Cancer Chemother Pharmacol DOI 10.1007/s00280-014-2509-6

Original Article

Frontline treatment with gemcitabine, oxaliplatin and erlotinib for the treatment of advanced or metastatic pancreatic cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG) O. Katopodis · J. Souglakos · E. Stathopoulos · A. Christopoulou · E. Kontopodis · A. Kotsakis · K. Kalbakis · N. Kentepozidis · A. Polyzos · D. Hatzidaki · V. Georgoulias 

Received: 12 March 2014 / Accepted: 2 June 2014 © Springer-Verlag Berlin Heidelberg 2014

Abstract  Purpose  Intravenous gemcitabine is the standard of care for patients with metastatic cancer of the pancreas. Gemcitabine-based chemotherapy combinations, either doublets or triplets, have been tested in the past but have offered a small advantage (Brodoefel et al. in Eur J Radiol 73:594– 600, 2010). In the present study, we present the results of the triplet gemcitabine–oxaliplatin–erlotinib combination as firstline treatment in this setting. Patients and methods  Seventy-one eligible patients were included in this study. All patients received chemotherapy with gemcitabine (1,100 mg/m2 on days 1 and 8) plus oxaliplatin (130 mg/m2 on day 8) and erlotinib (100 mg p.o./day for 21 days). The treatment cycle was 21 days. Results  Partial response was achieved in 15 patients (21 %; 95 % CI 11.63–30.62) and stable disease in 15 patients (21 %). Forty-one patients (57.8 %) experienced disease progression. Median progression-free survival was 5.2 months (range 0.6–34.7; 95 % CI 3.71–6.76). The median overall survival was 10.5 months (95 % CI 7.39–13.61) and the 1-year survival estimate 47.3 %. The main adverse events were grade 3/4 anemia occurring in three (4.2 %) patients and grade 3 and 4 thrombocytopenia occurring in eight (11.3 %) and three (4.2 %) patients, respectively. Grade 4 neutropenia was rare (1.4 %), and one patient presented febrile neutropenia.

O. Katopodis (*) · J. Souglakos · E. Stathopoulos · A. Christopoulou · E. Kontopodis · A. Kotsakis · K. Kalbakis · N. Kentepozidis · A. Polyzos · D. Hatzidaki · V. Georgoulias  Hellenic Oncology Research Group (HORG), 55 Lombardou Str., 11470 Athens, Greece e-mail: [email protected] V. Georgoulias e-mail: [email protected]; [email protected]

Conclusion This study demonstrated that the combination of gemcitabine, oxaliplatin and erlotinib is active, well tolerated and safe for patients with metastatic adenocarcinoma of the pancreas. However, the results do not seem to be better than those reported with chemotherapy alone. Keywords Gemcitabine · Oxaliplatin · Erlotinib · Phase II trial · Pancreas

Introduction A recently published study in Annals of Oncology [2] showed that pancreatic cancer is the only cancer for which deaths are predicted to increase rather than decrease in 2014 and beyond. The study confirmed that currently pancreatic cancer is the fourth leading cause of cancer death in Europe and the fifth biggest in the UK, despite the fact that in 2006 it was the eighth leading cause of cancer-related death in men and the ninth in women [3]. The majority of patients (up to 60 %) have advanced and thus inoperable disease at the time of diagnosis. The median survival of patients with locally advanced disease is 6–10 months and for patients with metastatic disease 3–6 months [4–6]. Since 1997, intravenous gemcitabine represents the standard of care for these patients [5, 7]. Combining other chemotherapy drugs with gemcitabine has not proved to improve the survival rate of this disease. Over the last 10 years, though, multiple gemcitabine-based combinations have been tried, offering a survival benefit [8, 9]. Published results exist in the literature for the following gemcitabine (Gem)-based double combinations: Gem/oxaliplatin, Gem/bevacizumab and Gem/cetuximab [10–12]. Randomized controlled trials have shown that the gemcitabine/oxaliplatin combination in patients

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with advanced pancreatic cancer increased the objective response rate (RR 17.3 vs. 26.8 %, P  = 0.004) and progression-free survival (PFS; 3.7 vs. 5.8 months, P = 0.04), but failed to improve the overall survival (OS) compared to gemcitabine alone [10, 13]. A meta-analysis of 15 randomized trials, published by Heinemann et al. [9], showed a reduction of the hazard of death by 15 % for all platinum-based/gemcitabine combinations; more specifically, the clinical benefit ratio (CBR) was improved from 26.9 to 38.2 % (P = 0.03). From all the recently published trials, a small benefit was observed with the addition of erlotinib to gemcitabine [6]. Erlotinib (Tarceva) inhibits epidermal growth factor receptor (EGFR) tyrosine kinase (TK) auto-phosphorylation by inhibition of the intracellular domain. Studies in cell lines and enzyme assays have both shown that erlotinib inhibits EGFR at concentrations significantly lower than those needed to inhibit c-src and v-abl [14]. The combination of gemcitabine and erlotinib in patients with advanced pancreatic cancer has shown to modestly increase OS compared to gemcitabine monotherapy. Although the combination was also associated with a PFS benefit, there was no difference in terms of response rate and response duration between the two groups [6]. The corresponding 1-year survival for patients who have received the combination gemcitabine and erlotinib was 24 versus 17 % for patients who received single-agent gemcitabine. Despite these findings, the gemcitabine/erlotinib regimen is not recommended as standard of care because of the modest OS benefit. Based on the data shown above, it was considered of interest to investigate whether the gemcitabine/oxaliplat in/erlotinib regimen offers a further clinical improvement in patients with previously untreated metastatic/advanced pancreatic cancer. This combination has already been used in patients with hepatocellular and biliary carcinomas [15]. Thus, the same maximum tolerated doses for the combining drugs as well as the treatment schedule have been kept at the present phase II study of the GI Working Group of the Hellenic Oncology Research Group [1].

Patients and methods Eligibility Patients with a histologically or cytologically confirmed diagnosis of locally advanced or metastatic carcinoma of pancreas, aged >18 years, were eligible for the study. No prior chemotherapy for metastatic disease was allowed; adjuvant gemcitabine-based chemotherapy was allowed provided that at least 6 months had elapsed from the administration of the last chemotherapy cycle. Other eligibility criteria were the following: at least one bidimensionally

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Cancer Chemother Pharmacol

measurable target lesion (i.e., lesions ≥2 cm other than the primary or ≥1.5 cm in case of lung metastasis, outside any previous irradiated area); WHO Performance Status (PS) of 0–2; adequate bone marrow (defined as neutrophils >1,500/mm3, platelets >100,000/mm3, Hb >10mgr/dl), liver [defined as bilirubin levels ≤1.5 times the institutional upper normal limit (UNL), after biliary drainage if previously abnormal and as AST and alkaline phosphatase ≤2.5 times the UNL, or ≤5 times the UNL for patients with liver metastasis] and renal function (defined as serum creatinine ≤1.5 times the UNL); and absence of ascites. Patients with other primary tumors within the last 10 years were excluded from the study, except adequately treated in situ cervical carcinoma and basal or squamous cell skin carcinoma. Patients were also excluded from the study if they had symptomatic central nervous system metastasis or carcinomatous leptomeningitis, a psychiatric disorder, active uncontrolled infection, a myocardial infarction within the last 12 months or congestive heart failure or cardiac arrhythmias not controlled on medication. All patients signed a written informed consent before their enrollment to the study. The protocol has been approved by the Εthics and the Scientific Committees of the participating Institutions. Treatment plan The gemcitabine/oxaliplatin regimen that has been used in the present study was based on a recommended regimen by Mavroudis et al. [16] on a dose escalation study for solid tumors. The chemotherapy regimen consisted of gemcitabine (Gemzar, Eli Lilly, USA), given intravenously (IV) at the dose of 1,100 mg/m2 as a 30–60 min intravenous (IV) infusion on days 1 and 8, oxaliplatin (Eloxatin, SanofiAventis, Bridgewater, USA) at the dose of 130 mg/m2 given as a 2–4-h IV infusion on day 8 and erlotinib (Tarceva; Roche, Switzerland) at a dose of 100 mg p.o. daily for 21 days. Standard ondansetron anti-emetic treatment was administered to all patients. The treatment cycle was repeated every 21 days. Prophylactic administration of recombinant granulocyte colony-stimulating factor (rG-CSF) was not allowed. Only in cases of grade 3 or 4 febrile neutropenia, subsequent cycles were repeated with rhG-CSF prophylactic administration (150 μγ/day, SC; granocyte, Sanofi-Aventis). Dose adjustment criteria were based on hematological parameters. In case of febrile neutropenia or grade 3 or 4 neutropenia, despite the prophylactic administration of rhG-CSF, gemcitabine and oxaliplatin doses were reduced by 25 %. In cases of grade 3 or 4 thrombocytopenia lasting for >5 days, the doses of both drugs were reduced by 25 %. Treatment was interrupted for ≥grade 2 non-hematological toxicity (with the exception of alopecia, nausea or

Cancer Chemother Pharmacol

vomiting, and anemia), and it was not restarted until either complete improvement or at least improvement to grade 1. Patients had to be withdrawn from the study if toxicity did not improve to at least grade 1 after 3 weeks with no treatment. Toxicity was graded according to the National Cancer Institute–Common Toxicity Criteria version 2.0 [17]. Treatment was given until disease progression or intolerable toxicity. Patient evaluation Pre-treatment evaluation included complete medical history and physical examination, full blood cell count including differential leukocyte and platelet count, a standard biochemical profile (and creatinine clearance when necessary), serum CA-19.9 determinations, electrocardiogram (ECG), chest X-ray, ultrasound of the upper abdomen and computed tomography [18] scans of the chest, upper and lower abdomen. Additional imaging studies were performed upon clinical indication. Full blood cell counts with differential were performed weekly; in case of grade 3 or 4 neutropenia or grade 4 thrombocytopenia, full blood cell counts with differential were evaluated daily until the absolute granulocyte count was >1,000/dl and the platelet count was >75,000/dl. A detailed medical and physical examination was completed before each course of treatment in order to document symptoms of the disease and treatment toxicities. Biochemical tests, ECG, serum CA-19.9 and chest X-ray were performed every 6 weeks. A neurologic evaluation was performed by clinical examination before each administration of oxaliplatin. Lesions were measured before the next cycle of chemotherapy if they were assessable by physical examination; lesions assessable by ultrasound or CT scans or chest X-ray were evaluated after three chemotherapy cycles. Response was defined according to the RECIST criteria. Increase of serum bilirubin levels without recovery after endoscopic retrograde choledocho-pancreatography (ERCP) or stent was considered as disease progression. A two-step deterioration in PS, a >10 % loss of pre-treatment weight or increasing symptoms did not by themselves constitute progression of the disease; however, the appearance of these complaints was followed by a new evaluation of the extent of the disease [19]. All responses had to be maintained for at least 4 weeks and be confirmed by an independent panel of radiologists. Statistical analysis This was an extended, two-step, phase II study. The primary end point of the study was the efficacy (objective response rate) [20]. Secondary end points were PFS, OS and tolerance of the regimen. Simon’s two-stage design was

used for calculation of the sample size. The null hypothesis that the true response rate is 10 % was to be tested against a one-sided alternative. In the first stage, 38 patients were planned to be accrued. If there were 12 or fewer responses in these 38 patients, the study would be stopped. Otherwise, 33 additional patients were to be accrued for a final total of 71 patients. The null hypothesis would be rejected if 13 or more responses were observed in the 71-patient pool. This design yields a type I error rate of 0.05 and power of 80 %, and the true response rate is 20 %. Duration of response was calculated from the day of the first demonstration of response until disease progression (PD). The time to tumor progression (TTP) was calculated from the day of entry into the study until documented PD. OS was calculated from the day of study enrollment until death. The median probability of survival and the median TTP were estimated by the Kaplan–Meier method; confidence intervals (CI) for response rates were calculated using methods for the exact binomial CI. Comparison of variables was performed using the χ2 test.

Results Patient characteristics Between January 2006 and September 2011, 71 patients were enrolled into the study. All patients received the combination of gemcitabine/oxaliplatin and erlotinib as frontline treatment for a locally advanced or metastatic pancreatic adenocarcinoma. Patient characteristics are shown on Table 1. The median patients’ age was 63 years (range 42– 81). Sixty-three patients (88.7 %) had a PS of 0–1, and four (5.6 %) presented with an adenocarcinoma of the ampulla of Vater. Fifty-six patients (78.9 %) had metastatic disease at diagnosis, and 45 of them (63.5 %) had liver metastasis. Compliance with treatment A total of 339 chemotherapy cycles were administered with a median of four cycles per patient (range 1–10). The median interval between cycles was 21 days (range 21–35). The median dose intensity for gemcitabine was 623.4 mg/m2/week (range 183.2–888.9), for oxaliplatin 35.0 mg/m2/week (range 13.3–47.3) and for erlotinib 100 mg/d corresponding to the 85, 81 and 100 % of the planned protocol dose, respectively. Twenty-eight (8.3 %) cycles were delayed from 3 to 28 days (median 5 days); the reasons for treatment delay were hematological (n  = 24 cycles) and non-hematological (n  = 4 cycles) toxicity. 56 (16.5 %) cycles were delayed for reasons unrelated to disease or treatment (late admission, imaging evaluation and patient’s request). Dose reduction was necessary

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Cancer Chemother Pharmacol

in 22 (6.5 %) cycles because of toxicity (hematological: n = 6 cycles; non-hematological: n = 10 cycles; and both hematological and non-hematological: n  = 1 cycle) or other reasons (i.e., patient’s request for personal reasons or Table 1  Patient demographics and clinical characteristics Characteristic

No. of patients (n = 71)

Age  Median (min–max) 63 (42–81) Sex  Male 44  Female 27 Performance status  0 35  1 28  2 8 Stage  IIIA 2  IIIB 13  IV 56 Localization of primary tumor  Head of pancreas 45  Body of pancreas 14  Tail of pancreas 8  Ampulla of Vater 4 Surgery  No 49  Currative 20  Paliative 2 Disease localization  Pancreas 58  Liver 45  Nodes 31  Lung 11  Peritoneum 3  Other

7

Fig. 1  Kaplan–Meier estimate of overall survival (OS) of patients treated with the gem citabine/oxaliplatin/erlotinib regimen

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%

62.0 38.0 49.3 39.4 11.3 2.8 18.3 78.9 63.4 19.7 11.3 5.6 69.0 28.2 2.8 81.7 63.4 43.7 15.5 1.2 9.9

no social security coverage) (n = 5 cycles; 1.5 %). Seven patients (10 %) discontinued treatment after the first cycle due to disease progression (n = 5 patients) or early death (n = 2 patients). Gemcitabine was reduced in six cycles (1.8 %), oxaliplatin in four cycles (1.2 %) and erlotinib in four cycles. Dose reduction for both gemcitabine and oxaliplatin occurred in five cycles (1.5 %), for both gemcitabine and erlotinib in two cycles (0.6 %) and for all three drugs in one cycle (0.3 %). Responses to treatment and survival Responses were analyzed on an intention-to-treat basis. There were no complete responses. Partial response (PR) was achieved in 15 (21.1 %; 95 % CI 11.63–30.62 %) patients and stable disease (SD) in 15 (21.1 %); 41 (57.8 %) patients experienced progressive disease. Sites with evaluable target lesions of tumor response were the pancreas in 13 of 15 patients (86.7 %), the liver in seven of 15 (46.7 %), the lymph nodes in five of 15 (33.3 %) and the lung in four of 15 (26.7 %) patients. A PR was observed in three out of 15 patients with inoperable stage III disease. Objective responses were documented in seven out of 35 (20 %) patients with a PS of 0 and in eight out of 36 patients (22.2 %) with a PS of 1–2. The median duration of response was 8.9 months (range 2.5–32.6). After a median follow-up period of 48.9 months (range 0.6–49.3), the median PFS was 5.2 months (range 0.6–34.7; 95 % CI 3.71–6.76) and the estimated 6-month and 12-month disease control (no progression) rate was 45.9 and 13.1 %, respectively (Fig. 1). The median PFS for patients who had either PR or SD was 7.9 months (range 3.5–34.7) and in patients with progressive disease 2.5 months (range 3.3– 17.4). At the time of this analysis, 20 (28.2 %) patients were alive and 51 (71.8 %) dead due to disease progression. The median OS was 10.5 months (95 % CI 7.39–13.61) and the 1-year survival estimate 47.3 % (Fig. 2). The median OS

Cancer Chemother Pharmacol Fig. 2  Kaplan–Meier estimate of progression-free survival (PFS) of patients treated with the gemcitabine/oxaliplatin/erlo tinib regimen

Table 2  Efficacy results of the gemcitabine/oxaliplatin/erlotinib regimen in patients with advanced pancreatic cancer (95 % CI) Median OS (months)  Stage III  Stage IV Median PFS (months)

10.5 18.9 9.1 PR + SD: 7.9 PD: 2.5 47.3 %

1-year survival estimate

7.39–13.61 16.2–21.7 6.2–11.9 6.4–9.3 1.7–3.3

n Response  PR  SD  PD

15 (21.1 %) 15 (21.1 %)

11.6–30.6 %

41 (57.8 %)

for patients with stage III disease was 18.9 months (95 % CI 16.2–21.7; range 3.4–49.3) and with stage IV disease 9.1 months (95 % CI 6.2–11.9; range 0.6–48.9). These efficacy results are summarized in Table 2. Increased pre-treatment serum CA-19.9 levels were available in 43 (60.6 %) of 71 evaluable patients. The levels of CA-19.9 were decreased or remained at pre-treatment levels in 15 (21.1 %) and 13 (18.3 %) patients, respectively. Conversely, CA-19.9 serum levels were increased in 15 patients. Weight gain and loss were documented in 17 (34 %) and 18 (36 %) of 50 evaluable patients, respectively, while it remained unchanged in the remaining 15 (30 %) patients. Treatment was associated with pain reduction in 16 (32 %) of the 50 patients who complained for pain at baseline, whereas three (6 %) patients complained for pain deterioration.

Toxicity All patients were evaluable for toxicity (Table 3). Grade 3 and 4 anemia occurred in three (4.2 %) patients who required blood transfusion. Additionally, nine (12.7 %) patients with grade 2 anemia were treated with recombinant erythropoietin. Grade 3 and 4 thrombocytopenia occurred in eight (11.3 %) and three (4.2 %) patients, respectively. No patient required hospitalization for hematologic treatment-related toxicity. Nine (12.7 %) patients presented with grade 3 neutropenia and one (1.4 %) with grade 4. One (1.4 %) patient developed febrile neutropenia requiring hospitalization and was treated with intravenous antibiotics with good recovery. Recombinant human G-CSF was administered in 55 chemotherapy cycles due to grade 2–4 neutropenia. Non-hematological toxicity was relatively mild (Table 3).

Discussion Despite recent developments in cancer treatment, progress in treating patients with advanced pancreatic cancer is very slow. The triplet gemcitabine, oxaliplatin and erlotinib combination has been used for hepatocellular carcinoma, and it has been proved to be well tolerated in this disease setting [15]. The present study evaluated the efficacy of the triple combination gemcitabine/oxaliplatin/erlotinib in patients with advanced pancreatic cancer as frontline treatment. The efficacy variables that were tested included objective response rate as the primary endpoint of the study, whereas the PFS and the OS were considered as secondary endpoints. To the best of our knowledge, this is the first study

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Cancer Chemother Pharmacol

Table 3  Toxicity of the gem citabine/oxaliplatin/erlotinib regimen

Grade I

Grade III

Grade IV

n

%

n

%

n

%

n

%

Leucopenia Neutropenia Thrombocytopenia Anemia Febr. neutropenia Nausea Vomiting Constipation Diarrhea Stomatitis Febrile Neurotoxicity Skin toxicity

17 14 24 39 – 5 3 – 10 4 6 9 6

23.9 19.7 33.8 54.9 – 7.0 4.2 – 14.1 5.6 8.5 12.7 8.5

14 12 5 18 – 6 3 2 5 –

19.7 16.9 7.0 25.4 – 8.5 4.2 2.8 7.0 –

6 9 8 2 – 1 1 – 2 –

8.5 12.7 11.3 2.8 – 1.4 1.4 – 2.8 –

1 1 3 1 1 – – – – –

1.4 1.4 4.2 1.4 1.4 – – – – –

2 5

2.8 7.0

1 1

1.4 1.4

– –

– –

Allergy

9

12.7

1

1.4

1

1.4





of this chemotherapy regimen in patients with pancreatic cancer. The regimen was well tolerated with only a small number of patients presenting with >grade 2 toxicities. In addition, the compliance with the treatment was very good since only eight patients had to stop their treatment because of an adverse treatment-related event, whereas 43 patients (60.6 %) managed to continue treatment until disease progression. Only few treatment delays and dose adjustments were observed. Most of the delays were unrelated to disease or treatment. Finally, there was no treatment-related death, and all deaths were due to disease progression. The study met its primary endpoint with an objective response rate of 21.1 %; moreover, the median PFS of 5.2 months and the OS of 10.5 months compare with previous studies reporting a PFS ranging from 2.7 to 5.8 months and an OS of 5.7– 9.0 months for the gemcitabine/oxaliplatin combination in patients with advanced pancreatic cancer [10, 13, 21]. In our study population, a small percentage of patients (5.6 %) with an ampulla of Vater primary were included. Some could argue that the final results of our study could be jeopardized by this. Statistically, this is a very small percentage to be able to influence the final result either positively or negatively, and in order to do that, this small number of patients should have an incredibly good or bad response, respectively. A recent study has been published using gemcitabine combined with oxaliplatin and erlotinib for patients with advanced biliary tract cancer. Patients with an ampulla of Vater were included in this study [22]. The addition of erlotinib to the chemotherapy regime for this group of patients improved the objective response (40 patients in the chemotherapy plus erlotinib group versus 21 patients in the chemotherapy only group; P  = 0.005), but similar to our study, there was no significant difference for

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Grade II

the OS. Considering the data of this study, we could not believe that the addition of the patients with ampulla of Vater advanced cancer could influence the result of the current study either way. Most of the published articles concerning chemotherapy for advanced pancreatic cancer usually include patients with stage III and IV disease. The prognosis of both stages is similarly bad (5-year observed survival 2 %) [23]. In our study, the majority of patients were with metastatic disease. The number of patients in each group, though, is rather small to be analyzed separately for a safe conclusion to be made. Studies with larger number of patients with metastatic disease would certainly be of great interest to assess the efficacy of the gemcitabine, oxaliplatin and erlotinib combination. Previous randomized studies clearly demonstrated the superiority of the gemcitabine/oxaliplatin combination in terms of response rate and PFS but not for OS compared to gemcitabine monotherapy in patients with advanced pancreatic cancer [10, 13]. In addition, a meta-analysis [9] showed a reduction of the hazard of death by 15 % for all platinum-based/gemcitabine combinations; more specifically, the CBR was improved with these combinations from 26.9 to 38.2 % (P = 0.03). On the other hand, Moore et al. [6] reported on a phase III trial that the gemcitabine erlotinib combination improved PFS, but there was no difference in terms of response rate and response duration and only a modest increase in median OS (6.24 vs. 5.91 months). Based on this study, gemcitabine/erlotinib stands as one of the standard firstline treatments for patients with advanced pancreatic cancer. Although we cannot directly compare our data with the results of the above studies, we will not be able to note that the addition of oxaliplatin in the gemcitabine/erlotinib

Cancer Chemother Pharmacol

regimen offers any meaningful clinical advantage. This is in line with the experience gained from the gemcitabine/erlotinib combination [24]. However, only a direct comparison of the two regimens could lead to safe conclusions, but we do not believe that a randomized trial is justified based on our results. It is now well established that targeted treatments such as erlotinib are effective in only a subpopulation of patients for whom the targeted agent can inhibit the driven oncogenic mechanism. Therefore, it is an unmet need to identify the patients that might get the benefit from the addition of erlotinib. Indeed, data from previous studies showed that patients who developed a >grade 2 skin rash experienced a better median (10.5 months) survival [6]. The association of rash and survival in patients with advanced pancreatic cancer was also noted analyzing the results of the AViTA trial [25]. In the current study, the median OS was 10.5 months (including patients with and without skin rash). Unfortunately, the number of patients enrolled in the current study, who developed clinically meaningful skin rash, was too small in order to perform a reliable subgroup analysis. On the other hand, it is obvious that skin rash could not be used to preselect patients for receiving treatment with erlotinib. Conversely, since KRAS mutations occur in about 70–90 % of patients with pancreatic cancer [26] and activation of KRAS gene can predict resistance to erlotinib in some malignancies, it would be of interest to evaluate whether the presence of these mutations could be used as a predictive biomarker for the selection of treatment with erlotinib. Over the last few years, new chemotherapy combinations such as a 5-flouoruracil, oxaliplatin, irinotecan combination (FOLFIRINOX) [27] and more recently gemcitabine combined with albumin-bound paclitaxel (nab-paclitaxel [abraxane]) [20] have been developed for the treatment of patients with advanced pancreatic cancer, and both regimens showed promising results. FOLFIRINOX showed a significantly prolonged median OS with an increase of 4.3 months compared to singleagent gemcitabine (11.1 vs. 6.8 months). The real problem with this chemotherapy regimen has been the safety profile. It is absolutely necessary that patients are of a younger age and have a good PS to be able to receive this chemotherapy combination [27]. Gemcitabine combined with nab-paclitaxel, a chemotherapy regimen with better safety profile compared to FOLFIRINOX, showed a median OS of 8.5 months compared to 6.7 months of gemcitabine monotherapy [20]. The response rate with this regimen was 23 versus 7 % with single-agent gemcitabine (P 

Frontline treatment with gemcitabine, oxaliplatin and erlotinib for the treatment of advanced or metastatic pancreatic cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG).

Intravenous gemcitabine is the standard of care for patients with metastatic cancer of the pancreas. Gemcitabine-based chemotherapy combinations, eith...
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