6–16) at cycle 2. The correlation between baseline homocysteine level and treatment-related toxicity was studied. Since very few patients had homocysteine level >12 µM, 10 µM was used as the cut-off point for analysis. As shown in Table 3, 89% (40/45) of patients with a baseline homocysteine level 10 µM and 91% (10/11) of those with a baseline homocysteine level >10 µM experienced a grade 3 or 4 hematological toxicity (P value for difference = 0.85). Similarly, 58% (26/45) of patients with a baseline homocysteine level 10 µM and 64% (7/11) of those with a homocysteine level >10 µM had a grade 3 or grade 4 non-hematological toxicity (P value for difference = 0.72). Similar results were obtained using homocysteine levels of 8 µM as cut-off point (data not shown).
|
dose reductions
Approximately 25% of the patients received the full dose during cycles 5–8. The median dose level administered was 1250 mg/m2 for gemcitabine and 500 mg/m2 for pemetrexed during cycles 1 and 2. Thirty-two per cent of the patients required a dose reduction after cycle 1, primarily due to hematological nadirs (88%), and
30% of patients required a dose reduction in cycles 4–8. Complete dose information for cycles 1–8 is presented in Table 4.
|
clinical activity
Overall, 14 (24%; 95% CI 16% to 39%) patients achieved a PR with a median duration of 8.3 months (range 1.6–16.9). Nine (15%; 95% CI: 5% to 32%) patients had SD for >6 months, with a median of 11 months (range 6.7–36.6). The median survival time was 10.3 months (95% CI 8.3–18.9) and the 1-year survival rate was 49% (95% CI 38% to 64%). The median time to progression was estimated to be 3.7 months (95% CI 2.3–5.3). The Kaplan–Meier curves for overall survival and time to progression are shown in Figure 1.
|
|
discussion |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
Metastatic breast cancer is expected to develop in approximately half of the women who will be diagnosed with breast cancer in 2004 [30
]. In spite of the availability of several hormonal or chemotherapeutic agents, 90% of patients who develop metastatic breast cancer are expected to die within 5 years, with an overall median survival of only 18–24 months. Several classes of cytotoxic agents, including anthracyclines and taxanes, are currently available to be used either singly or in combination. In the first-line setting, the response rates of individual chemotherapy agents range from 20% to 50%. In the second-line setting, these response rates drop to 15–20%. Even in those patients who achieve an objective response, the median time to progression is around 3–8 months. Combination chemotherapy regimens result in higher response rates; however, significant prolongation in overall survival is yet to be demonstrated. In addition, the increasing use of anthracyclines and taxanes in the adjuvant setting has limited further chemotherapy options in relapsed disease. The testing of novel agents and combinations in metastatic breast cancer, especially for tumors that were previously treated with anthracycline and taxane, is therefore warranted.
Pemetrexed is a novel antifolate that has demonstrated promising antitumor activity in breast cancer, including in anthracycline- and taxane-pretreated tumors. Its excellent tolerability, including lack of alopecia and modest levels of myelosuppression, nausea and mucous membrane toxicity, makes it an attractive candidate for combination therapies. The synergic effect of pemetrexed and gemcitabine observed in preclinical studies provided the rationale for combining these two agents in clinical trials. The present report describes a phase II study of pemetrexed in combination with gemcitabine in the treatment of patients with metastatic breast cancer who have received a prior anthracycline and a taxane in the adjuvant or metastatic setting, or a combination of both. The results of this study are encouraging, with an overall response rate of 24% (95% CI 16% to 39%). This finding met the predefined efficacy parameter of at least 13 responses in 55 patients. It produced a clinical benefit (PR + SD 6 months) in 39% of patients. The median survival time was 10.3 months (95% CI 8.3–18.9) and the 1-year survival rate was 49% (95% CI 38% to 64%). The median time to progression was estimated to be 3.7 months (95% CI 2.3–5.3).
This is the first study with pemetrexed in combination with gemcitabine in patients with metastatic breast cancer who were previously treated with an anthracycline and a taxane. Spielmann et al. [31] reported a subset analysis of a phase II study with single-agent pemetrexed in 31 metastatic breast cancer patients previously treated with an anthracycline and a taxane. A higher dose of pemetrexed at 600 mg/m2 was given intravenously every 21 days. The overall response rate (26%), median duration of response (5.4 months) and median survival (12.8 months) appeared to be similar to the result from our combination regimen. However, it is difficult to draw any conclusions because different doses of pemetrexed were used and the number of patients was small in both studies. Single-agent gemcitabine is also active in metastatic breast cancer. In patients who have previously received an anthracycline and a taxane, the response rate of single-agent gemcitabine has ranged from 0% to 18% in phase II studies [32–35]. Again, it is difficult to compare these results with our phase II study because of the relative small number of patients in these phase II studies and potential differences in the patient population. Future studies comparing the combination of pemetrexed and gemcitabine with either pemetrexed or gemcitabine alone in a larger patient population would seem to be a reasonable approach.
The most common grade 3/4 toxicity for the combination of pemetrexed and gemcitabine in this phase II study was neutropenia, occurring in 83% of patients (17% grade 3, 66% grade 4), which is higher than that observed in the subset analysis of a phase II study with single-agent pemetrexed in a similar patient population [31]. In that study, grade 3/4 neutropenia was experienced in 58% of patients (26% grade 3, 32% grade 4). The higher incidence of toxicity in our study is to be expected with the combination regimen. The tolerability may improve with dose adjustment of gemcitabine to the standard 1000 mg/m2 rather than 1250 mg/m2 used in this study.
The sequencing of pemetrexed and gemcitabine administration has been shown to be important for this combination with regards to toxicity and efficacy [25, 36]. A randomized phase II trial reported recently by our group compared three different schedules of pemetrexed and gemcitabine in patients with advanced non-small-cell lung cancer [36]. The schedule of pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8 was found to induce less toxicity with possibly better efficacy when compared with the other two schedules, one of which was similar to what was used in the present study. Therefore, modification of the treatment schedule might result in a better efficacy and tolerability for this combination in patients with metastatic breast cancer. It may also be reasonable to omit the 90-min interval between the infusions of pemetrexed and gemcitabine, since no pharmacokinetic interactions were observed between these two agents in a phase IB study reported recently by our group [37].
Previous studies indicated that pretherapy homocysteine levels were an important predictor of severe toxicities for single-agent pemetrexed in the absence of vitamin B12 and folic acid supplementation. In this phase II study of the combination of pemetrexed and gemcitabine, all patients received vitamin supplementation. No difference in grade 3 and 4 toxicities was observed among patients with different pretherapy homocysteine levels. This result is to be expected because of the use of vitamin supplementation. It is also important to note that most of our patients had homocysteine levels of <10 µM at baseline, indicating a relatively good nutritional status for this patient population. It is unclear whether vitamin supplementation offers any additional protective effects in patients with homocysteine levels of <10 µM.
The efficacy and tolerability of pemetrexed in combination with gemcitabine is comparable to other chemotherapy options for this patient population. Vinorelbine yielded a response rate of 32% and overall survival of 15.5 months in patients who had received prior treatment with anthracyclines. Grade 3/4 neutropenia occurred in 78% and asthenia in 13% of patients [38]. Capecitabine may be the best tolerated chemotherapeutic agent in this patient population. The most common grade 3 or 4 toxicities of capecitabine were diarrhea (14%) and hand–foot syndrome (10%). It had a response rate of 20%, median time to progression of 3.1 months and median overall survival of 12.8 months in patients with paclitaxel-resistant and anthracycline-exposed breast cancer [39].
In conclusion, our study provides another viable treatment option for patients with metastatic breast cancer who have been treated with anthracyclines and taxanes. Future studies using lower doses of gemcitabine at 1000 mg/m2 and modification of administration schedules for the combination of pemetrexed and gemcitabine are needed in a larger patient population to evaluate the efficacy and tolerability.
|
Acknowledgements |
|---|
The authors wish to thank Mrs Raquel Ostby for excellent secretarial support, and all the patients, nurses and clinical research associates who made this study a success. Supported in part by a grant from Eli Lilly and Company, and RSG-01-155-01-CCE from the American Cancer Society.
Received for publication August 15, 2005. Revision received September 23, 2005. Accepted for publication September 23, 2005.
|
References |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
1. Hanauske AR, Chen V, Paoletti P, Niyikiza C. Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors. Oncologist 2001; 6: 363–373.
2. Shih C, Chen VJ, Gossett LS et al. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 1997; 57: 1116–1123.
3. Niyikiza C, Baker SD, Seitz DE et al. Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 2002; 1: 545–552.
4. Clarke S. Protein isoprenylation and methylation at carboxyl-terminal cysteine residues. Annu Rev Biochem 1992; 61: 355–386.[Web of Science][Medline]
5. Spielmann M, Martin M. HMe: activity of the multi-targeted antifolate MTA (multitargeted antifolate, LY231514) in metastatic breast cancer (MBC) patients previously treated with an anthracycline and a taxane. Breast Cancer Res Treat 1999; 57: 123.
6. Martin M, Spielmann M, Namer M et al. Phase II study of pemetrexed in breast cancer patients pretreated with anthracyclines. Ann Oncol 2003; 14: 1246–1252.
7. Miles DW, Smith IE, Coleman RE et al. A phase II study of pemetrexed disodium (LY231514) in patients with locally recurrent or metastatic breast cancer. Eur J Cancer 2001; 37: 1366–1371.[CrossRef][Web of Science][Medline]
8. John W, Picus J, Blanke CD et al. Activity of multitargeted antifolate (pemetrexed disodium, LY231514) in patients with advanced colorectal carcinoma: results from a phase II study. Cancer 2000; 88: 1807–1813.[CrossRef][Web of Science][Medline]
9. Cripps C, Burnell M, Jolivet J et al. Phase II study of first-line LY231514 (multi-targeted antifolate) in patients with locally advanced or metastatic colorectal cancer: an NCIC Clinical Trials Group study. Ann Oncol 1999; 10: 1175–1179.
10. Pivot X, Raymond E, Laguerre B et al. Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. Br J Cancer 2001; 85: 649–655.[CrossRef][Web of Science][Medline]
11. Dent SF, Klaassen D, Pater JL et al. Second primary malignancies following the treatment of early stage ovarian cancer: update of a study by the National Cancer Institute of Canada–Clinical Trials Group (NCIC-CTG). Ann Oncol 2000; 11: 65–68.
12. Paz-Ares L, Tabernero J, Moyano A. Significant activity of the multi-targeted antifolate MTA (LY231514) in advanced transitional cell carcinoma (TCC) of the bladder: results of a phase II trial. Ann Oncol 1998; 9: 292.
13. Goedhals L, van Wijk AL. MTA (LY231514) in advanced carcinoma of the cervix. Ann Oncol 1998; 9: 339a.
14. Thodtmann R, Sauter T, Weinknecht S et al. A phase II trial of pemetrexed in patients with metastatic renal cancer. Invest New Drugs 2003; 21: 353–358.[CrossRef][Web of Science][Medline]
15. Miller KD, Picus J, Blanke C et al. Phase II study of the multitargeted antifolate LY231514 (ALIMTA, MTA, pemetrexed disodium) in patients with advanced pancreatic cancer. Ann Oncol 2000; 11: 101–103.
16. Calvert H. Pemetrexed (Alimta): a promising new agent for the treatment of breast cancer. Semin Oncol 2003; 30: 2–5.[Medline]
17. O'Shaughnessy JA. Pemetrexed: an active new agent for breast cancer. Semin Oncol 2002; 29: 57–62.[Medline]
18. Llombart-Cussac A, Theodoulou M, Rowland K. A phase II trial of pemetrexed disodium (Alimta, LY121514) in metastatic breast cancer (MBC) patients who have failed anthracyclines (A) and taxanes (T) (salvage chemotherapy). Breast Cancer Res Treat 2000; 64: 122 (Abstr 526).
19. Mennel RG, O'Shaughnessy JA, Blum JL et al. Pemetexed disodium (ALIMTA, LY231514, MTA) in advanced breast cancer (ABC) patients (pts) with prior anthracycline or anthracenedione, taxane and capecitabine treatment: a phase II study. Proc Am Soc Clin Oncol 2001; 20: 49a (Abstr 194).
20. Plunkett W, Huang P, Xu YZ et al. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol 1995; 22: 3–10.[Web of Science][Medline]
21. Guchelaar HJ, Richel DJ, van Knapen A. Clinical, toxicological and pharmacological aspects of gemcitabine. Cancer Treat Rev 1996; 22: 15–31.[CrossRef][Web of Science][Medline]
22. Carmichael J, Possinger K, Phillip P et al. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol 1995; 13: 2731–2736.[Abstract]
23. Carmichael J, Walling J. Phase II activity of gemcitabine in advanced breast cancer. Semin Oncol 1996; 23: 77–81.[Web of Science][Medline]
24. Adjei AA, Erlichman C, Thornton D et al. Synergistic cytotoxicity of MTA (LY231514) and gemcitabine in vitro and in vivo. In 10th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam: 1998. Abstract, p. 644.
25. Adjei AA. Preclinical and clinical studies with combinations of pemetrexed and gemcitabine. Semin Oncol 2002; 29: 30–34.[Web of Science][Medline]
26. Adjei AA, Erlichman C, Davis JN et al. A phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity. Cancer Res 2000; 60: 1871–1877.
27. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1–10.[Medline]
28. Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[CrossRef][Web of Science]
29. Duffy DE, Santer TJ. Confidence intervals for a binomial parameter based on multistage tests. Biometrics 1987; 43: 81–93.[CrossRef]
30. Jemal A, Tiwari RC, Murray T et al. Cancer statistics, 2004. CA Cancer J Clin 2004; 54: 8–29.
31. Spielmann M, Martin M, Namer M et al. Activity of pemetrexed (ALIMTA, multitargeted antifolate, LY231514) in metastatic breast cancer patients previously treated with an anthracycline and a taxane: an interim analysis. Clin Breast Cancer 2001; 2: 47–51.[Medline]
32. Heinemann V. Role of gemcitabine in the treatment of advanced and metastatic breast cancer. Oncology 2003; 64: 191–206.[CrossRef][Web of Science][Medline]
33. Smorenburg CH, Bontenbal M, Seynaeve C et al. Phase II study of weekly gemcitabine in patients with metastatic breast cancer relapsing or failing both an anthracycline and a taxane. Breast Cancer Res Treat 2001; 66: 83–87.[CrossRef][Web of Science][Medline]
34. Schmid P, Akrivakis K, Flath B et al. Phase II trial of gemcitabine as prolonged infusion in metastatic breast cancer. Anticancer Drugs 1999; 10: 625–631.[Medline]
35. Brodowicz T, Kostler WJ, Moslinger R et al. Single-agent gemcitabine as second- and third-line treatment in metastatic breast cancer. Breast 2000; 9: 338–342.[CrossRef][Web of Science][Medline]
36. Ma CX, Nair S, Thomas S et al. Randomized phase II trial of three schedules of pemetrexed and gemcitabine as front-line therapy for advanced non-small-cell lung cancer. J Clin Oncol 2005; 23: 5929–5937.
37. Dy GK, Suri A, Reid JM et al. A phase IB study of the pharmacokinetics of gemcitabine and pemetrexed, when administered in rapid sequence to patients with advanced solid tumors. Cancer Chemother Pharmacol 55: 522–530.
38. Weber BL, Vogel C, Jones S et al. Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer. J Clin Oncol 1995; 13: 2722–2730.[Abstract]
39. Blum JL, Jones SE, Buzdar AU et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17: 485–493.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. D. Patel, T. A. Hensing, A. Rademaker, E. M. Hart, M. G. Blum, D. T. Milton, and P. D. Bonomi Phase II Study of Pemetrexed and Carboplatin Plus Bevacizumab With Maintenance Pemetrexed and Bevacizumab As First-Line Therapy for Nonsquamous Non-Small-Cell Lung Cancer J. Clin. Oncol., July 10, 2009; 27(20): 3284 - 3289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. R. Simon, C. F. Verschraegen, P. A. Janne, C. J. Langer, A. Dowlati, S. M. Gadgeel, K. Kelly, G. P. Kalemkerian, A. M. Traynor, G. Peng, et al. Pemetrexed Plus Gemcitabine As First-Line Chemotherapy for Patients With Peritoneal Mesothelioma: Final Report of a Phase II Trial J. Clin. Oncol., July 20, 2008; 26(21): 3567 - 3572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Benson III Adjuvant Therapy for Pancreatic Cancer: One Small Step Forward JAMA, January 17, 2007; 297(3): 311 - 313. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||