Purpose: Epidermal growth factor receptor (EGFR) inhibitors may improve both the therapeutic efficacy of radiotherapy and the radiosensitizing activity of gemcitabine. Based on this rationale and the nonoverlapping toxicity profiles of gemcitabine and the monoclonal EGFR antibody panitumumab, we designed a phase I trial to investigate the maximum-tolerated dose (MTD), safety, and activity of panitumumab added to gemcitabine-based chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer (LAPC).

Experimental Design: Patients with LAPC and WHO performance status 0 to 1 were treated with weekly panitumumab at four dose levels (1–2.5 mg/kg), combined with weekly gemcitabine 300 mg/m2 and radiotherapy (50.4 Gy in 28 fractions) for 6 weeks, followed by gemcitabine 1,000 mg/m2 weekly for 3 weeks every 4 weeks until disease progression or unacceptable toxicity. Each cohort was monitored during the combination therapy to establish dose limiting toxicity. Tumor evaluation was performed after CRT and during gemcitabine monotherapy.

Results: Fourteen patients were enrolled; 14 were evaluable for toxicity and 13 for response. The MTD for panitumumab was 1.5 mg/kg. Three of the 6 patients, treated at MTD, experienced grade 3 adverse events during the combination therapy; neutropenia (n = 2; 33%), fatigue (n = 1; 17%), nausea (n = 1; 17%), and vomiting (n = 1; 17%). Partial response was achieved by 3 patients (23%), 1 in each dose cohort. Median progression free survival of the three cohorts together was 8.9 months.

Conclusions: The addition of panitumumab to gemcitabine-based chemoradiotherapy in LAPC has manageable toxicity and potential clinical efficacy. Clin Cancer Res; 21(20); 4569–75. ©2015 AACR.

Translational Relevance

Epidermal growth factor receptor (EGFR) expression is high in pancreatic cancer. Preclinical evidence indicates that EGFR pathway inhibition improves antitumor efficacy of radiotherapy independent of the K-RAS mutation status of a tumor. Preclinical in vivo studies have also shown that EGFR inhibition enhances the radiosensitizing activity of gemcitabine. Panitumumab, a fully human anti-EGFR monoclonal antibody, increased the antitumor efficacy of gemcitabine in a pancreatic tumor model. In this phase 1 trial, we investigated the maximum-tolerated dose (MTD), safety, and activity of panitumumab when combined to gemcitabine-based chemoradiotherapy in patients with locally advanced pancreatic cancer (LAPC). The addition of panitumumab to gemcitabine-based chemoradiotherapy in LAPC has manageable toxicity and showed first evidence of clinical efficacy. These observations support the further evaluation of this combination in a phase II study.

In the Western world, approximately 5% of cancer mortality is due to pancreatic ductal adenocarcinoma (PDAC). At presentation, only 10% to 20% of patients with PDAC have localized disease that can be considered for resection. The remaining patients cannot be cured with resection due to locally advanced pancreatic cancer (LAPC; approximately 35%) or metastatic disease.

Treatment of LAPC is extremely challenging. Despite recent advances in the treatment of metastatic pancreatic cancer using combination chemotherapy (CHT) regimens, including oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX; ref. 1), or gemcitabine–paclitaxel protein bound (2), not much progress has been made in the treatment of LAPC in the last decade. Because both metastatic spread and locoregional disease progression are of major concern, combinations of systemic CHT and radiotherapy (RT) are often used. Numerous chemoradiotherapy (CRT) studies have been performed, attempting to postpone disease progression and also to increase the possibility of resection (3, 4). Results of these CRT regimens are comparable, and do not consistently show benefit of combination treatment or from CHT alone (5). However, a recent meta-analysis including 15 randomized trials in which CRT with RT or CHT alone were compared for LAPC showed superiority of CRT in 6- and 12-month survival at the expense of more toxicity (6). Survival at 18 months was not significantly different. Ongoing developments include the use of CRT regimens based upon full dose CHT with added radiation, rather than the other way round (7, 8) or to add additional drugs to improve outcome of CRT (9). Although CRT is considered as standard treatment for LAPC, improvement in efficacy and reduction of toxicity is urgently needed.

The epidermal growth factor receptor (EGFR; also known as ErbB-1 and HER1 in humans) signaling cascade plays an important role in the biology of various malignancies, including pancreatic cancer. Human pancreatic cancer cells overexpress EGFR and its known ligands (10, 11), which is correlated with rapidly progressive disease (12). EGFR inhibition by the addition of erlotinib, a tyrosine kinase inhibitor, to gemcitabine is associated with a modest survival benefit in PDAC (13). In colorectal cancer, the clinical efficacy of antibodies against EGFR is restricted to patients with wild-type RAS tumors (14, 15). PDAC is known for its high K-RAS mutation phenotype (>90%; ref. 16) and harbors the highest reported incidence of RAS mutations among all human cancers. These mutations rarely affect H-RAS or N-RAS and concentrate almost exclusively on the K-RAS locus, with reports of mutation rates up to 95% (17).

Interestingly, several studies have shown that EGFR pathway inhibition can improve the antitumor efficacy of RT independent of the K-RAS mutation status of a tumor (18, 19). Furthermore, preclinical in vivo studies indicated that the radiosensitizing activity of gemcitabine may be enhanced by specific EGFR inhibition (20) and also showed, in a pancreatic tumor model, that treatment with panitumumab, a fully human anti-EGFR monoclonal antibody (mAb), enhanced the antitumor efficacy of gemcitabine monotherapy (61% vs. 38% growth inhibition; ref. 21). Panitumumab is generally well tolerated. Skin toxicity, hypomagnesaemia, and diarrhea are the most common toxicities observed (22). Based on these promising preclinical data in favor of combining EGFR pathway inhibition (independent of K-RAS mutational status) with both gemcitabine and radiation therapy and the nonoverlapping toxicity profiles of gemcitabine and panitumumab, we designed a phase I/II feasibility trial evaluating the addition of panitumumab to gemcitabine-based CRT in patients with LAPC. Here, we report the phase I feasibility part of this study. The primary endpoint was to determine the maximum tolerated dose (MTD) of panitumumab to be used in combination with gemcitabine-based CRT in patients with LAPC. Secondary endpoints included early signs of clinical activity of the study treatment, clinical response rate, progression free survival (PFS), and overall survival (OS).

Eligibility

Adult patients with untreated LAPC were eligible for this phase I trial. Encasement >270° of the superior mesenteric or portal vein or >90° tumor contact with the superior mesenteric artery, celiac trunk, or common hepatic artery in the absence of distant metastasis was considered in a multidisciplinary team as LAPC. Histologic or cytologic confirmation of pancreatic cancer was required. Patients with imminent bowel obstruction, active bleeding, uncontrolled infection, or a second current malignant disease (except basal cell carcinoma of the skin) were not eligible. Inclusion criteria also included measurable or evaluable disease as defined by response evaluation criteria in solid tumors (RECIST) 1.1 criteria, an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1, adequate hematological, hepatic (≤2.5× upper limit of normal, ULN) and renal function (estimated glomerular filtration rate >50 mL/min), normal calcium and magnesium levels. Patients with a history of allergic reactions to antibody treatment, impossibility of adequate radiation therapy, for example, due to tumor size, and patient suffering from any serious concomitant systemic disorders incompatible with the clinical study were considered not eligible. The institutional Medical Ethical board of the two participating centers, VU University Medical Center and the Academic Medical Center (both in Amsterdam, the Netherlands), approved the conduction of the trial (ClinicalTrials.gov Identifier: NCT01175733), which was in accordance with the Declaration of Helsinki and Good Clinical Practice. Written informed consent was obtained from all patients prior to inclusion into the study.

Study treatment

The treatment scheme is summarized in Fig. 1. The study was designed as 3 + 3 dose escalation clinical trial (23, 24). Panitumumab was administered weekly for 6 weeks by intravenous infusion in different dose levels per cohort (1, 1.5, 2, and 2.5 mg/kg) during gemcitabine-based CRT. Gemcitabine was administered weekly by intravenous infusion at a dose of 300 mg/m2 during RT in the first 6 weeks, followed by a dose of 1,000 mg/m2 weekly for 3 weeks every 4 weeks from day 50 until disease progression or unacceptable toxicity and otherwise continued for a maximum period of 1 year. The RT schedule consisted of a dose of 1.8 Gy per fraction for 28 days (total dose of 50.4 Gy) between days 1 and 38, on days 3 to 5 of the first week and on day 1 to 5 in the five consecutive weeks. The planning target volume for the radiation treatment consisted of all gross tumor on a 4D-CT scan including regional enlarged lymph nodes, enlarged with a 1.0-cm margin. The craniocaudal margin was extended with an extra 1 cm, when a 3D-CT scan was used. Typically, a multiple coplanar field technique or a volumetric modulated arc technique was used for treatment planning. Depending on the radiation oncology center (VUmc or AMC), either spinal column imaging or intratumoral fiducial markers were used for daily set-up.

Figure 1.

Treatment schedule for patients with LAPC.

Figure 1.

Treatment schedule for patients with LAPC.

Close modal

Follow-up lasted until death of the patient. In case of progressive disease, the choice of offering further treatment with palliative CHT was at the discretion of the treating physician.

Toxicity evaluation, dose escalation rules, and response assessment

Dose limiting toxicity (DLT) and adverse events (AE) were graded by the NCI Common Terminology Criteria of Adverse Events (CTC-AE) grading system version 3.0 (25). Patients were continuously monitored for toxicity. Patients were enrolled per dose level in cohorts of 3. At the final dose level, a minimum of 6 patients were treated to determine the MTD, defined as less than 2 patients out of 6 with a DLT.

DLTs were defined as any of the following hematologic events during the first 43 days from start of combination treatment and attributable to combination therapy: febrile neutropenia, neutropenic infection, grade 4 neutropenia lasting over 7 days, grade ≥3 thrombocytopenia for >7 days, and grade 4 thrombocytopenia. Nonhematological DLTs included grade ≥3 nausea, vomiting, or diarrhea despite optimal medical support, grade 3 fatigue persisting >7 days, or grade 4 fatigue. Any other grade ≥3 AE (except alopecia), failure to recover from related toxicities to grade ≤1 or baseline severity (or grade ≤2 at investigator and sponsor discretion) after delaying the next cycle up to 7 days and failure to complete the first 6 weeks of treatment (≤75% of planned dose of RT, gemcitabine, and panitumumab) were also considered as a DLT. Mucositis, diarrhea, dermatitis, and rash were considered as specific panitumumab-related toxicities. The use of prophylactic treatment for skin toxicities was allowed. All patients underwent a baseline CT scan and an efficacy evaluation CT after chemoradiation, during gemcitabine monotherapy at 3, 5, 7, and 9 months and every 3 months thereafter until progressive disease. The RECIST version 1.1 (26) were used for response assessment. Time to progression (TTP), mentioned in the study protocol as secondary endpoint, was defined as the time from registration in the study to progression or death, whichever came first. TTP is further described in this study as PFS. Measurements of CA19.9 (U/mL) were performed before and during treatment. CA19.9 response was defined as a decrease in CA19.9 concentration of at least 50% from the baseline concentration to the lowest value (nadir) measured during the study.

Patient characteristics

Twenty patients were registered in this study. Five patients were considered ineligible, because of either metastatic disease (n = 3), elevated liver enzymes (n = 1), and patient withdrawal before start of treatment (n = 1). Between July 2010 and November 2013, treatment was initiated in 15 patients. One patient in the 1.5 mg/kg cohort withdrew her consent after 2 weeks and was therefore considered not evaluable. The clinicopathologic characteristics of the 14 treated patients are listed in Table 1.

Table 1.

Clinicopathologic characteristics for 14 patients receiving chemoradiation with panitumumab for LAPC

Patients, n
Characteristic(N = 14)%
Age (years at the start of the treatment) 63 (46–77)  
Sex 
 Male 11 79 
 Female 21 
Histology/cytology 
 Adenocarcinoma 13 93 
 Other: neuro-endocrine tumor 
Diagnosis based on 
 Cytology  
 Histology 10  
T-stage 
 T3 
 T4 13 93 
N stage 
 N0 14 100 
 N1 
ECOG PS at start 
 0 64 
 1 36 
Ca19,9 prior to therapy, U/mL 
 Median 103  
 Range 5–1,499  
Patients, n
Characteristic(N = 14)%
Age (years at the start of the treatment) 63 (46–77)  
Sex 
 Male 11 79 
 Female 21 
Histology/cytology 
 Adenocarcinoma 13 93 
 Other: neuro-endocrine tumor 
Diagnosis based on 
 Cytology  
 Histology 10  
T-stage 
 T3 
 T4 13 93 
N stage 
 N0 14 100 
 N1 
ECOG PS at start 
 0 64 
 1 36 
Ca19,9 prior to therapy, U/mL 
 Median 103  
 Range 5–1,499  

DLT and maximum-tolerated and safe dose

No DLTs were observed in the first 3 patients in the first and second dose level (1 and 1.5 mg/kg panitumumab). Two of the 5 patients treated in the third dose level (2 mg/kg panitumumab) experienced a DLT and therefore this dose level was considered nontolerable. One of these patients fulfilled the DLT criteria, because of nausea grade 3 despite optimal medical support, including hospitalization. This was reported as a serious adverse event (SAE) related to panitumumab in combination with gemcitabine and RT. The other patient experienced a DLT based on failure to complete the first 6 weeks of treatment as defined by the protocol, due to multiple grade 1 to 2 toxicities. The next 3 patients were enrolled in the second dose level (1.5 mg/kg) and none had a DLT, providing the MTD as defined in the protocol. Toxicity was manageable at a panitumumab dose of 1.5 mg/kg (MTD). All 6 patients in this dose cohort experienced some grade of nausea and vomiting and 3 of the 6 patients experienced one or more (possibly) treatment-related grade 3 AEs during the first 43 days of treatment. One patient experienced neutropenia, the second patient experienced neutropenia, nausea, and vomiting, and the third patient experienced fatigue. These AEs were manageable and resolved within 4 days (nausea and vomiting), 5/6 days (neutropenia), and 6 days (fatigue). No grade 4 AEs were observed at the MTD. All AEs during CRT with panitumumab are listed in Table 2. Rash, nausea, vomiting, weight loss, taste alteration, diarrhea, paronychia, and dermatitis are considered as (possible) panitumumab-related AEs. Four patients experienced hypomagnesaemia grade 1, 3 patients only during CRT, 1 patient also during the first 2 months of gemcitabine monotherapy. A total of 12 SAEs were reported in 8 of the 14 study participants, which were evaluable for toxicity. Only one SAE was related to the study treatment. AEs reported after the CRT period (first 43 days) of the study are listed in Supplementary Table S1. No unexpected AEs were reported during gemcitabine monotherapy.

Table 2.

Adverse events during chemoradiation with panitumumab (maximum grade of each AE per patient) during the chemoradiation with panitumumab (first 43 days)

Cohort 1.0 mg/kg (n = 3)Cohort 1.5 mg/kg (n = 6)Cohort 2.0 mg/kg (n = 5)
AE, n (%)Grade 1/2Grade 3/4Grade 1/2Grade 3/4Grade 1/2Grade 3/4
Blood/bone marrow 
 Thrombocytopenia — — 2 (33) — — — 
 Neutropenia — — 2 (33) 2 (33) — 1 (20) 
Constitutional symptoms 
 Fatique (asthenia, lethargy, malaise) 2 (67) — 4 (67) 1 (17) 2 (40) — 
 Weary legs — — 1 (17) — — — 
 Fever 1 (33) — 2 (33) — — — 
 Weight loss — — 1 (17) — 2 (40) — 
 Insomnia — — — — 1 (20) — 
Neurology 
 Dizziness when getting up — — — — 1 (20) — 
 Neuropathy — — 1 (17) — — — 
Syndromes 
 Flu like syndrome — — 1 (17) — — — 
Pulmonary/upper respiratory 
 Cough — — 1 (17) — — — 
 Hiccups — — 1 (17) — 1 (20) — 
Gastrointestinal 
 Nausea 1 (33) — 5 (83) 1 (17) 3 (60) 1 (20) 
 Vomiting — — 5 (83) 1 (17) 4 (80) — 
 Stomach complaints 1 (33) — 1 (17) — — — 
 Anorexia 1 (33) — 4 (67) — 4 (80) — 
 Flatulence — — 1 (17) — — — 
 Constipation — — 3 (50) — — — 
 Taste alteration — — 1 (17) — — — 
 Diarrhea — — 1 (17) — 1 (20) — 
 Pyrosis — — — — 1 (20) — 
Pain 
 Glossodynia 1 (33) — — — — — 
 Tumor pain — — 1 (17) — — — 
 Pain 1 (33) — — — 1 (20) — 
 Abdominal pain 1 (33) — 2 (33) — — — 
Dermatology/skin 
 Dry skin — — 1 (17) — — — 
 Acneiform rash 2 (67) — 2 (33) — 3 (60) — 
 Paronychia big toe 1 (33) — — — — — 
 Node in groin region 1 (33) — — — — — 
Rash 1 (33) — 2 (33) — 1 (20) — 
 Red skin (face) — — 1 (17) — — — 
 Pruritus/itching — — — — 1 (20) — 
 Erythema (face/groin/abdomen) — — 1 (17) — — — 
Renal/genitourinary 
 Dysuria — — 1 (17) — — — 
Hemorrhage/bleeding 
 Epistaxis — — — — 1 (20) — 
 Gastrointestinal — — — — 1 (20) — 
Metabolic/laboratory 
 Elevated transaminases — — 1 (17) — — — 
 Hypomagnesemia — — — — 1 (20) — 
Infection 
 Cellulitis 1 (33) — — — — — 
 Urinary tract infection — — 1 (17) — — — 
Cohort 1.0 mg/kg (n = 3)Cohort 1.5 mg/kg (n = 6)Cohort 2.0 mg/kg (n = 5)
AE, n (%)Grade 1/2Grade 3/4Grade 1/2Grade 3/4Grade 1/2Grade 3/4
Blood/bone marrow 
 Thrombocytopenia — — 2 (33) — — — 
 Neutropenia — — 2 (33) 2 (33) — 1 (20) 
Constitutional symptoms 
 Fatique (asthenia, lethargy, malaise) 2 (67) — 4 (67) 1 (17) 2 (40) — 
 Weary legs — — 1 (17) — — — 
 Fever 1 (33) — 2 (33) — — — 
 Weight loss — — 1 (17) — 2 (40) — 
 Insomnia — — — — 1 (20) — 
Neurology 
 Dizziness when getting up — — — — 1 (20) — 
 Neuropathy — — 1 (17) — — — 
Syndromes 
 Flu like syndrome — — 1 (17) — — — 
Pulmonary/upper respiratory 
 Cough — — 1 (17) — — — 
 Hiccups — — 1 (17) — 1 (20) — 
Gastrointestinal 
 Nausea 1 (33) — 5 (83) 1 (17) 3 (60) 1 (20) 
 Vomiting — — 5 (83) 1 (17) 4 (80) — 
 Stomach complaints 1 (33) — 1 (17) — — — 
 Anorexia 1 (33) — 4 (67) — 4 (80) — 
 Flatulence — — 1 (17) — — — 
 Constipation — — 3 (50) — — — 
 Taste alteration — — 1 (17) — — — 
 Diarrhea — — 1 (17) — 1 (20) — 
 Pyrosis — — — — 1 (20) — 
Pain 
 Glossodynia 1 (33) — — — — — 
 Tumor pain — — 1 (17) — — — 
 Pain 1 (33) — — — 1 (20) — 
 Abdominal pain 1 (33) — 2 (33) — — — 
Dermatology/skin 
 Dry skin — — 1 (17) — — — 
 Acneiform rash 2 (67) — 2 (33) — 3 (60) — 
 Paronychia big toe 1 (33) — — — — — 
 Node in groin region 1 (33) — — — — — 
Rash 1 (33) — 2 (33) — 1 (20) — 
 Red skin (face) — — 1 (17) — — — 
 Pruritus/itching — — — — 1 (20) — 
 Erythema (face/groin/abdomen) — — 1 (17) — — — 
Renal/genitourinary 
 Dysuria — — 1 (17) — — — 
Hemorrhage/bleeding 
 Epistaxis — — — — 1 (20) — 
 Gastrointestinal — — — — 1 (20) — 
Metabolic/laboratory 
 Elevated transaminases — — 1 (17) — — — 
 Hypomagnesemia — — — — 1 (20) — 
Infection 
 Cellulitis 1 (33) — — — — — 
 Urinary tract infection — — 1 (17) — — — 

Response, PFS, and OS

One patient in the 1 mg/kg cohort was diagnosed with LAPC based on cytology, but when he developed metastatic disease, histology revealed a pancreatic neuroendocrine tumor. Therefore, this patient was evaluated for toxicity, but not for tumor response, PFS, and OS. In Table 3, the median PFS and OS of the patients treated in this study are shown. The median PFS of all cohorts together is 8.9 months (range, 3.5–23), including 1 patient who had stable disease under study treatment according to protocol after 10.9 months of follow-up. The median PFS in the MTD cohort is 11.8 months (range, 3.7–23). Two of the 13 patients evaluable for response were still alive at the time of evaluation; both were treated in the MTD cohort. The median OS in all cohorts together is 12.3 months (range, 4.0–30.1 months), including the 2 patients who were alive at the last evaluation (respectively 10.9 and 20.1 months from start until last evaluation). The median OS in the MTD cohort is 17.0 months (range, 10.9–25.8), including 2 patients who were alive at the last evaluation. Three patients achieved a partial response (23%), whereas all other patients had stable disease as best response. Median duration of gemcitabine monotherapy after chemoradiation is 3.9 months for all patients and 4.3 months for the patients treated in the MTD cohort, including the last patient still under study treatment after 10.9 months follow-up. CA19.9 response was reached by 8 of the 13 (61.5%) for response evaluable patients, 5 of them were treated in the MTD cohort. These 8 patients had stable disease when reaching CA19.9 response and a median PFS and OS of respectively 9.9 and 13.0 months.

Table 3.

Median PFS and OS for each dose cohort

1.0 mg/kg1.5 mg/kg2.0 mg/kg
N3a6b5
Median PFS (per cohort) 11.0 11.8 4.3 
median OS (per cohort) 19.5 17.0 9.1 
1.0 mg/kg1.5 mg/kg2.0 mg/kg
N3a6b5
Median PFS (per cohort) 11.0 11.8 4.3 
median OS (per cohort) 19.5 17.0 9.1 

aOne patient in the 1 mg/kg cohort is not assessable for tumor response, PFS, and OS.

bIn the 1.5 mg/kg cohort, 1 patient was progression free at evaluation and 2 patients were alive at evaluation.

Here, we report the results of a phase I study designed to determine the safety, tolerability, and potential clinical efficacy of the anti-EGFR mAb panitumumab added to standard gemcitabine-based CRT in patients with LAPC. The MTD of panitumumab was determined to be 1.5 mg/kg. We concluded that adding panitumumab to gemcitabine-based CRT is feasible with considerable, but manageable toxicity, as expected based on the nonoverlapping toxicity profile of CRT and panitumumab. No differences in performance status, nodal status (Table 1), comorbidity, intensity of RT (tumor-size and radiation fields were equal between the cohorts; Supplementary Table S2), or dosing of gemcitabine by itself could explain the observed DLTs in cohort three compared with the other two cohorts and were therefore most likely caused by the addition of a higher dose of panitumumab to the combination treatment. Major toxicities potentially related to the addition of panitumumab were nausea, vomiting, neutropenia, fatigue, and anorexia, whereas acneiform rash was considered to be definitively related. These toxicities, apart from skin toxicity (22), are not common for treatment with anti-EGFR mAb treatment, and are likely to be predominately caused by the combination with gemcitabine-based CRT (8, 27). In addition, patients with LAPC often suffer from fatigue and gastrointestinal symptoms such as nausea and vomiting, even without treatment. Because of these common gastrointestinal problems and the small number of patients per cohort in this study, we cannot rule out that establishing the MTD might be influenced by mild differences of gastrointestinal or even other complaints in the three cohorts before start of treatment. However, these differences were not clinically recognized despite intensive observation and there is no evidence of objective measurable differences that may have influenced gastrointestinal complaints between the cohorts except for the difference in combination treatment (e.g., higher dose of panitumumab in cohort 3 compared with cohorts 1 and 2).

Whether this combination treatment is of clinical benefit needs to be studied in the phase II part of this study. The first preliminary results on this small study population with a median PFS and OS of respectively 11.8 and 17.0 months in the MTD cohort suggest some efficacy. However, a true comparison of efficacy related to the different dose cohorts is not possible due to the small numbers of patients. OS and PFS were relatively short for patients treated in the high-dose cohort, while having comparable base line characteristics compared with patients in the MTD cohort (respectively 60% vs. 50% WHO PS 0 and respectively 90% vs. 83% elevated baseline Ca 19.9). The distribution of T4 tumors was also equal between the different cohorts. Multiple studies included targeted therapy. Different CHT schedules and RT modalities report variable outcomes without a clear advantage of one treatment schedule. Our previous reports on chemoradiation for LAPC revealed a median survival of 10 months for the combination of gemcitabine 300 mg/m2 weekly with RT (24 Gy in three consecutive weekly fractions of 8 Gy; ref. 27) and for the combination of UFT 300 mg/m2 daily, leucovorin 30 mg and celecoxib 800 mg daily for 28 days concomitant with RT (20 × 2.5 Gy; ref. 28). In the present trial, radiation and CHT seemed to be better tolerated compared with our previous studies. The day to day position variation (29) of pancreatic tumors and their intrafraction motion (30) due to breathing pose are challenging concerns in RT of LAPC. Currently, we tackle these issues by performing image guided radiation therapy (IGRT), using gold fiducial markers (31).

Our study is the first clinical trial in which panitumumab is combined with gemcitabine-based CRT in LAPC. Previously, the combination of panitumumab 6 mg/kg on days 1, 15, and 29 in combination with 5FU/capecitabine-based CRT followed by gemcitabine and panitumumab followed by maintenance panitumumab for 6 months in LAPC was reported at ASCO 2012 (32). At a median follow-up of 12.3 months, median OS and PFS were 12.1 and 7.4 months, respectively. AEs (67% grade 3 and 20% grade 4), especially during the chemo-RT portion, were considerable and affected administration of subsequent systemic maintenance therapy. The observed toxicities in the current dose finding study suggest that the panitumumab dose was too high, at least during CRT. Other anti-EGFR mAbs such as cetuximab have also been evaluated as a treatment strategy for LAPC. Panitumumab and cetuximab both target the EGFR but they differ in their isotype and they might differ in their mechanism of action. An OS of 7.5 months was reported for RT in combination with single-agent cetuximab. This OS is less than for most CRT trials in LAPC but the toxicity was also very moderate (33). Crane and colleagues demonstrated a favorable OS of 19.2 months of cetuximab in combination with induction CHT (gemcitabine and oxaliplatin) in LAPC followed by capecitabine based CRT (50.4 Gy) in combination with cetuximab (34). The toxicity was comparable to this study, except an increased incidence of sensory neuropathy, which is associated with oxaliplatin.

Other targeted therapies such as the VEGF mAb bevacizumab, the tyrosine kinase inhibitor sorafenib, and the cyclooxygenase-2 inhibitor, celecoxib, have also been investigated in combination with chemoradiation, but did not result in a significant improvement in OS (28, 35, 36). The combination of erlotinib, bevacizumab, and external beam radiation therapy without CHT in a phase I trial was reasonably well tolerated as presented at ASCO GI in 2011 (37). CRT trials that have been performed studying the added effect of targeted therapy are summarized in Table 4.

Table 4.

Trials of CRT + targeted therapies for pancreatic cancer

Characteristics of CRT trials in combination with targeted therapy
Ref.Study treatmentPatients, nMedian TTP (mo)Median survival (mo)
This study, 2015 RT(50.4 Gy)+GEM+PAN-GEM 13 8.9 MTD cohort: 11.8 12.3 MTD cohort: 17.0 
Kim, 2012 (abstr) (32) PAN+5FU/CAP+RT (50.4 Gy)-GEM+PAN-PAN 51 7.4 12.1 
Rembielak et al. (33) CET+RT (50.4 Gy) 21 5.1 7.5 
Crane et al. (34) CET+GEM+OX- CAP+CET+RT (50.4 Gy) 69 12.5 19.2 
Crane et al. (35) CAP+RT (50.4 Gy)+BEV-GEM+BEV. 82 8.9 11.9 
Chiorean et al. (36) SOR + GEM + RT (50 Gy)-GEM 25 10.6 11.4 
Morak et al. (28) UFT + L + C + RT (50 Gy) 83 6.9 10.6 
Czito et al. (37) E + BEV + RT (50.4 Gy) a a 
Characteristics of CRT trials in combination with targeted therapy
Ref.Study treatmentPatients, nMedian TTP (mo)Median survival (mo)
This study, 2015 RT(50.4 Gy)+GEM+PAN-GEM 13 8.9 MTD cohort: 11.8 12.3 MTD cohort: 17.0 
Kim, 2012 (abstr) (32) PAN+5FU/CAP+RT (50.4 Gy)-GEM+PAN-PAN 51 7.4 12.1 
Rembielak et al. (33) CET+RT (50.4 Gy) 21 5.1 7.5 
Crane et al. (34) CET+GEM+OX- CAP+CET+RT (50.4 Gy) 69 12.5 19.2 
Crane et al. (35) CAP+RT (50.4 Gy)+BEV-GEM+BEV. 82 8.9 11.9 
Chiorean et al. (36) SOR + GEM + RT (50 Gy)-GEM 25 10.6 11.4 
Morak et al. (28) UFT + L + C + RT (50 Gy) 83 6.9 10.6 
Czito et al. (37) E + BEV + RT (50.4 Gy) a a 

Abbreviations: BEV, bevacizumab; C, celecoxib; CAP, capecitabine; CET, cetuximab; GEM, gemcitabine; E, Erlotinib; L, leucovorin; OX, oxaliplatin; PAN, panitumumab; SOR, sorafenib; UFT, Uracil/Tegafur.

aMed TTP and OS not mentioned in abstract, study is not published.

Novel local therapies such as radiofrequency ablation (RFA) and irreversible electroporation (IRE) are used and studied in increasing frequency in the treatment of LAPC (38). RFA is a thermal local therapy based on high-frequency electrical currents. Variable outcomes of the efficacy of RFA are described in small nonrandomized trials (39, 40). IRE is a promising nonthermal ablative technique using direct current, which irreversibly damages the cell's homeostatic mechanism, causing apoptosis. Two series were reported of IRE in PDAC with promising results and manageable toxicity (41, 42). Stereotactic body RT (SBRT) is a recent advancement that allows for the precise delivery of a large ablative radiation dose to the tumor in one to five fractions. A total dose between 24 and 36 Gy in one to five fractions has been reported (43–45). SBRT could be delivered quickly and effectively in patients with LAPC with acceptable side effects and minimal interference with gemcitabine CHT. An advantage of IRE and stereotactic RT over RFA is that they can be used for tumors in close proximity to large vessels without risk of vascular trauma or a reduced effect of RFA due to the heat sink effect (46). No randomized studies of RFA, IRE, or stereotactic radiation have been published. These local treatment modalities in this setting are of interest because they are presumably better tolerated than CRT. Yet the efficacy of these approaches compared with the efficacy of CRT for LAPC has to be established. The above local treatment possibilities illustrate the challenging options for patients with LAPC.

In conclusion, we report that the use of panitumumab at a MTD of 1.5 mg/kg can be safely added to gemcitabine-based CRT in patients with LAPC. The observed PFS and OS rates suggest some efficacy. These observations support the further evaluation of this combination in a phase II study along with the search of predictive biomarkers to allow future selection of patients with an increased chance of experiencing clinical benefit from this type of combination therapy.

No potential conflicts of interest were disclosed.

Conception and design: H.J. van der Vliet, H.M.W. Verheul

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): A.A van Zweeden, H.J. van der Vliet, J.W. Wilmink, M.R. Meijerink, O.W.M. Meijer, G. van Tienhoven, G. Kazemier

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.A van Zweeden, M.R. Meijerink, H.M.W. Verheul

Writing, review, and/or revision of the manuscript: A.A van Zweeden, H.J. van der Vliet, J.W. Wilmink, M.R. Meijerink, O.W.M. Meijer, A.M.E. Bruynzeel, G. van Tienhoven, E. Giovannetti, G. Kazemier, M.A.J.M. Jacobs, H.M.W. Verheul

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): A.A van Zweeden

Study supervision: H.M.W. Verheul

Amgen provided financial support for this work.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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