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					           original article                                                                                                             Annals of Oncology 19: 86–91, 2008
                                                                                                                                        Published online 17 September 2007

           A phase I study of erlotinib in combination with
           gemcitabine and radiation in locally advanced,
           non-operable pancreatic adenocarcinoma
           A. Duffy1, J. Kortmansky2, G. K. Schwartz1, M. Capanu3, S. Puleio4, B. Minsky5, L. Saltz1,
           D. P. Kelsen & E. M. O’Reilly1*
            Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; 2Medical Oncology and Hematology, New Haven, CT; 3Department of Epidemiology
           and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY; 4Clinical Trials Office, Memorial Sloan-Kettering Cancer Center, New York, NY; 5Department
           of Radiation Oncology, University of Chicago Medical Center, Chicago, IL, USA

           Received 8 June 2007; revised 6 August 2007; accepted 9 August 2007

           Purpose: To determine the maximum tolerated dose (MTD) of erlotinib when administered concurrently with twice
           weekly gemcitabine and radiation therapy (RT) for locally advanced pancreatic cancer, assess the safety and toxicity
           profile of this combination and secondarily evaluate response, time to tumor progression and overall survival.
           Methods: Patients with untreated locally advanced pancreas cancer were treated with daily erlotinib in combination
           with gemcitabine 40 mg/m2/30 min twice weekly and RT delivered at 180 cGy/day in 28 fractions over 5.5 weeks for
           a total of 5040 cGy. Erlotinib was dose escalated in successive cohorts (100 mg, 125 mg). When the MTD was
           determined, the cohort was expanded to better define toxicity and preliminarily efficacy. All patients were surgically
           staged. After chemoradiation, patients received maintenance weekly gemcitabine 1000 mg/m2 on days 1 and 8 of

           a 21 day cycle and daily erlotinib for four cycles.
           Results: Three patients were treated at dose level 1 (erlotinib 100 mg) without limiting toxicity. Two of six patients at
           dose level 2 (erlotinib 125 mg) had dose-limiting toxicities, neutropenia and thrombocytopenia, causing dose delay and
           elevated liver enzymes. The MTD for erlotinib in combination with twice weekly gemcitabine-based chemoradiation
           was 100 mg/day. Eleven additional patients were treated at dose level 1. All twenty patients were assessable for
           toxicity. Seventeen patients were assessable for response. The partial response rate was 35% and 53% had stable
           disease. The median survival for all patients was 18.7 months.
           Conclusion: In combination with fixed dose gemcitabine at 40 mg/m2 twice weekly and radiation at 180 cGy/day,
           the MTD of erlotinib was found to be 100 mg/day. This is a relatively well tolerated, biologically active combination in
           a poor prognostic cancer.
           Key words: chemoradiation, erlotinib, gemcitabine, pancreas cancer, phase I

           introduction                                                                       5-FU as the major systemic drug in the management of
                                                                                              pancreas cancer based on the results of a prospective
           Adenocarcinoma of the pancreas is the fourth leading cause of                      randomized clinical trial [5], and efforts have focused on
           cancer-related mortality in the USA. This disease has an                           incorporating it into a chemoradiation schedule [6–9].
           extremely poor prognosis, with an overall 5 year survival of                          Epidermal growth factor receptor (EGFR) and its ligands,
           <5% [1]. For patients who present with locally advanced,                           Epidermal growth factor (EGF) and transforming growth
           unresectable disease (40% [2]), combined                                          factor-alpha (TGF-alpha), are important in cell proliferation, as
           chemoradiotherapy is an accepted standard approach, although                       well as motility, adhesion, invasion, survival and angiogenesis
           increasingly the timing of radiotherapy remains controversial.                     [10]. Pancreatic cancers contain high levels of EGFR
           Earlier studies have focused on the role of 5-flourouracil                          overexpression [11, 12]. Erlotinib, also known as OSI-774
           (5-FU) as a radiation sensitizer [3] as proposed by Heidelberger                   (TarcevaäÒ) is an orally bioavailable EGFR tyrosine inhibitor.
           et al. [4] in 1958. In recent times, gemcitabine has supplanted                    Additive effects have been observed with gemcitabine and
                                                                                              erlotinib in animal models [13]. A recent randomized phase III
           *Correspondence to: Dr E. M. O’Reilly, Department of Medicine, Gastrointestinal
                                                                                              trial of 569 patients with untreated inoperable pancreatic
           Oncology Solid Tumor Service, Memorial Sloan-Kettering Cancer Center, Box 324,
           1275 York Avenue, NY 10021, USA. Tel: +1-212-639-6672; Fax: +1-212-717-3320;       cancer demonstrated a small but significant survival benefit for
           E-mail:                                                         the combination of gemcitabine and erlotinib versus

           ª 2007 European Society for Medical Oncology. For Permissions, please email:
Annals of Oncology                                                                                              original article
gemcitabine alone [14]. This was the first trial to show                         determined for erlotinib in combination with gemcitabine and radiation, an
a survival benefit for any combination therapy in pancreas                       additional 11 patients were treated at the MTD to better define toxicity and
cancer and led to Food and Drug Administration (FDA)                            response.
approval of this combination in the front-line therapy of                       combined chemoradiation. Patients began treatment on day 1 with radiation
pancreas cancer in 2005.                                                        and erlotinib. Gemcitabine was dosed at 40 mg/m2/30 min on a twice
   The aim of this phase I study was to determine the maximum                   weekly either Monday/Thursday or Tuesday/Friday schedule beginning on
tolerated dose (MTD) of erlotinib when administered                             day 1 or day 2 at the treating physician’s discretion.
concurrently with twice weekly gemcitabine and radiation
therapy (RT) for locally advanced pancreatic cancer, assess the                 radiation technical details. The intent of the treatment was to deliver 50.4
safety and toxicity profile of this combination and secondarily                  Gy to the tumor and the primary draining lymph nodes. Patients were
evaluate response, time to tumor progression and overall                        placed supine, immobilized and underwent simulation with a CT simulator.
                                                                                In general the field borders were the following (whichever field was the
survival (OS).

                                                                                AP/PA Fields: (i) superior: inlet of the diaphragm or 2 cm above the celiac
patients and methods
                                                                                     axis or 2 cm above the gross tumor volume (GTV); (ii) inferior: L3/4
eligilibility criteria                                                               interspace or 2 cm below the GTV; (iii) lateral: the edge of the
Patients with histologically confirmed, newly diagnosed, locally advanced             transverse processes to include the paraaortic nodes or 2 cm beyond
nonmetastatic adenocarcinoma of the pancreas were eligible for entry onto            the GTV.
this study. Metastases were required to be excluded by diagnostic               Lateral Fields: (i) superior and inferior: same as AP/PA; (ii) anterior:
laparoscopy or exploratory laparotomy in all patients. Additional inclusion          included the paraaortic nodes and 2 cm beyond the GTV;
criteria were as follows: No prior chemotherapy or radiation for pancreas            (iii) posterior: include at least half of the vertebral bodies while
cancer; Age >18 years; ECOG performance status (PS) zero to two; Life                blocking the spinal cord.
expectancy of >12 weeks; Adequate organ and marrow function; Patients of
                                                                                CT based treatment planning was carried out and the dose was prescribed
child-bearing potential were required to use adequate contraception
                                                                                to the isodose line which covered the GTV with a 1 cm margin. Dose-
(hormonal or barrier method of birth control) before study entry and for
                                                                                limiting structures included spinal cord (45 Gy), kidney (at least 50% of
the duration of study participation; Ability to understand and willingness to
                                                                                the total volume received <18 Gy) and liver (at lease 40% of the total
sign a written informed consent document; Measurable or assessable disease
                                                                                volume received <30 Gy). Treatment was delivered with a 15 MV linear
was required. Patients were excluded if they had received prior
                                                                                accelerator with multileaf collimators. Patients received 1.8 Gy/day,
chemotherapy or radiotherapy for pancreas cancer, had an active
                                                                                5 days/week and had weekly port films for field verification.
intercurrent illness or gastrointestinal disease or pathology that limited
                                                                                   Erlotinib was self-administered orally daily continuously throughout the
absorption of oral medication. This study was reviewed and monitored by
                                                                                radiation period. Erlotinib was dose-escalated in successive patient cohorts
the Memorial Sloan-Kettering Cancer Center (MSKCC) Institutional
                                                                                starting at 100 mg/day (see study design section and also Table 3).
Review Board and MSKCC’s Data and Safety Monitoring Committee.
                                                                                maintenance chemotherapy. For patients who did not demonstrate any
screening evaluations/pretreatment assessment                                   evidence of extra-pancreatic tumor progression maintenance therapy was
All patients signed an informed consent document before study enrollment.       administered with gemcitabine and erlotinib commencing 4 weeks, but
Patients underwent a complete history and physical examination.                 not later than 7 weeks, after completion of radiation. Patients received
A complete blood count, including differential and platelet count,              gemcitabine administered by i.v. infusion at a dose of 1000 mg/m2
chemistry panel, including, electrolytes, blood urea nitrogen, creatinine,      >30 minutes, on days 1 and 8 of each 21 day cycle for a total of four
glucose, bilirubin, asparate aminotransferase (AST), alkaline phosphatase,      cycles. Starting on day 1, erlotinib was given orally at a fixed dose of
albumin, total protein, calcium, phosphorus and lactate dehydrogenase,          100 mg/day daily for four cycles. Radiologic restaging was carried out at
carcinoembryonic antigen, Ca19-9, coagulation profile including                  week 6 and 12. For patients who tolerated maintenance therapy well and in
International Normalised Ratio, were obtained. A baseline urinalysis was        whom no evidence of disease progression was evident at 12 weeks, the
carried out. For females of child-bearing potential, a serum or urine           option to continue protocol therapy was allowed with the same protocol
pregnancy test was carried out . All the above tests were conducted within 7    maintenance treatment criteria and assessment scan intervals observed.
days of enrollment. An electrocardiogram (EKG) within the previous 6
months of enrollment was necessary (unless any interval cardiac history,
when a new electrocardiogram EKG was obtained within 4 weeks of                 study design/end points
initiation of therapy).                                                         This is a phase I clinical trial studying the effect of adding erlotinib to
   A chest X-ray and either a computed tomography scan (CT) abdomen/            gemcitabine and radiation in patients with locally advanced unresectable
pelvis with oral/IV contrast (5 mm cuts through the pancreas) or an             pancreatic adenocarcinoma. The principal objective of the study was to
magnetic resonance imaging of the abdomen and pelvis with gadolinium,           determine the MTD of erlotinib that can be added to a gemcitabine–
were required within 21 days of study enrollment. Tumor paraffin block           radiation combination. The secondary objectives were to assess toxicity,
was collected and assayed for confirmation of diagnosis and for correlative      response rate, time to tumor progression and OS in this patient population.
immunohistochemical studies, where available. Additional tissue, if             The tertiary objective was to study a panel of markers before treatment in
available, was snap frozen for additional biologic correlates.                  both normal and tumor tissues. The correlative study results (including
                                                                                kras and EGFR status, mutation analysis and gene copy number, with
agent administration                                                            correlation to clinical outcome) will be reported in a later publication. For
All treatment was administered on an outpatient basis. There were two           the primary tumor end points, descriptive statistics were employed to
parts to this study: (i) Combination chemotherapy, radiation and erlotinib;     document the toxic effects and/or side-effects at each dose level. For tumor
(ii) Maintenance chemotherapy and erlotinib. Once the MTD was                   response measurements, response data for each patient were recorded.

Volume 19 | No. 1 | January 2008                                                                                   doi:10.1093/annonc/mdm441 | 87
original article                                                                                                                   Annals of Oncology

Response rate was estimated using the binomial probability and exact 95%        Table 1. Dose levels of erlotinib during combined chemoradiation
confidence intervals (CIs) were provided. Time to progression and OS
curves were estimated using Kaplan–Meier methodology. Time to                   Dose level                                             Erlotinib (mg)
progression was determined as being the time elapsed from the date of
                                                                                21                                                      75
study enrollment to documentation of clear-cut progression of disease.
                                                                                1                                                      100
OS was dated from the time of study enrollment to the date of death.
                                                                                2                                                      125
   Three dose levels were considered: 100 mg/day, 125 mg/day and 150 mg/
                                                                                3                                                      150
day. Three patients were enrolled per each cohort at each dose level to
a maximum erlotinib dose of 150 mg/day. If dose-limiting toxicity (DLT)
was observed in one of three patients the cohort was expanded to six
patients. Patients enrolled at a given dose level were observed for DLT until
2 weeks following completion of combination chemoradiotherapy before            Table 2. Patient characteristics
accrual began in the next cohort, hence the observation period per
cohort was a minimum of 8 weeks. The MTD was defined as an erlotinib             Characteristics                       Number of                    %
dose of 150 mg/day or one dose level below the cohort in which we                                                     patients
observed DLT in 2 of 3 or 2 of 6 patients. Once the MTD was determined          Sex
an expanded cohort of patients were treated at the MTD to better assess           Male                                11                             55
tolerability and preliminarily to assess efficacy of the regimen.                  Female                               9                             45
   At the completion of combined modality therapy, patients underwent             Total                               20a
a 4-week break during which no gemcitabine, erlotinib or radiation was            Age                                 44–79 years (median
administered. Patients were radiologically restaged between 3 and 4 weeks                                                age: 58 years)
following completion of radiation. Those with stable or responsive disease      ECOG PS
and acceptable treatment tolerance continued on the maintenance phase of          0                                    2                            10
the study.                                                                        1                                   18                            90
   The MTD of erlotinib was based on the development of DLTs. DLT’s             Laparoscopy/exploratory               20                           100
were evaluated according to the National Cancer Institute Common                  laparotomy
Toxicity Criteria, version 3.0 (
v30.html), and were defined as any of the following: grade 4                      A total of 21 patients were enrolled. One patient after completing
thrombocytopenia (platelets < 25 000/ll), grade 3 neutropenia [absolute         registration had an elevated alanine aminotransferase and was therefore
neutrophil count (ANC) < 1000/ll] lasting ‡ 4 days, neutropenic fever           ineligible to receive protocol treatment.
(fever > 38.1°C and ANC < 1000/ll), grade 3 or 4 diarrhea or                    ECOG, Eastern Cooperative Oncology Group; PS, performance status.
gastrointestinal bleeding. Any other grade 3 or 4 toxicity, excluding rash,
that in the opinion of the Principal Investigator was possibly, probably or
definitely related to the combination of erlotinib, gemcitabine and              cohort experienced grade 3 elevation’s in AST and ALT which
radiation. Grade IV fatigue was dose limiting if lasting >7 days. Any           were possibly related to therapy and therefore adjudicated as
toxicity-related treatment interruptions that resulted in a 2 week or           DLT. All of the six patients treated at erlotinib 125 mg
greater delay in completing chemoradiation was also adjudicated as dose         experienced delays in treatment because of toxicity and four
limiting. This was a phase I open label, nonrandomized, Cancer Therapy          required a dose reduction of gemcitabine. One of these patients
Evaluation Program-supported study.                                             was hospitalized for recurrent fevers and hypotension which
                                                                                were possibly related to treatment and was removed from
                                                                                protocol. No patient was treated at dose level 3, erlotinib
results                                                                         150 mg. The MTD was therefore defined as erlotinib 100 mg/
patient characteristics                                                         day, along with gemcitabine 40 mg/m2/twice weekly and
Patient demographics are shown in Table 2. Twenty-one                           180 cGy/day radiation.
patients were enrolled from 3 June 2003 to 24 March 2005. The                     Once the MTD was determined, a further 11 patients were
cut-off point for data analysis was 15 January 2007. Of these 21,               enrolled at this dose as part of an expanded cohort to further
17 were assessable for having completed all protocol therapy,                   define toxicity and assess response. Five of these patients
three were assessable for toxicity alone due to incomplete                      experienced treatment delays and two were removed from
treatment and one patient was withdrawn before receiving                        protocol due to excessive toxicity, one patient because of
treatment due to an elevated alanine aminotransferase (ALT).                    persistent thrombocytopenia and the other for diarrhea with
This latter patient was not included in any of the study end                    weight loss and electrolyte abnormalities. In total, four patients
point analyses.                                                                 required a dose reduction of gemcitabine during this portion of
                                                                                the study, see Tables 3 and 4 for a summary of DLT’s and grade
                                                                                3–4 toxic effects encountered during chemoradiation.
determination of MTD
Three patients were enrolled to cohort 1 at dose level 1 (100 mg
erlotinib), (see Tables 1 and 3). No DLT was observed. A                        toxic effects during maintenance therapy
further cohort of three patients was enrolled at dose level 2 (125              In total, 17 patients completed chemoradiotherapy. Fourteen of
mg erlotinib). One of these three patients experienced DLT                      these patients proceeded to the maintenance portion of the
(platelets and neutropenia). This cohort was therefore                          study. Two patients had developed evidence of progressive
expanded to six patients. One patient from the expanded                         disease and were removed from protocol. One patient, upon

88 | Duffy et al.                                                                                                  Volume 19 | No. 1 | January 2008
Annals of Oncology                                                                                 original article
                                                                    Table 3. DLTs during chemoradiation

                                                                    Dose level             N       Number        DLT specifics
                                                                                                   of DLTs
                                                                    1 (Erlotinib 100 mg)    3      –
                                                                                           11a     3b            Neutropenia, hypokalemia,
                                                                                                                   hyponatremia (n = 1);
                                                                                                                   Diarrhea (n = 2)
                                                                    2 (Erlotinib 125 mg)    3+3 1+1              Neutropenia; platelets
                                                                                                                   (n = 1)c; liver
                                                                                                                   enzymes (n = 1)d
                                                                      Eleven patients were enrolled as part of an expanded cohort once the MTD
                                                                    had been established, to better characterize toxicity and efficacy.
                                                                      These toxic effects occurred during the expanded portion of the study, and
                                                                    therefore are not true DLT’s, however they did satisfy DLT criteria which
Figure 1. Time to Tumor Progression (in months).
                                                                    pertained to the dose escalation portion.
                                                                      One patient developed recurrent neutropenia and thrombocytopenia
                                                                    which, although did not satisfy strict definition of DLT, necessitated
                                                                    multiple treatment interruptions and prolongation of chemoradiation
                                                                    beyond 8 weeks. The protocol was amended to include treatment delay
                                                                    ‡2 weeks as a DLT.
                                                                      Grade 3 elevation in alanine and aspartate aminotransferase.
                                                                    DLT, dose-limiting toxicity; MTD, maximum tolerated dose.

                                                                    Seventeen patients were evaluated for response to therapy, time
                                                                    to progression and OS. The median follow-up time was
                                                                    18 months (range 3–27). Eleven patients completed all protocol
                                                                    therapy. Response determination was the best response
                                                                    identified post chemoradiation therapy or on completion of the
                                                                    12 weeks of maintenance therapy, according to Response
                                                                    Evaluation Criteria In Solid Tumors criteria. Six (35%) patients
                                                                    had a PR to treatment (exact 95% CI 14% to 62%). Nine
Figure 2. Overall survival.                                         patients (53%) had stable disease as their best response. In
                                                                    total, four patients exhibited local disease failure in the
                                                                    pancreas at 4, 4, 19 and 22 months. Two of these patients had
completion of chemoradiotherapy, was deemed potentially             progression of disease on protocol therapy and two had
resectable after a restaging CT scan. This patient was removed      subsequent progression after initially having stable disease as
from protocol (but included in the analysis) and proceeded to       a best response. The median survival duration for the seventeen
have an R0 pancreaticoduodenectomy for T3, N1, M0 and               patients was 18.7 months (95% CI 13.3–24.8) (Figure 2).
American Joint Committee on Cancer stage II-B disease.              The median time to tumor progression was 13 months
   There was one grade 5 toxicity occurrence during this            (95% CI 4.8–17.8) (Figure 1).
portion of the study. In this instance the patient had completed
the combination chemoradiotherapy portion of therapy with
one treatment delay due to neutropenia. He had completed two
cycles of maintenance therapy and had demonstrated a partial        Combination concurrent chemotherapy and RT for locally
response (PR) to treatment. On the day before his third cycle of    advanced unresectable pancreas cancer is a widely employed
maintenance therapy the patient was hospitalized with an acute      standard approach. Gemcitabine has superceded 5-FU as the
gastrointestinal bleed. An esophagoduodenoscopy revealed            standard therapy for metastatic pancreatic cancer and is FDA
gastric and duodenal ulceration secondary to invasion of            approved for first-line treatment of patients with locally
tumor. The patient died shortly afterwards. An attribution to       advanced (nonresectable stage II or stage III) or metastatic
treatment cannot be excluded.                                       (stage IV) adenocarcinoma of the pancreas. Gemcitabine has
   There were no grade 4 toxic effects in the maintenance           been shown to be a potent radiosensitizer in human colorectal,
portion of the study (see table 5). Four patients required a dose   pancreatic and other solid tumor cell lines [15–17]. A phase I
reduction of gemcitabine and one required a dose reduction of       study has shown that a twice-weekly dosing schedule of
erlotinib. Eleven patients completed the maintenance portion.       gemcitabine 40 mg/m2 with concurrent radiation is feasible and
Four of these opted to continue extra treatment per protocol        well tolerated [18]. This dose was adopted by the Cancer and
option, and the number of extra cycles ranged from 1 to 22.         Leukaemia Group B for a phase II study [19] in which patients

Volume 19 | No. 1 | January 2008                                                                        doi:10.1093/annonc/mdm441 | 89
original article                                                                                                                        Annals of Oncology

Table 4. All grade 3 or 4 toxicity during chemoradiation

Dose level                    N              Hematologic (number/%)                                      Non-hematologic (number/%)
1 (Erlotinib 100 mg)          14                                    G3                  G4                                      G3                     G4
                                             Lymphopenia            14 (100%)           –                Fatigue                1 (7%)                 –
                                             Platelets               3 (21%)            –                Diarrhea               3 (21%)                –
                                             Neutropenia             3 (21%)            1 (7%)           Rashb                  2 (14%)                –
                                             Anemia                  1 (7%)             –
2 (Erlotinib 125 mg)              6                                 G3                  G4
                                             Lymphopenia             6 (100%)           –
                                             Platelets               2 (33%)            –
                                             Neutropenia             3 (50%)            –
                                             Anemia                  1 (17%)            –
 This number comprises of the three patients from the initial dose escalation part of the study and 11 patients from the expanded cohort of patients treated at
the MTD.
  There were in addition three episodes of grade 2 rash.
MTD, maximum tolerated dose.

Table 5. Grade 3 and 4 toxicity during maintenance therapy

Dose                                           N              Hematologic                                            Non-hematologic
Erlotinib 100 mg/day + gemcitabine             14                                     G3                 G4                             G3                  G4
  1000 mg/m2                                                  Lymphopenia             8 (57%)            –           Fatigue            1 (7%)              –
                                                              Neutropenia             3 (21%)            –

received maintenance gemcitabine upon completion of the                           who received the gemcitabine/erlotinib combination had
chemoradiotherapy with a median OS of 8.2 months. Some                            improved progression-free survival (HR 0.77, 95% CI,
studies have also attempted to incorporate even higher doses of                   0.64–0.92; P = 0.004), one-year survival (23% versus 17%;
gemcitabine into a combined chemoradiation approach with                          P = 0.023) and median OS (6.24 months versus 5.91 months,
success [8, 20, 21].                                                              HR 0.82, 95% CI, 0.69–0.99; P = 0.038) compared with the
   Pancreatic cancers contain high levels of EGFR                                 gemcitabine/placebo group. The proportion of patients with
overexpression [12]. EGFR and its ligands EGF and TGF-alpha                       EGFR mutations has not been published. Kwak et al. [31],
are important in cell proliferation, as well as motility, adhesion,               analyzed 55 cases of pancreatic cancer for EGFR mutations.
invasion, survival and angiogenesis [10]. In non-small-cell lung                  Five of these specimens were from patients who had been
cancer (NSCLC) a specific subpopulation exists that harbour                        enrolled on a study of erlotinib and capecitabine as second-line
somatic mutations in the EGFR. This appears to account for                        therapy and who had sufficient clinical response to remain on
10% of NSCLC cases although the proportion varies                                study for at least 100 days. Two of 55 (3.6%) were found to
according to the population studied [22–24]. The occurrence                       have EGFR mutations, both from the five patients who had
of these mutations correlates with an exquisite sensitivity to                    demonstrated nonprogression of disease on erlotinib and
inhibition of the EGFR tyrosine kinase with gefitinib or                           capecitabine. While none of the 50 unselected pancreas cancer
erlotinib in the majority of cases [25–27]. Erlotinib has been                    patients’ specimens were found to have EGFR mutations, the
shown by Shepherd et al. [28] to prolong survival in patients                     authors state that technical factors relating to an excessive
with NSCLC who have been previously treated with                                  stromal component to, and lack of microdissection of, the
chemotherapy. In that study, higher response rates were                           specimens may have resulted in lower sensitivity for detection
found in patients who had amplification of the EGFR gene                           of mutations.
(but not mutations of the EGFR gene). In multivariate                                A common criticism of clinical trials in pancreatic cancer is
analysis, however, survival was not significantly associated with                  that patients with stage III and stage IV disease are often
the number of EGFR copies or EGFR mutational status [29].                         grouped together, rendering interpretation of survival data
   A similar degree of responsiveness has not been observed in                    more difficult and potentially obscuring a survival advantage
other cancers, and this phenomenon of ‘oncogene addiction’                        in genuine stage III patients. A strength of our study is that
[30], interrupted so exquisitely by gefitinib or erlotinib, appears                all the patients were surgically staged and therefore the
to be limited to NSCLC. There is some activity for EGFR                           population is homogenous. Although the primary end point
inhibitors in pancreas cancer, albeit more modest. In the study                   was not survival and recognizing the limitations of interpreting
by Moore et al. [14] 569 patients with, untreated locally                         survival data in selected good PS patients conducted in single-
advanced or metastatic pancreas cancer were randomized to                         institution phase I studies, the median OS of 18.7 months, is
receive gemcitabine with either erlotinib or placebo. Patients                    nonetheless, striking.

90 | Duffy et al.                                                                                                     Volume 19 | No. 1 | January 2008
Annals of Oncology                                                                                                              original article
   This phase I study investigated the combination of erlotinib,                                 concomitant increases in the levels of epidermal growth factor and transforming
an EGFR inhibitor with gemcitabine-based chemoradiation.                                         growth factor alpha. J Clin Invest 1992; 90: 1352–1360.
This is one of the first studies reporting on this combination in                           13.   Hidalgo M. Erlotinib: preclinical investigations. Oncology (Williston Park) 2003;
                                                                                                 17: 11–16.
pancreas cancer. Ianniti et al. [32] conducted a phase I study of
                                                                                           14.   Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with
erlotinib in combination with gemcitabine, paclitaxel and
                                                                                                 gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial
radiation, followed by maintenance erlotinib in locally                                          of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol
advanced pancreatic cancer. The majority of the patients on                                      2007; 25 (15): 1960–1966.
that study (14 of 17) were surgically staged. The MTD                                      15.   Shewach DS, Lawrence TS. Radiosensitization of human solid tumor cell lines
determined was erlotinib 50 mg/day and the median survival                                       with gemcitabine. Semin Oncol 1996; 23: 65–71.
was 14 months.                                                                             16.   Shewach DS, Lawrence TS. Radiosensitization of human tumor cells by
   In conclusion, in association with fixed dose gemcitabine at                                   gemcitabine in vitro. Semin Oncol 1995; 22: 68–71.
40 mg/m2 twice-weekly and radiation at 180 cGy/day,                                        17.   Shewach DS, Lawrence TS. Gemcitabine and radiosensitization in human tumor
respectively, the MTD of erlotinib was found to be 100 mg/day.                                   cells. Invest New Drugs 1996; 14: 257–263.
                                                                                           18.   Blackstock AW, Bernard SA, Richards F et al. Phase I trial of twice-weekly
The results of the correlative studies should provide some
                                                                                                 gemcitabine and concurrent radiation in patients with advanced pancreatic
further insights into the mechanistic understanding of the role                                  cancer. J Clin Oncol 1999; 17: 2208–2212.
of EGFR therapy in pancreas adenocarcinoma.                                                19.   Blackstock AW, Tepper JE, Niedwiecki D et al. Cancer and leukemia group B
   This is a relatively well tolerated, biologically active                                      (CALGB) 89805: phase II chemoradiation trial using gemcitabine in patients with
combination in a poor prognostic cancer. The encouraging                                         locoregional adenocarcinoma of the pancreas. Int J Gastrointest Cancer 2003;
results are worthy of further development in pancreas cancer, in                                 34: 107–116.
an adjuvant or neo-adjuvant setting and provide a further                                  20.   Joensuu TK, Kiviluoto T, Karkkainen P et al. Phase I-II trial of twice-weekly
building block for treatment of locoregionally advanced disease.                                 gemcitabine and concomitant irradiation in patients undergoing
                                                                                                 pancreaticoduodenectomy with extended lymphadenectomy for locally advanced
                                                                                                 pancreatic cancer. Int J Radiat Oncol Biol Phys 2004; 60: 444–452.
                                                                                           21.   Magnino A, Gatti M, Massucco P et al. Phase II trial of primary radiation therapy
references                                                                                       and concurrent chemotherapy for patients with locally advanced pancreatic
 1. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2007. CA Cancer J Clin 2007;             cancer. Oncology 2005; 68: 493–499.
    57: 43–66.                                                                             22.   Zhang X, Chang A. Somatic mutations of the epidermal growth factor receptor
 2. Kelly DM, Benjamin IS. Pancreatic carcinoma. Ann Oncol 1995; 6: 19–28.                       and non-small cell lung cancer. J Med Genet 2007; 44 (3): 166–172.
 3. Abrams RA. Adjuvant therapy for pancreatic adenocarcinoma: what have we                23.   Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth
    learned since 1985? Int J Radiat Oncol Biol Phys 2003; 56: 3–9.                              factor receptor underlying responsiveness of non-small-cell lung cancer to
 4. Heidelberger C, Griesbach L, Montag BJ et al. Studies on fluorinated pyrimidines.             gefitinib. N Engl J Med 2004; 350: 2129–2139.
    II. Effects on transplanted tumors. Cancer Res 1958; 18: 305–317.                      24.   Huang SF, Liu HP, Li LH et al. High frequency of epidermal growth factor
 5. Burris HA III, Moore MJ, Andersen J et al. Improvements in survival and clinical             receptor mutations with complex patterns in non-small cell lung cancers
    benefit with gemcitabine as first-line therapy for patients with advanced                      related to gefitinib responsiveness in Taiwan. Clin Cancer Res 2004; 10:
    pancreas cancer: a randomized trial. J Clin Oncol 1997; 15: 2403–2413.                       8195–8203.
 6. Blackstock AW, Mornex F, Partensky C et al. Adjuvant gemcitabine and                   25.   Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with
    concurrent radiation for patients with resected pancreatic cancer: a phase II                clinical response to gefitinib therapy. Science 2004; 304: 1497–1500.
    study. Br J Cancer 2006; 95: 260–265.                                                  26.   Amann J, Kalyankrishna S, Massion PP et al. Aberrant epidermal growth factor
 7. Talamonti MS, Small W Jr., Mulcahy MF et al. A multi-institutional phase II trial of         receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer.
    preoperative full-dose gemcitabine and concurrent radiation for patients with                Cancer Res 2005; 65: 226–235.
    potentially resectable pancreatic carcinoma. Ann Surg Oncol 2006; 13: 150–158.         27.   Han SW, Kim TY, Hwang PG et al. Predictive and prognostic impact of epidermal
 8. Oya N, Shibuya K, Sakamoto T et al. Chemoradiotherapy in patients with                       growth factor receptor mutation in non-small-cell lung cancer patients treated
    pancreatic carcinoma: phase-I study with a fixed radiation dose and escalating                with gefitinib. J Clin Oncol 2005; 23: 2493–2501.
    doses of weekly gemcitabine. Pancreatology 2006; 6: 109–116.                           28.   Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated
 9. Mishra G, Butler J, Ho C et al. Phase II trial of induction gemcitabine/CPT-11               non-small-cell lung cancer. N Engl J Med 2005; 353: 123–132.
    followed by a twice-weekly infusion of gemcitabine and concurrent external             29.   Tsao MS, Sakurada A, Cutz JC et al. Erlotinib in lung cancer—molecular and
    beam radiation for the treatment of locally advanced pancreatic cancer. Am J                 clinical predictors of outcome. N Engl J Med 2005; 353: 133–144.
    Clin Oncol 2005; 28: 345–350.                                                          30.   Weinstein IB. Cancer. Addiction to oncogenes—the Achilles heal of cancer.
10. Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer               Science 2002; 297: 63–64.
    therapy. Pharmacol Ther 1999; 82: 241–250.                                             31.   Kwak EL, Jankowski J, Thayer SP et al. Epidermal growth factor receptor kinase
11. Bloomston M, Bhardwaj A, Ellison EC, Frankel WL. Epidermal growth factor                     domain mutations in esophageal and pancreatic adenocarcinomas. Clin Cancer
    receptor expression in pancreatic carcinoma using tissue microarray technique.               Res 2006; 12: 4283–4287.
    Dig Surg 2006; 23: 74–79.                                                              32.   Iannitti D, Dipetrillo T, Akerman P et al. Erlotinib and chemoradiation followed by
12. Korc M, Chandrasekar B, Yamanaka Y et al. Overexpression of the epidermal                    maintenance erlotinib for locally advanced pancreatic cancer: a phase I study.
    growth factor receptor in human pancreatic cancer is associated with                         Am J Clin Oncol 2005; 28: 570–575.

Volume 19 | No. 1 | January 2008                                                                                                    doi:10.1093/annonc/mdm441 | 91

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