- Email: [email protected]
Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial
original article
Annals of Oncology 18: 745–751, 2007 doi:10.1093/annonc/mdl463 Published online 17 January 2007
Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial S. Boeck1, K. Weigang-Ko¨hler2, M. Fuchs3, E. Kettner4, D. Quietzsch5, J. Trojan6, O. Sto¨tzer7, S. Zeuzem8, F. Lordick9, C.-H. Ko¨hne10, H. Kro¨ning11, T. Steinmetz12, H. Depenbrock13 & V. Heinemann1*
Background: A standard second-line chemotherapy regimen has yet to be defined for patients with gemcitabine (Gem)-refractory advanced pancreatic cancer (PC).
Patients and methods: In this multicenter phase II trial, patients with unresectable or metastatic PC who had progressed on single-agent Gem or a Gem-containing regimen received pemetrexed 500 mg/m2 as a 10-min infusion every 3 weeks until disease progression or occurrence of unacceptable toxicity. The primary end point was the 3-month survival rate. Results: A total of 192 treatment cycles were given to 52 patients. The overall response rate was 3.8% (two partial responses); 10 patients (19.2%) experienced stable disease, nine of them for >12 weeks. At least one CA 19-9 reduction ‡50% occurred in 12 patients (23.1%). The 3-month survival rate was 75% (95% confidence interval 63.2% to 86.8%), the median time to tumor progression was 7 weeks (range 1–62 weeks) and the median overall survival time was 20 weeks (range 1–84 weeks). Grade 3/4 hematological toxic effects included (percent of patients): neutropenia (17.3%), thrombocytopenia (5.8%) and anemia (3.8%). The most frequent non-hematological toxic effects were diarrhea, nausea and stomatitis/pharyngitis (23.1% each). Conclusion: Pemetrexed is a safe treatment option with moderate activity in patients with advanced PC after failure of Gem. Key words: gemcitabine, multitargeted antifolate, pancreatic cancer, pemetrexed, second-line therapy
introduction Pancreatic cancer (PC) is the fourth most frequent cause of death from cancer in the United States with an estimated 32 000 new cases in 2005. Survival remains poor with a 5-year survival rate of only 4% [1]. More than 80% of patients are initially diagnosed with an advanced stage of PC, for which the treatment goal, in most cases, is to control disease-related symptoms and prolong survival. Single-agent gemcitabine (Gem) was approved for first-line chemotherapeutic treatment of advanced PC on the basis of improvement in clinical benefit response and survival [2]. *Correspondence to: Prof. Volker Heinemann, Department of Internal Medicine III, University Hospital Grosshadern, Marchioninistr. 15, D-81377 Munich, Germany. Tel: +49-89-7095 2208; Fax: +49-89-7095 5256; E-mail: [email protected]
ª 2007 European Society for Medical Oncology
Gem-based combinations with a platinum compound or a topoisomerase inhibitor have shown no survival advantage compared with single-agent Gem [3]. The combination of Gem with erlotinib (an orally available tyrosine kinase inhibitor, targeting the epidermal growth factor receptor), however, resulted in a statistically significant prolongation of progressionfree survival (PFS) and median survival time in patients receiving the combination therapy compared with patients receiving single-agent Gem [4]. Furthermore, the results of a recent phase III trial comparing Gem versus Gem plus capecitabine also showed a significant survival benefit in patients receiving the combination therapy (6.0 versus 7.4 months, respectively) [5]. Because of optimized chemotherapy and supportive treatment in patients with advanced PC, more patients are in good clinical condition when progression on first-line therapy is
original article
Received 8 July 2006; revised 25 October 2006; accepted 13 November 2006
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
1 Department of Internal Medicine III, University Hospital Grosshadern, Ludwigs-Maximilians University, Munich; 2Medical Department V, Hospital Nu¨rnberg-Nord, Nu¨rnberg; 3Medical Department II, Hospital Bogenhausen, Munich; 4Department of Hematology and Oncology, City Hospital Magdeburg, Magdeburg; 5Department of Internal Medicine II, Hospital Chemnitz, Chemnitz; 6Medical Department I, Johann Wolfgang Goethe University Hospital, Frankfurt am Main; 7Practice for Oncology, Munich; 8Department of Internal Medicine II, University Hospital Saarland, Homburg/Saar; 9Medical Department III, Klinikum rechts der Isar, Technical University, Munich; 10Medical Department I, University Hospital Dresden; 11Practice for Oncology, Magdeburg; 12Practice for Oncology, Cologne; 13Medical Department, Lilly Deutschland GmbH, Bad Homburg, Germany
original article
Annals of Oncology
alone (6.2 months versus 6.3 months, respectively), although the tumor response rate was significantly higher on the combination arm (14.8% versus 7.1%, P = 0.004). On the basis of these results, this open-label, multicenter, phase II trial was conducted to evaluate the efficacy and safety of pemetrexed as a second-line treatment in patients with advanced PC who had progressed on single-agent Gem or Gem-based first-line chemotherapy.
patients and methods patient population Patients at least 18 years of age with histologically or cytologically confirmed diagnosis of unresectable or metastatic pancreatic adenocarcinoma not amenable to resection with curative intent were included in this trial. Documented tumor progression on prior systemic first-line chemotherapy with single-agent Gem or a combination regimen including Gem was required. No prior systemic treatment with 5-FU and no more than one prior systemic chemotherapy regimen was allowed. Previous radiation was allowed to <25% of the bone marrow if completed at least 4 weeks before study entry. Patients had to have completely recovered from the acute toxic effects of prior first-line treatment. Additional eligibility criteria included unidimensionally measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of two or less, a life expectancy of at least 12 weeks and adequate bone marrow, hepatic and renal function. Patients with documented brain metastases, clinically significant third-space fluid collections (e.g. ascites or pleural effusions) or with second primary malignancies (except in situ carcinoma of the cervix uteri, adequately treated nonmelanomatous skin cancers or other malignancy treated at least 5 years previously with no evidence of recurrence) were excluded. Pregnant or breast-feeding women and patients unable to use an approved contraceptive method during and for 3 months after the study were also excluded. The study was approved by the ethical committees in all participating centers in Germany and each patient gave written informed consent before any studyspecific procedure. This study was conducted according to the Helsinki Declaration and according to the guidelines on good clinical practice.
study design and treatment plan Table 1. Selected clinical trials of second-line chemotherapy in gemcitabine-pretreated patients with advanced pancreatic cancer Treatment regimen [reference]
No. of RR DCR mPFS patients (%) (%) (weeks)
Paclitaxel [11] 18 Rubitecan [13] 198 Raltitrexed [14] 19 5-FU + celecoxib [12] 17 5-FU/FA/oxaliplatin [6] 23 5-FU/FA/oxaliplatin [7] 30 Irinotecan/oxaliplatin [8] 30 Gemcitabine/oxaliplatin [9] 33 Raltitrexed/oxaliplatin [10] 41 Raltitrexed/irinotecan [14] 19 Capecitabine/erlotinib [15] 30
6 6 0 12 NA 23 10 23 24 16 11
33 28 37 24 NA 53 33 58 51 47 68
NA 8 11 8 (TTP) NA 22 (TTP) 17 (TTP) 18 (TTP) 8 17 NA
mOS (weeks) 18 15 18 15 21 25 25 26 22 28 29
RR, response rate; DCR, disease control rate; mPFS, median progressionfree survival time; mOS, median overall survival time; NA, not available; 5-FU, 5-fluorouracil; TTP, time to disease progression; FA, folinic acid.
746 | Boeck et al.
This was an open-label, single arm, multicenter phase II trial of pemetrexed. The primary objective was to assess the 3-month survival rate; secondary end points were tumor response rate, time to disease progression (TTP), overall survival (OS) and toxicity. An additional post hoc analysis was done to evaluate the carbohydrate antigen 19-9 (CA 19-9) response. Pemetrexed was given at a dose of 500 mg/m2 intravenously over 10 min every 3 weeks in an outpatient setting. A dose escalation by 100 mg/m2 every other cycle was allowed—according to defined escalation criteria—at the investigator’s discretion (up to a maximum dose of 900 mg/m2). All patients received adequate vitamin supplementation with folic acid (400 lg p.o. daily) and vitamin B12 (1000 lg i.m. every 9 weeks) starting 1–2 weeks before treatment initiation and continuing until 3 weeks after discontinuation from the study drug. Dexamethasone (4 mg p.o. twice daily on the day before, the day of and the day after pemetrexed) was used to prevent rash. If necessary, defined dose reductions of pemetrexed were carried out according to clinical and laboratory parameters. Chemotherapy with pemetrexed was continued until disease progression or unacceptable toxicity occurred.
evaluation criteria for efficacy and toxicity Physical examinations and assessments of PS, vital signs, hematology and serum chemistry were carried out before each treatment administration.
Volume 18 | No. 4 | April 2007
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
detected. It is unclear, however, if these patients could benefit (e.g. regarding survival) from further chemotherapy. Thus, a standard chemotherapeutic regimen after Gem failure remains to be defined. Until recently, only a few studies with a small number of patients have investigated the role of second-line chemotherapy in advanced PC. On the basis of the interim results of a randomized study, the median survival time after failure of first-line Gem treatment was 10 weeks in patients receiving best supportive care (BSC) alone as subsequent therapy versus 21 weeks in patients receiving second-line chemotherapy with oxaliplatin/folinic acid/5-fluorouracil (5FU) plus BSC [6]. Four phase II trials also using an oxaliplatinbased second-line regimen after Gem failure reported median survival times (measured from the start of second-line therapy) of 25 weeks for oxaliplatin/leucovorin/5-FU [7], 5.9 months for irinotecan/oxaliplatin [8], 6 months for Gem/oxaliplatin [9] and 5.2 months for raltitrexed/oxaliplatin [10]. Other phase II studies of second-line chemotherapy assessed paclitaxel monotherapy [11] and a combination of the cytotoxic drug 5-FU with the Cox-2 inhibitor celecoxib [12]. Table 1 provides an overview of selected clinical trials evaluating second-line chemotherapy in patients with advanced PC [6–15]. Pemetrexed (ALIMTA, Eli Lilly and Company, Indianapolis, IN) is a novel multitargeted antifolate that targets several enzymes involved in folate metabolism: thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase [16]. Pemetrexed has shown in vitro and in vivo antitumor activity in several malignancies, and has been approved in the United States and the European Union for the treatment of inoperable mesothelioma (in combination with cisplatin) and for second-line chemotherapy in pretreated patients with non-small-cell lung cancer [17, 18]. In patients with advanced PC, front-line chemotherapy with pemetrexed has shown clinical activity as a single agent [19] as well as in combination with Gem [20]. Nevertheless, in a large randomized phase III trial [20], the combination of Gem with pemetrexed did not yield a survival benefit compared with Gem
original article
Annals of Oncology
Tumor response was evaluated by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST criteria [21]. For the best overall response of ‘stable disease’ (SD) (defined as less than 30% reduction and less than 20% increase in the sum of the longest diameter of target lesions and the appearance of no new lesions), follow-up measurements were required to have met the SD criteria at least once at a minimum interval after the initial assessment of 9 weeks. In patients with no further lesion measurement after the baseline assessment and no evidence of disease progression (e.g. drop out due to consent withdrawal), best overall response was classified as ‘unknown’. CT or MRI scans for response evaluation were carried out at baseline and were repeated routinely before every other cycle (every 6 weeks). CA 19-9 serum levels were measured within 2 weeks before the first dose of study drug and subsequently on day one of every cycle. All patients who had received at least one dose of pemetrexed were included in the analyses of TTP, OS and toxicity. Toxicity was assessed at each cycle according to the National Cancer Institute Common Toxicity Criteria, version 2.0.
The primary outcome measure of this study was the 3-month survival rate. Survival was defined as the time from treatment administration to the date of death from any cause. Assuming a 3-month survival rate of 50%, no censoring, and a sample size of 50 patients, the width of the corresponding 95% confidence interval (CI) (i.e. 27.8%) was regarded as having an adequate precision. The TTP was defined as the time from treatment administration to the first observation of disease progression or death. TTP was censored at the date of death for patients who had died without documented disease progression and at the date of the last visit for those patients who were alive without documented disease progression. All time to event parameters were analyzed according to the Kaplan–Meier method [22]. The 3-month survival rate was evaluated using the product limit estimate calculated with PROC LIFETEST in SAS Version 8.2 (SAS Institute, Inc., 1989). All further data for categorical or continuous variables are given as absolute and relative frequencies or as medians with ranges, if not otherwise indicated. For response rates the corresponding 95% CIs were also given.
results patient characteristics A total of 54 patients were recruited from October 2003 to August 2004 at 12 sites in Germany, with follow-up for survival until October 2005. Fifty-two patients (96.3%) received at least one dose of pemetrexed and were, therefore, assessable for survival, response and toxicity. Patient and disease characteristics at baseline are summarized in Table 2. The median age at the start of second-line pemetrexed was 62.5 years (range 28–78 years). All but one patient had stage III or IV disease; the main metastatic sites in stage IV patients were liver, lung and abdominal lymph nodes. Thirty-two patients (61.5%) underwent prior surgery of curative (Whipple operation 36.5%) or palliative intent. Seven patients (13.5%) had received prior radiotherapy, and all 52 patients had undergone one previous Gem or Gem-based chemotherapy regimen. Of seven patients (13.5%) with prior adjuvant chemotherapy (five patients Gem, two patients Gem + oxaliplatin), five patients had developed distant metastases on or after adjuvant treatment.
Volume 18 | No. 4 | April 2007
Characteristic Median age (range), years Gender Male Female Performance status (ECOG), n (%) 0 1 2 Median time from PC diagnosis (range), weeks Stage of disease, n (%) Stage IIb Stage III Stage IV Sites of distant metastasesa, n (%) Liver Lung Abdominal lymph nodes Prior surgery, n (%) Whipple operation Prior radiotherapy, n (%) Adjuvant Palliative Prior chemotherapy, n (%) Adjuvant Gemcitabine Gemcitabine + oxaliplatin Palliative Gemcitabine Gemcitabine + cisplatin Gemcitabine + oxaliplatin Gemcitabine + other
62.5 (28–78) 31 (59.6) 21 (40.4) 18 31 3 32
(34.6) (59.6) (5.8) (7–232)
1 (1.9) 5 (9.6) 46 (88.5) 31 6 11 32 19 7 3 4 52 7 5 2 45 34 7 2 2
(59.6) (11.5) (21.2) (61.5) (36.5) (13.5) (5.8) (7.7) (100) (13.5) (9.6) (3.8) (86.5) (65.4) (13.5) (3.8) (3.8)
a
Includes multiple namings. ECOG, Eastern Cooperative Oncology Group; PC, pancreatic cancer.
treatment A total of 192 cycles of pemetrexed were administered in this study, with a median number of two completed cycles per patient (range 1–19 cycles). The median dose of pemetrexed per cycle was 500 mg/m2 (range 212–700 mg/m2). At the time of the final analysis, all 52 patients had discontinued study treatment. The main reasons for discontinuation were disease progression (37 patients, 71.2%), patient refusal (six patients, 11.5%), death from study disease (five patients, 9.6%) and adverse advents (three patients, 5.8%). Dose escalations were carried out according to the protocol in two patients (3.8%) to 600 mg/m2 and 700 mg/m2. The pemetrexed dose was reduced in nine patients (17.3%) mainly due to hematological toxicity (in five patients). efficacy results survival. Thirty-nine patients were still alive 90 days after study entry, resulting in a 3-month survival rate of 75% (95% CI 63.2% to 86.8%). After a median follow-up of 20 weeks (range 1–83 weeks), 47 patients (90.4%) had died, four patients (7.7%) were still alive and one patient (1.9%) was lost to follow-up.
doi:10.1093/annonc/mdl463 | 747
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
sample size and statistical analyses
Table 2. Baseline patient and disease characteristics (N = 52)
original article
Annals of Oncology
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
Figure 1. Overall survival (1a) and time to tumor progression (1b) calculated from the date of first pemetrexed dose (N = 52).
The median OS time calculated from the first dose of pemetrexed was 20 weeks (range 1–84 weeks) and the median OS calculated from the initial diagnosis of PC was 58 weeks (range 8–271 weeks). The median TTP was 7 weeks (range 1–62 weeks). Kaplan–Meier plots for the estimates of OS and TTP are shown in Figure 1a and 1b, respectively. response by imaging criteria. Tumor response is summarized in Table 3. Overall, two patients (3.8%) achieved a partial response (PR) (30% decrease in the sum of the longest diameter of target lesions and no appearance of new lesions), with a duration of 51 days and 198 days. Ten patients (19.2%) experienced SD for ‡9 weeks as defined in the study protocol. Twelve (23.1%) of the assessable patients had SD for >6 weeks and 9 (17.3%) patients had SD for >12 weeks. Thus, the disease control rate (DCR = PR + SD) in this study was 23.1%.
748 | Boeck et al.
Table 3. Response rates (N = 52) Response
No. of patients (%)
95% CI (%)
Complete response Partial response Stable disease (‡9 weeks) Progressive disease Unknown
– 2 10 31 9
– 0.5% 9.6% 45.1% 8.2%
(3.8) (19.2) (59.6) (17.3)
to to to to
13.2% 32.5% 73.0% 30.3%
CI, confidence interval; –, no data.
CA 19-9 tumor marker response. Forty-five (86.5%) of the 52 patients treated with pemetrexed had elevated CA 19-9 levels (defined as values >30 U/ml) at baseline with a median value of 2 341 U/ml (range 38–8.7 · 105 U/ml). Follow-up CA 19-9 levels
Volume 18 | No. 4 | April 2007
original article
Annals of Oncology
Table 4. Relevant hematological and non-hematological toxic effects (maximum by patient, N = 52) No. of patients (%) by toxicity grade (NCI-CTC, version 2.0) Grade 1 Grade 2 Grade 3 Grade 4
Neutropenia Leukopenia Thrombocytopenia Anemia Creatinine increase Hypokalemia Diarrhea Nausea Stomatitis/pharyngitis Abdominal pain Infection Rash/desquamation Fatigue Alopecia Allergic reaction/hypersensitivity
– 2 5 3 1 – 5 9 10 3 – 2 5 3 2
2 6 3 5 1 – (9.6) 5 (17.3) 3 (19.2) 2 (5.8) 3 3 (3.8) 2 (9.6) 2 (5.8) – (3.8) – (3.8) (9.6) (5.8) (1.9)
(3.8) (11.5) (5.8) (9.6) (1.9) (9.6) (5.8) (3.8) (5.8) (5.8) (3.8) (3.8)
7 5 2 1 – 1 2 – – 2 3 1 – – –
(13.5) (9.6) (3.8) (1.9) (1.9) (3.8)
(3.8) (5.8) (1.9)
2 3 1 1 – – – – – – – – – – –
(3.8) (5.8) (1.9) (1.9)
NCI-CTC, National Cancer Institute Common Toxicity Criteria.
were available from 42 patients. Twelve patients (23.1% of N = 52) had a decline of CA 19-9 ‡50% (in relation to CA 19-9 pretreatment levels) at least once during treatment with pemetrexed.
toxicity Hematological and non-hematological toxicity results are summarized in Table 4. Overall, hematological toxic effects of any grade included neutropenia (11 patients, 21.2%), thrombocytopenia (11 patients, 21.2%) and anemia (10 patients, 19.2%). The most frequent grade 3/4 hematological toxic effects were neutropenia (17.3%), thrombocytopenia (5.8%) and anemia (3.8%). Febrile neutropenia occurred in two patients (3.8%). The most frequent non-hematological toxic effects (any grade) were diarrhea, nausea and stomatitis/ pharyngitis (23.1% each). Three patients (5.8%) had a grade 3 infection and two patients (3.8%) each had grade 3 diarrhea or abdominal pain. No grade 4 non-hematological toxicity and no treatment-related death occurred.
discussion This study, which included 52 patients, is currently the largest completed phase II trial to evaluate the role of second-line chemotherapy after Gem failure in patients with advanced PC. Until recently, only three randomized trials were initiated in this patient population. Oettle et al. designed a phase III trial that compared BSC alone versus BSC plus chemotherapy using a combination regimen of oxaliplatin/folinic acid/5-FU after failure of first-line Gem. The planned sample size of this randomized study was 165 patients. Preliminary data reported from 46 patients indicated a possible survival benefit for second-line chemotherapy (BSC = 10 weeks; BSC + chemotherapy = 21 weeks) [6]. Two other randomized studies which compared rubitecan (an oral topoisomerase I inhibitor)
Volume 18 | No. 4 | April 2007
doi:10.1093/annonc/mdl463 | 749
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
Toxicity
to ‘physicians’ best choice of care’ (n = 409) and irinotecan plus raltitrexed to raltitrexed alone (n = 38) reported median survival times from 13 to 28 weeks, respectively [13, 14]. In the randomized phase II study by Ulrich-Pur et al. [14], the addition of irinotecan to the selective thymidilate synthase inhibitor raltitrexed resulted in a clinically meaningful increase of response rate (0% versus 16%), median PFS time (2.5 versus 4.0 months) and median OS time (4.3 versus 6.5 months). On the basis of promising results of palliative first-line treatment we selected pemetrexed as the investigational agent for this multicenter study. Because CR (complete response) or PR to chemotherapy is not necessarily a primary treatment goal in patients with advanced PC [2], the 3-month survival rate was defined as the primary end point in this phase II trial. This survival parameter may be more clinically relevant than the overall response rate in this setting. This study used the standard dose of 500 mg/m2 pemetrexed given every 3 weeks with vitamin B12 and folic acid supplementation to reduce toxicity. The 500-mg/m2 standard dose had been established in earlier studies without vitamin B12 and folic acid supplementation [23]. In order to tailor the dose to individual patients, intrapatient dose escalation was allowed in patients meeting a predefined criteria of low toxicity. The option was used in two patients only (dose escalation to 600 mg/m2 and 700 mg/m2), and thus had no impact on the overall results of the study. Pemetrexed was generally well tolerated and toxicity was manageable. As expected, the main toxicity observed was hematological. With adequate vitamin supplementation, grade 3/4 neutropenia was reported in 17.3% (febrile neutropenia: 3.8%) and grade 3/4 thrombocytopenia in 5.8% of patients. Hematologic toxicity was also the main reason for pemetrexed dose reductions. These toxicity data appear more favorable than those reported in a previous phase II trial in which pemetrexed (600 mg/m2 every 3 weeks) was given as first-line treatment without folic acid and vitamin B12 supplementation [19]. Grade 4 non-hematological toxicity was not observed and nonlaboratory toxicity was limited mainly to diarrhea, nausea and stomatitis/pharyngitis. Under adequate prophylaxis with oral dexamethasone, the observed dermatological toxicity was mild, with only one patient experiencing grade 3 skin rash. In general, also the evaluation of quality of life should be regarded as an important parameter for treatment evaluation in clinical trials. Quality-of-life data were, however, not obtained in this study. The objective response rate (3.8%) in the present study was similar to that seen in the first-line study [19]; in this secondline setting, a disease control rate of 23.1% was achieved. Other investigators, mainly those who incorporated oxaliplatin in their treatment regimen, recently reported response rates of >20% and disease control rates of >50% for salvage chemotherapy in Gem-refractory patients [7, 9, 10], whereas objective response rates in large phase III trials investigating first-line (mainly Gem-based) combination chemotherapy in advanced PC only ranged between 6% and 27% [3, 24]. On the other hand, the survival data in this trial (a 3-month survival rate of 75% and a median survival time of 20 weeks after initiation of pemetrexed) were comparable to the survival data of these oxaliplatin-based combination regimens [6, 7, 9, 10]. Other
original article
acknowledgements The authors wish to thank all patients and their families, nurses, study coordinators and investigators for their active participation in this study. They also thank Eva Mueller for project management, and Claudia Nicolay and Frank Langer for statistical support (all Eli Lilly). This trial was sponsored by Eli Lilly and Company, Indianapolis, IN. This study was presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, 2–6 June 2006, Atlanta, GA. The following persons and study centers participated in this trial: Heinemann/Boeck, Klinikum der Universita¨t Mu¨nchen, Grosshadern; Kettner, Klinikum Magdeburg; Ko¨hne, Universita¨tsklinikum Dresden; Kro¨ning, Onkologische Praxis Magdeburg; Lordick, Klinikum rechts der Isar der
750 | Boeck et al.
Technischen Universita¨t Mu¨nchen; Quietzsch, Klinikum Chemnitz; Salat/Sto¨tzer, Onkologische Praxis Mu¨nchen; Schepp/Fuchs, Sta¨dt. Krankenhaus Mu¨nchen-Bogenhausen; Steinmetz, Onkologische Praxis Ko¨ln; Trojan, Universita¨tsklinikum Frankfurt; Weigang-Ko¨hler, Klinikum Nu¨rnberg-Nord; Zeuzem, Universita¨tsklinikum des Saarlandes, Homburg.
references 1. Herbst RS, Bajorin DF, Bleiberg H et al. Clinical cancer advanced 2005: major research advanced in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology. J Clin Oncol 2006; 24: 190–205. 2. Burris HA, Moore MJ, Andersen J et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15: 2403–2413. 3. Heinemann V. Gemcitabine in the treatment of advanced pancreatic cancer: a comparative analysis of randomized trials. Semin Oncol 2002; 29 (Suppl 20): 9–16. 4. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinicals trials group [NCIC-CTG]. Proc Am Soc Clin Oncol 2005; 23: (Abstr 1). 5. Cunningham D, Chau I, Stocken D et al. Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. Eur J Cancer Suppl 2005; 3: (Abstr PS11). 6. Oettle H, Pelzer U, Stieler J et al. Oxaliplatin/folinic acid/5-fluorouracil [24h] (OFF) plus best supportive care versus best supportive care alone (BSC) in second-line therapy of gemcitabine-refractory advanced pancreatic cancer (CONKO 003). Proc Am Soc Clin Oncol 2005; 23: (Abstr 4031). 7. Tsavaris N, Kosmas C, Skopelitis H et al. Second-line treatment with oxaliplatin, leucovorin and 5-fluorouracil in gemcitabine-pretreated advanced pancreatic cancer: a phase II study. Invest New Drugs 2005; 23: 369–375. 8. Cantore M, Rabbi C, Fiorentini G et al. Combined irinotecan and oxaliplatin in patients with advanced pre-treated pancreatic cancer. Oncology 2004; 67: 93–97. 9. Demols A, Peeters M, Polus M et al. Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced pancreatic adenocarcinoma: a phase II study. Br J Cancer 2006; 94: 481–485. 10. Reni M, Pasetto L, Aprile G et al. Raltitrexed-eloxantin salvage chemotherapy in gemcitabine-resistant metastatic pancreatic cancer. Br J Cancer 2006; 94: 785–791. 11. Oettle H, Arnold D, Esser M et al. Paclitaxel as weekly second-line therapy in patients with advanced pancreatic carcinoma. Anticancer Drugs 2000; 11: 635–638. 12. Milella M, Gelibter A, Di Cosimo S et al. Pilot study of celecoxib and infusional 5-fluorouracil as second-line treatment for advanced pancreatic carcinoma. Cancer 2004; 101: 133–138. 13. Jacobs AD, Burris HA, Rivkin S et al. A randomized phase III study of rubitecan (ORA) vs. best choice (BC) in 409 patients with refractory pancreatic cancer. Report from a North-American multi-center study. Proc Am Soc Clin Oncol 2004; 22: (Abstr 4013). 14. Ulrich-Pur H, Ru¨derer M, Kornek GV et al. Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma. Br J Cancer 2003; 88: 1180–1184. 15. Blaszkowsky LS, Kulke KH, Ryan DP et al. A phase II study of erlotinib in combination with capecitabine in previously treated patients with metastatic pancreatic cancer. Proc Am Soc Clin Oncol 2005; 23: (Abstr 4099). 16. 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. 17. Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003; 21: 2636–2644.
Volume 18 | No. 4 | April 2007
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
phase II trials investigating regimens with only one cytotoxic drug in the second-line setting reported median survival times of 17.5 weeks and 15 weeks [11, 12]. Encouraging preliminary data were also obtained from the first trial that included a targeted agent in second-line treatment after Gem failure. Blaszkowsky et al. administered capecitabine plus erlotinib in 30 patients with metastatic PC and achieved a remission rate of 11% (corresponding DCR 68%) and a median OS time of nearly 29 weeks [15]. The comparison of survival data between small phase II trials is difficult due to differences in the evaluated patient populations. Certain baseline patient characteristics (e.g. PS) have been shown to be strong and independent of prognostic factors regarding survival [24, 25]. A recently presented retrospective, multicenter survey that evaluated the role of fluoropyrimidine-based second-line chemotherapy in 160 patients with advanced PC showed that the most important independent prognostic factor for PFS in the second-line setting was PS [26], indicating that careful patient selection for salvage chemotherapy may be important in clinical practice as well as future clinical trials. Therefore, the study population can determine—in part—the survival results of a clinical trial. Previously published phase II trials of salvage chemotherapy in advanced PC included a wide range of different and noncomparable patient populations. For example, populations differed in terms of PS (the proportion of patients with ECOG 0/Karnofsky >90% ranged from 0% to 61%) or prior chemotherapy (patients with >1 prior chemotherapy ranged from 0% to 29%) [10]. Only a well-designed, randomized phase III trial that stratifies patients according to prognostic factors such as tumor stage or PS will be able to determine a potential survival benefit of a second-line regimen in patients with advanced PC. In this setting, pemetrexed-based combination regimens (e.g. with a platinum [17, 27] or a targeted agent) may be a promising approach to further improve the efficacy of second-line treatment after failure of first-line Gem chemotherapy. In conclusion, pemetrexed is a safe treatment option with limited activity in second-line chemotherapy after Gem failure. On the basis of its safety profile and clinical activity as a single agent, pemetrexed-based combinations merit further investigation in this setting.
Annals of Oncology
Annals of Oncology
18. Hanna N, Shepherd FA, Fossella FV et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22: 1589–1597. 19. 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. 20. Oettle H, Richards D, Ramanathan RK et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 2005; 16: 1639–1645. 21. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92: 205–216. 22. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.
original article 23. Rollins KD, Lindley C. Pemetrexed: a multitargeted antifolate. Clin Ther 2005; 27: 1343–1382. 24. Louvet C, Labinaca R, Hammel P et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005; 23: 3509–3516. 25. Ueno H, Okada S, Okusaka T, Ikeda M. Prognostic factors in patients with metastatic pancreatic adenocarcinoma receiving systemic chemotherapy. Oncology 2000; 59: 296–301. 26. Mancuso-Petricca A, Saletti P, Tronconi MC et al. The efficacy of fluoropyrimidine-based second line chemotherapy in advanced and metastatic pancreatic cancer: results of an ongoing Italian/Swiss multicenter survey. Ann Oncol 2006; 17 (Suppl 9): ix323 (Abstr 1131P). 27. Scagliotti GV. Pemetrexed plus carboplatin or oxaliplatin in advanced non-small cell lung cancer. Semin Oncol 2005; 32 (Suppl 2): 5–8.
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
Volume 18 | No. 4 | April 2007
doi:10.1093/annonc/mdl463 | 751
Annals of Oncology 18: 745–751, 2007 doi:10.1093/annonc/mdl463 Published online 17 January 2007
Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial S. Boeck1, K. Weigang-Ko¨hler2, M. Fuchs3, E. Kettner4, D. Quietzsch5, J. Trojan6, O. Sto¨tzer7, S. Zeuzem8, F. Lordick9, C.-H. Ko¨hne10, H. Kro¨ning11, T. Steinmetz12, H. Depenbrock13 & V. Heinemann1*
Background: A standard second-line chemotherapy regimen has yet to be defined for patients with gemcitabine (Gem)-refractory advanced pancreatic cancer (PC).
Patients and methods: In this multicenter phase II trial, patients with unresectable or metastatic PC who had progressed on single-agent Gem or a Gem-containing regimen received pemetrexed 500 mg/m2 as a 10-min infusion every 3 weeks until disease progression or occurrence of unacceptable toxicity. The primary end point was the 3-month survival rate. Results: A total of 192 treatment cycles were given to 52 patients. The overall response rate was 3.8% (two partial responses); 10 patients (19.2%) experienced stable disease, nine of them for >12 weeks. At least one CA 19-9 reduction ‡50% occurred in 12 patients (23.1%). The 3-month survival rate was 75% (95% confidence interval 63.2% to 86.8%), the median time to tumor progression was 7 weeks (range 1–62 weeks) and the median overall survival time was 20 weeks (range 1–84 weeks). Grade 3/4 hematological toxic effects included (percent of patients): neutropenia (17.3%), thrombocytopenia (5.8%) and anemia (3.8%). The most frequent non-hematological toxic effects were diarrhea, nausea and stomatitis/pharyngitis (23.1% each). Conclusion: Pemetrexed is a safe treatment option with moderate activity in patients with advanced PC after failure of Gem. Key words: gemcitabine, multitargeted antifolate, pancreatic cancer, pemetrexed, second-line therapy
introduction Pancreatic cancer (PC) is the fourth most frequent cause of death from cancer in the United States with an estimated 32 000 new cases in 2005. Survival remains poor with a 5-year survival rate of only 4% [1]. More than 80% of patients are initially diagnosed with an advanced stage of PC, for which the treatment goal, in most cases, is to control disease-related symptoms and prolong survival. Single-agent gemcitabine (Gem) was approved for first-line chemotherapeutic treatment of advanced PC on the basis of improvement in clinical benefit response and survival [2]. *Correspondence to: Prof. Volker Heinemann, Department of Internal Medicine III, University Hospital Grosshadern, Marchioninistr. 15, D-81377 Munich, Germany. Tel: +49-89-7095 2208; Fax: +49-89-7095 5256; E-mail: [email protected]
ª 2007 European Society for Medical Oncology
Gem-based combinations with a platinum compound or a topoisomerase inhibitor have shown no survival advantage compared with single-agent Gem [3]. The combination of Gem with erlotinib (an orally available tyrosine kinase inhibitor, targeting the epidermal growth factor receptor), however, resulted in a statistically significant prolongation of progressionfree survival (PFS) and median survival time in patients receiving the combination therapy compared with patients receiving single-agent Gem [4]. Furthermore, the results of a recent phase III trial comparing Gem versus Gem plus capecitabine also showed a significant survival benefit in patients receiving the combination therapy (6.0 versus 7.4 months, respectively) [5]. Because of optimized chemotherapy and supportive treatment in patients with advanced PC, more patients are in good clinical condition when progression on first-line therapy is
original article
Received 8 July 2006; revised 25 October 2006; accepted 13 November 2006
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
1 Department of Internal Medicine III, University Hospital Grosshadern, Ludwigs-Maximilians University, Munich; 2Medical Department V, Hospital Nu¨rnberg-Nord, Nu¨rnberg; 3Medical Department II, Hospital Bogenhausen, Munich; 4Department of Hematology and Oncology, City Hospital Magdeburg, Magdeburg; 5Department of Internal Medicine II, Hospital Chemnitz, Chemnitz; 6Medical Department I, Johann Wolfgang Goethe University Hospital, Frankfurt am Main; 7Practice for Oncology, Munich; 8Department of Internal Medicine II, University Hospital Saarland, Homburg/Saar; 9Medical Department III, Klinikum rechts der Isar, Technical University, Munich; 10Medical Department I, University Hospital Dresden; 11Practice for Oncology, Magdeburg; 12Practice for Oncology, Cologne; 13Medical Department, Lilly Deutschland GmbH, Bad Homburg, Germany
original article
Annals of Oncology
alone (6.2 months versus 6.3 months, respectively), although the tumor response rate was significantly higher on the combination arm (14.8% versus 7.1%, P = 0.004). On the basis of these results, this open-label, multicenter, phase II trial was conducted to evaluate the efficacy and safety of pemetrexed as a second-line treatment in patients with advanced PC who had progressed on single-agent Gem or Gem-based first-line chemotherapy.
patients and methods patient population Patients at least 18 years of age with histologically or cytologically confirmed diagnosis of unresectable or metastatic pancreatic adenocarcinoma not amenable to resection with curative intent were included in this trial. Documented tumor progression on prior systemic first-line chemotherapy with single-agent Gem or a combination regimen including Gem was required. No prior systemic treatment with 5-FU and no more than one prior systemic chemotherapy regimen was allowed. Previous radiation was allowed to <25% of the bone marrow if completed at least 4 weeks before study entry. Patients had to have completely recovered from the acute toxic effects of prior first-line treatment. Additional eligibility criteria included unidimensionally measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of two or less, a life expectancy of at least 12 weeks and adequate bone marrow, hepatic and renal function. Patients with documented brain metastases, clinically significant third-space fluid collections (e.g. ascites or pleural effusions) or with second primary malignancies (except in situ carcinoma of the cervix uteri, adequately treated nonmelanomatous skin cancers or other malignancy treated at least 5 years previously with no evidence of recurrence) were excluded. Pregnant or breast-feeding women and patients unable to use an approved contraceptive method during and for 3 months after the study were also excluded. The study was approved by the ethical committees in all participating centers in Germany and each patient gave written informed consent before any studyspecific procedure. This study was conducted according to the Helsinki Declaration and according to the guidelines on good clinical practice.
study design and treatment plan Table 1. Selected clinical trials of second-line chemotherapy in gemcitabine-pretreated patients with advanced pancreatic cancer Treatment regimen [reference]
No. of RR DCR mPFS patients (%) (%) (weeks)
Paclitaxel [11] 18 Rubitecan [13] 198 Raltitrexed [14] 19 5-FU + celecoxib [12] 17 5-FU/FA/oxaliplatin [6] 23 5-FU/FA/oxaliplatin [7] 30 Irinotecan/oxaliplatin [8] 30 Gemcitabine/oxaliplatin [9] 33 Raltitrexed/oxaliplatin [10] 41 Raltitrexed/irinotecan [14] 19 Capecitabine/erlotinib [15] 30
6 6 0 12 NA 23 10 23 24 16 11
33 28 37 24 NA 53 33 58 51 47 68
NA 8 11 8 (TTP) NA 22 (TTP) 17 (TTP) 18 (TTP) 8 17 NA
mOS (weeks) 18 15 18 15 21 25 25 26 22 28 29
RR, response rate; DCR, disease control rate; mPFS, median progressionfree survival time; mOS, median overall survival time; NA, not available; 5-FU, 5-fluorouracil; TTP, time to disease progression; FA, folinic acid.
746 | Boeck et al.
This was an open-label, single arm, multicenter phase II trial of pemetrexed. The primary objective was to assess the 3-month survival rate; secondary end points were tumor response rate, time to disease progression (TTP), overall survival (OS) and toxicity. An additional post hoc analysis was done to evaluate the carbohydrate antigen 19-9 (CA 19-9) response. Pemetrexed was given at a dose of 500 mg/m2 intravenously over 10 min every 3 weeks in an outpatient setting. A dose escalation by 100 mg/m2 every other cycle was allowed—according to defined escalation criteria—at the investigator’s discretion (up to a maximum dose of 900 mg/m2). All patients received adequate vitamin supplementation with folic acid (400 lg p.o. daily) and vitamin B12 (1000 lg i.m. every 9 weeks) starting 1–2 weeks before treatment initiation and continuing until 3 weeks after discontinuation from the study drug. Dexamethasone (4 mg p.o. twice daily on the day before, the day of and the day after pemetrexed) was used to prevent rash. If necessary, defined dose reductions of pemetrexed were carried out according to clinical and laboratory parameters. Chemotherapy with pemetrexed was continued until disease progression or unacceptable toxicity occurred.
evaluation criteria for efficacy and toxicity Physical examinations and assessments of PS, vital signs, hematology and serum chemistry were carried out before each treatment administration.
Volume 18 | No. 4 | April 2007
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
detected. It is unclear, however, if these patients could benefit (e.g. regarding survival) from further chemotherapy. Thus, a standard chemotherapeutic regimen after Gem failure remains to be defined. Until recently, only a few studies with a small number of patients have investigated the role of second-line chemotherapy in advanced PC. On the basis of the interim results of a randomized study, the median survival time after failure of first-line Gem treatment was 10 weeks in patients receiving best supportive care (BSC) alone as subsequent therapy versus 21 weeks in patients receiving second-line chemotherapy with oxaliplatin/folinic acid/5-fluorouracil (5FU) plus BSC [6]. Four phase II trials also using an oxaliplatinbased second-line regimen after Gem failure reported median survival times (measured from the start of second-line therapy) of 25 weeks for oxaliplatin/leucovorin/5-FU [7], 5.9 months for irinotecan/oxaliplatin [8], 6 months for Gem/oxaliplatin [9] and 5.2 months for raltitrexed/oxaliplatin [10]. Other phase II studies of second-line chemotherapy assessed paclitaxel monotherapy [11] and a combination of the cytotoxic drug 5-FU with the Cox-2 inhibitor celecoxib [12]. Table 1 provides an overview of selected clinical trials evaluating second-line chemotherapy in patients with advanced PC [6–15]. Pemetrexed (ALIMTA, Eli Lilly and Company, Indianapolis, IN) is a novel multitargeted antifolate that targets several enzymes involved in folate metabolism: thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase [16]. Pemetrexed has shown in vitro and in vivo antitumor activity in several malignancies, and has been approved in the United States and the European Union for the treatment of inoperable mesothelioma (in combination with cisplatin) and for second-line chemotherapy in pretreated patients with non-small-cell lung cancer [17, 18]. In patients with advanced PC, front-line chemotherapy with pemetrexed has shown clinical activity as a single agent [19] as well as in combination with Gem [20]. Nevertheless, in a large randomized phase III trial [20], the combination of Gem with pemetrexed did not yield a survival benefit compared with Gem
original article
Annals of Oncology
Tumor response was evaluated by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST criteria [21]. For the best overall response of ‘stable disease’ (SD) (defined as less than 30% reduction and less than 20% increase in the sum of the longest diameter of target lesions and the appearance of no new lesions), follow-up measurements were required to have met the SD criteria at least once at a minimum interval after the initial assessment of 9 weeks. In patients with no further lesion measurement after the baseline assessment and no evidence of disease progression (e.g. drop out due to consent withdrawal), best overall response was classified as ‘unknown’. CT or MRI scans for response evaluation were carried out at baseline and were repeated routinely before every other cycle (every 6 weeks). CA 19-9 serum levels were measured within 2 weeks before the first dose of study drug and subsequently on day one of every cycle. All patients who had received at least one dose of pemetrexed were included in the analyses of TTP, OS and toxicity. Toxicity was assessed at each cycle according to the National Cancer Institute Common Toxicity Criteria, version 2.0.
The primary outcome measure of this study was the 3-month survival rate. Survival was defined as the time from treatment administration to the date of death from any cause. Assuming a 3-month survival rate of 50%, no censoring, and a sample size of 50 patients, the width of the corresponding 95% confidence interval (CI) (i.e. 27.8%) was regarded as having an adequate precision. The TTP was defined as the time from treatment administration to the first observation of disease progression or death. TTP was censored at the date of death for patients who had died without documented disease progression and at the date of the last visit for those patients who were alive without documented disease progression. All time to event parameters were analyzed according to the Kaplan–Meier method [22]. The 3-month survival rate was evaluated using the product limit estimate calculated with PROC LIFETEST in SAS Version 8.2 (SAS Institute, Inc., 1989). All further data for categorical or continuous variables are given as absolute and relative frequencies or as medians with ranges, if not otherwise indicated. For response rates the corresponding 95% CIs were also given.
results patient characteristics A total of 54 patients were recruited from October 2003 to August 2004 at 12 sites in Germany, with follow-up for survival until October 2005. Fifty-two patients (96.3%) received at least one dose of pemetrexed and were, therefore, assessable for survival, response and toxicity. Patient and disease characteristics at baseline are summarized in Table 2. The median age at the start of second-line pemetrexed was 62.5 years (range 28–78 years). All but one patient had stage III or IV disease; the main metastatic sites in stage IV patients were liver, lung and abdominal lymph nodes. Thirty-two patients (61.5%) underwent prior surgery of curative (Whipple operation 36.5%) or palliative intent. Seven patients (13.5%) had received prior radiotherapy, and all 52 patients had undergone one previous Gem or Gem-based chemotherapy regimen. Of seven patients (13.5%) with prior adjuvant chemotherapy (five patients Gem, two patients Gem + oxaliplatin), five patients had developed distant metastases on or after adjuvant treatment.
Volume 18 | No. 4 | April 2007
Characteristic Median age (range), years Gender Male Female Performance status (ECOG), n (%) 0 1 2 Median time from PC diagnosis (range), weeks Stage of disease, n (%) Stage IIb Stage III Stage IV Sites of distant metastasesa, n (%) Liver Lung Abdominal lymph nodes Prior surgery, n (%) Whipple operation Prior radiotherapy, n (%) Adjuvant Palliative Prior chemotherapy, n (%) Adjuvant Gemcitabine Gemcitabine + oxaliplatin Palliative Gemcitabine Gemcitabine + cisplatin Gemcitabine + oxaliplatin Gemcitabine + other
62.5 (28–78) 31 (59.6) 21 (40.4) 18 31 3 32
(34.6) (59.6) (5.8) (7–232)
1 (1.9) 5 (9.6) 46 (88.5) 31 6 11 32 19 7 3 4 52 7 5 2 45 34 7 2 2
(59.6) (11.5) (21.2) (61.5) (36.5) (13.5) (5.8) (7.7) (100) (13.5) (9.6) (3.8) (86.5) (65.4) (13.5) (3.8) (3.8)
a
Includes multiple namings. ECOG, Eastern Cooperative Oncology Group; PC, pancreatic cancer.
treatment A total of 192 cycles of pemetrexed were administered in this study, with a median number of two completed cycles per patient (range 1–19 cycles). The median dose of pemetrexed per cycle was 500 mg/m2 (range 212–700 mg/m2). At the time of the final analysis, all 52 patients had discontinued study treatment. The main reasons for discontinuation were disease progression (37 patients, 71.2%), patient refusal (six patients, 11.5%), death from study disease (five patients, 9.6%) and adverse advents (three patients, 5.8%). Dose escalations were carried out according to the protocol in two patients (3.8%) to 600 mg/m2 and 700 mg/m2. The pemetrexed dose was reduced in nine patients (17.3%) mainly due to hematological toxicity (in five patients). efficacy results survival. Thirty-nine patients were still alive 90 days after study entry, resulting in a 3-month survival rate of 75% (95% CI 63.2% to 86.8%). After a median follow-up of 20 weeks (range 1–83 weeks), 47 patients (90.4%) had died, four patients (7.7%) were still alive and one patient (1.9%) was lost to follow-up.
doi:10.1093/annonc/mdl463 | 747
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
sample size and statistical analyses
Table 2. Baseline patient and disease characteristics (N = 52)
original article
Annals of Oncology
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
Figure 1. Overall survival (1a) and time to tumor progression (1b) calculated from the date of first pemetrexed dose (N = 52).
The median OS time calculated from the first dose of pemetrexed was 20 weeks (range 1–84 weeks) and the median OS calculated from the initial diagnosis of PC was 58 weeks (range 8–271 weeks). The median TTP was 7 weeks (range 1–62 weeks). Kaplan–Meier plots for the estimates of OS and TTP are shown in Figure 1a and 1b, respectively. response by imaging criteria. Tumor response is summarized in Table 3. Overall, two patients (3.8%) achieved a partial response (PR) (30% decrease in the sum of the longest diameter of target lesions and no appearance of new lesions), with a duration of 51 days and 198 days. Ten patients (19.2%) experienced SD for ‡9 weeks as defined in the study protocol. Twelve (23.1%) of the assessable patients had SD for >6 weeks and 9 (17.3%) patients had SD for >12 weeks. Thus, the disease control rate (DCR = PR + SD) in this study was 23.1%.
748 | Boeck et al.
Table 3. Response rates (N = 52) Response
No. of patients (%)
95% CI (%)
Complete response Partial response Stable disease (‡9 weeks) Progressive disease Unknown
– 2 10 31 9
– 0.5% 9.6% 45.1% 8.2%
(3.8) (19.2) (59.6) (17.3)
to to to to
13.2% 32.5% 73.0% 30.3%
CI, confidence interval; –, no data.
CA 19-9 tumor marker response. Forty-five (86.5%) of the 52 patients treated with pemetrexed had elevated CA 19-9 levels (defined as values >30 U/ml) at baseline with a median value of 2 341 U/ml (range 38–8.7 · 105 U/ml). Follow-up CA 19-9 levels
Volume 18 | No. 4 | April 2007
original article
Annals of Oncology
Table 4. Relevant hematological and non-hematological toxic effects (maximum by patient, N = 52) No. of patients (%) by toxicity grade (NCI-CTC, version 2.0) Grade 1 Grade 2 Grade 3 Grade 4
Neutropenia Leukopenia Thrombocytopenia Anemia Creatinine increase Hypokalemia Diarrhea Nausea Stomatitis/pharyngitis Abdominal pain Infection Rash/desquamation Fatigue Alopecia Allergic reaction/hypersensitivity
– 2 5 3 1 – 5 9 10 3 – 2 5 3 2
2 6 3 5 1 – (9.6) 5 (17.3) 3 (19.2) 2 (5.8) 3 3 (3.8) 2 (9.6) 2 (5.8) – (3.8) – (3.8) (9.6) (5.8) (1.9)
(3.8) (11.5) (5.8) (9.6) (1.9) (9.6) (5.8) (3.8) (5.8) (5.8) (3.8) (3.8)
7 5 2 1 – 1 2 – – 2 3 1 – – –
(13.5) (9.6) (3.8) (1.9) (1.9) (3.8)
(3.8) (5.8) (1.9)
2 3 1 1 – – – – – – – – – – –
(3.8) (5.8) (1.9) (1.9)
NCI-CTC, National Cancer Institute Common Toxicity Criteria.
were available from 42 patients. Twelve patients (23.1% of N = 52) had a decline of CA 19-9 ‡50% (in relation to CA 19-9 pretreatment levels) at least once during treatment with pemetrexed.
toxicity Hematological and non-hematological toxicity results are summarized in Table 4. Overall, hematological toxic effects of any grade included neutropenia (11 patients, 21.2%), thrombocytopenia (11 patients, 21.2%) and anemia (10 patients, 19.2%). The most frequent grade 3/4 hematological toxic effects were neutropenia (17.3%), thrombocytopenia (5.8%) and anemia (3.8%). Febrile neutropenia occurred in two patients (3.8%). The most frequent non-hematological toxic effects (any grade) were diarrhea, nausea and stomatitis/ pharyngitis (23.1% each). Three patients (5.8%) had a grade 3 infection and two patients (3.8%) each had grade 3 diarrhea or abdominal pain. No grade 4 non-hematological toxicity and no treatment-related death occurred.
discussion This study, which included 52 patients, is currently the largest completed phase II trial to evaluate the role of second-line chemotherapy after Gem failure in patients with advanced PC. Until recently, only three randomized trials were initiated in this patient population. Oettle et al. designed a phase III trial that compared BSC alone versus BSC plus chemotherapy using a combination regimen of oxaliplatin/folinic acid/5-FU after failure of first-line Gem. The planned sample size of this randomized study was 165 patients. Preliminary data reported from 46 patients indicated a possible survival benefit for second-line chemotherapy (BSC = 10 weeks; BSC + chemotherapy = 21 weeks) [6]. Two other randomized studies which compared rubitecan (an oral topoisomerase I inhibitor)
Volume 18 | No. 4 | April 2007
doi:10.1093/annonc/mdl463 | 749
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
Toxicity
to ‘physicians’ best choice of care’ (n = 409) and irinotecan plus raltitrexed to raltitrexed alone (n = 38) reported median survival times from 13 to 28 weeks, respectively [13, 14]. In the randomized phase II study by Ulrich-Pur et al. [14], the addition of irinotecan to the selective thymidilate synthase inhibitor raltitrexed resulted in a clinically meaningful increase of response rate (0% versus 16%), median PFS time (2.5 versus 4.0 months) and median OS time (4.3 versus 6.5 months). On the basis of promising results of palliative first-line treatment we selected pemetrexed as the investigational agent for this multicenter study. Because CR (complete response) or PR to chemotherapy is not necessarily a primary treatment goal in patients with advanced PC [2], the 3-month survival rate was defined as the primary end point in this phase II trial. This survival parameter may be more clinically relevant than the overall response rate in this setting. This study used the standard dose of 500 mg/m2 pemetrexed given every 3 weeks with vitamin B12 and folic acid supplementation to reduce toxicity. The 500-mg/m2 standard dose had been established in earlier studies without vitamin B12 and folic acid supplementation [23]. In order to tailor the dose to individual patients, intrapatient dose escalation was allowed in patients meeting a predefined criteria of low toxicity. The option was used in two patients only (dose escalation to 600 mg/m2 and 700 mg/m2), and thus had no impact on the overall results of the study. Pemetrexed was generally well tolerated and toxicity was manageable. As expected, the main toxicity observed was hematological. With adequate vitamin supplementation, grade 3/4 neutropenia was reported in 17.3% (febrile neutropenia: 3.8%) and grade 3/4 thrombocytopenia in 5.8% of patients. Hematologic toxicity was also the main reason for pemetrexed dose reductions. These toxicity data appear more favorable than those reported in a previous phase II trial in which pemetrexed (600 mg/m2 every 3 weeks) was given as first-line treatment without folic acid and vitamin B12 supplementation [19]. Grade 4 non-hematological toxicity was not observed and nonlaboratory toxicity was limited mainly to diarrhea, nausea and stomatitis/pharyngitis. Under adequate prophylaxis with oral dexamethasone, the observed dermatological toxicity was mild, with only one patient experiencing grade 3 skin rash. In general, also the evaluation of quality of life should be regarded as an important parameter for treatment evaluation in clinical trials. Quality-of-life data were, however, not obtained in this study. The objective response rate (3.8%) in the present study was similar to that seen in the first-line study [19]; in this secondline setting, a disease control rate of 23.1% was achieved. Other investigators, mainly those who incorporated oxaliplatin in their treatment regimen, recently reported response rates of >20% and disease control rates of >50% for salvage chemotherapy in Gem-refractory patients [7, 9, 10], whereas objective response rates in large phase III trials investigating first-line (mainly Gem-based) combination chemotherapy in advanced PC only ranged between 6% and 27% [3, 24]. On the other hand, the survival data in this trial (a 3-month survival rate of 75% and a median survival time of 20 weeks after initiation of pemetrexed) were comparable to the survival data of these oxaliplatin-based combination regimens [6, 7, 9, 10]. Other
original article
acknowledgements The authors wish to thank all patients and their families, nurses, study coordinators and investigators for their active participation in this study. They also thank Eva Mueller for project management, and Claudia Nicolay and Frank Langer for statistical support (all Eli Lilly). This trial was sponsored by Eli Lilly and Company, Indianapolis, IN. This study was presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, 2–6 June 2006, Atlanta, GA. The following persons and study centers participated in this trial: Heinemann/Boeck, Klinikum der Universita¨t Mu¨nchen, Grosshadern; Kettner, Klinikum Magdeburg; Ko¨hne, Universita¨tsklinikum Dresden; Kro¨ning, Onkologische Praxis Magdeburg; Lordick, Klinikum rechts der Isar der
750 | Boeck et al.
Technischen Universita¨t Mu¨nchen; Quietzsch, Klinikum Chemnitz; Salat/Sto¨tzer, Onkologische Praxis Mu¨nchen; Schepp/Fuchs, Sta¨dt. Krankenhaus Mu¨nchen-Bogenhausen; Steinmetz, Onkologische Praxis Ko¨ln; Trojan, Universita¨tsklinikum Frankfurt; Weigang-Ko¨hler, Klinikum Nu¨rnberg-Nord; Zeuzem, Universita¨tsklinikum des Saarlandes, Homburg.
references 1. Herbst RS, Bajorin DF, Bleiberg H et al. Clinical cancer advanced 2005: major research advanced in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology. J Clin Oncol 2006; 24: 190–205. 2. Burris HA, Moore MJ, Andersen J et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15: 2403–2413. 3. Heinemann V. Gemcitabine in the treatment of advanced pancreatic cancer: a comparative analysis of randomized trials. Semin Oncol 2002; 29 (Suppl 20): 9–16. 4. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinicals trials group [NCIC-CTG]. Proc Am Soc Clin Oncol 2005; 23: (Abstr 1). 5. Cunningham D, Chau I, Stocken D et al. Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. Eur J Cancer Suppl 2005; 3: (Abstr PS11). 6. Oettle H, Pelzer U, Stieler J et al. Oxaliplatin/folinic acid/5-fluorouracil [24h] (OFF) plus best supportive care versus best supportive care alone (BSC) in second-line therapy of gemcitabine-refractory advanced pancreatic cancer (CONKO 003). Proc Am Soc Clin Oncol 2005; 23: (Abstr 4031). 7. Tsavaris N, Kosmas C, Skopelitis H et al. Second-line treatment with oxaliplatin, leucovorin and 5-fluorouracil in gemcitabine-pretreated advanced pancreatic cancer: a phase II study. Invest New Drugs 2005; 23: 369–375. 8. Cantore M, Rabbi C, Fiorentini G et al. Combined irinotecan and oxaliplatin in patients with advanced pre-treated pancreatic cancer. Oncology 2004; 67: 93–97. 9. Demols A, Peeters M, Polus M et al. Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced pancreatic adenocarcinoma: a phase II study. Br J Cancer 2006; 94: 481–485. 10. Reni M, Pasetto L, Aprile G et al. Raltitrexed-eloxantin salvage chemotherapy in gemcitabine-resistant metastatic pancreatic cancer. Br J Cancer 2006; 94: 785–791. 11. Oettle H, Arnold D, Esser M et al. Paclitaxel as weekly second-line therapy in patients with advanced pancreatic carcinoma. Anticancer Drugs 2000; 11: 635–638. 12. Milella M, Gelibter A, Di Cosimo S et al. Pilot study of celecoxib and infusional 5-fluorouracil as second-line treatment for advanced pancreatic carcinoma. Cancer 2004; 101: 133–138. 13. Jacobs AD, Burris HA, Rivkin S et al. A randomized phase III study of rubitecan (ORA) vs. best choice (BC) in 409 patients with refractory pancreatic cancer. Report from a North-American multi-center study. Proc Am Soc Clin Oncol 2004; 22: (Abstr 4013). 14. Ulrich-Pur H, Ru¨derer M, Kornek GV et al. Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma. Br J Cancer 2003; 88: 1180–1184. 15. Blaszkowsky LS, Kulke KH, Ryan DP et al. A phase II study of erlotinib in combination with capecitabine in previously treated patients with metastatic pancreatic cancer. Proc Am Soc Clin Oncol 2005; 23: (Abstr 4099). 16. 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. 17. Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003; 21: 2636–2644.
Volume 18 | No. 4 | April 2007
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
phase II trials investigating regimens with only one cytotoxic drug in the second-line setting reported median survival times of 17.5 weeks and 15 weeks [11, 12]. Encouraging preliminary data were also obtained from the first trial that included a targeted agent in second-line treatment after Gem failure. Blaszkowsky et al. administered capecitabine plus erlotinib in 30 patients with metastatic PC and achieved a remission rate of 11% (corresponding DCR 68%) and a median OS time of nearly 29 weeks [15]. The comparison of survival data between small phase II trials is difficult due to differences in the evaluated patient populations. Certain baseline patient characteristics (e.g. PS) have been shown to be strong and independent of prognostic factors regarding survival [24, 25]. A recently presented retrospective, multicenter survey that evaluated the role of fluoropyrimidine-based second-line chemotherapy in 160 patients with advanced PC showed that the most important independent prognostic factor for PFS in the second-line setting was PS [26], indicating that careful patient selection for salvage chemotherapy may be important in clinical practice as well as future clinical trials. Therefore, the study population can determine—in part—the survival results of a clinical trial. Previously published phase II trials of salvage chemotherapy in advanced PC included a wide range of different and noncomparable patient populations. For example, populations differed in terms of PS (the proportion of patients with ECOG 0/Karnofsky >90% ranged from 0% to 61%) or prior chemotherapy (patients with >1 prior chemotherapy ranged from 0% to 29%) [10]. Only a well-designed, randomized phase III trial that stratifies patients according to prognostic factors such as tumor stage or PS will be able to determine a potential survival benefit of a second-line regimen in patients with advanced PC. In this setting, pemetrexed-based combination regimens (e.g. with a platinum [17, 27] or a targeted agent) may be a promising approach to further improve the efficacy of second-line treatment after failure of first-line Gem chemotherapy. In conclusion, pemetrexed is a safe treatment option with limited activity in second-line chemotherapy after Gem failure. On the basis of its safety profile and clinical activity as a single agent, pemetrexed-based combinations merit further investigation in this setting.
Annals of Oncology
Annals of Oncology
18. Hanna N, Shepherd FA, Fossella FV et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22: 1589–1597. 19. 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. 20. Oettle H, Richards D, Ramanathan RK et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 2005; 16: 1639–1645. 21. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92: 205–216. 22. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.
original article 23. Rollins KD, Lindley C. Pemetrexed: a multitargeted antifolate. Clin Ther 2005; 27: 1343–1382. 24. Louvet C, Labinaca R, Hammel P et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005; 23: 3509–3516. 25. Ueno H, Okada S, Okusaka T, Ikeda M. Prognostic factors in patients with metastatic pancreatic adenocarcinoma receiving systemic chemotherapy. Oncology 2000; 59: 296–301. 26. Mancuso-Petricca A, Saletti P, Tronconi MC et al. The efficacy of fluoropyrimidine-based second line chemotherapy in advanced and metastatic pancreatic cancer: results of an ongoing Italian/Swiss multicenter survey. Ann Oncol 2006; 17 (Suppl 9): ix323 (Abstr 1131P). 27. Scagliotti GV. Pemetrexed plus carboplatin or oxaliplatin in advanced non-small cell lung cancer. Semin Oncol 2005; 32 (Suppl 2): 5–8.
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 12, 2015
Volume 18 | No. 4 | April 2007
doi:10.1093/annonc/mdl463 | 751