Annals of Oncology Advance Access originally published online on September 17, 2007
Annals of Oncology 2008 19(1):86-91; doi:10.1093/annonc/mdm441
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gastrointestinal tumors |
A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma
1 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
2 Medical Oncology and Hematology, New Haven, CT
3 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY
4 Clinical Trials Office, Memorial Sloan-Kettering Cancer Center, New York, NY
5 Department of Radiation Oncology, University of Chicago Medical Center, Chicago, IL, USA
* Correspondence to: Dr E. M. O'Reilly, Department of Medicine, Gastrointestinal 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; E-mail: oreillye{at}mskcc.org
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Abstract |
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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
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Adenocarcinoma of the pancreas is the fourth leading cause of cancer-related mortality in the USA. This disease has an extremely poor prognosis, with an overall 5 year survival of <5% [1]. For patients who present with locally advanced, unresectable disease (
40% [2]), combined chemoradiotherapy is an accepted standard approach, although increasingly the timing of radiotherapy remains controversial. Earlier studies have focused on the role of 5-flourouracil (5-FU) as a radiation sensitizer [3] as proposed by Heidelberger et al. [4] in 1958. In recent times, gemcitabine has supplanted 5-FU as the major systemic drug in the management of pancreas cancer based on the results of a prospective randomized clinical trial [5], and efforts have focused on incorporating it into a chemoradiation schedule [6–9]. Epidermal growth factor receptor (EGFR) and its ligands, Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha), are important in cell proliferation, as well as motility, adhesion, invasion, survival and angiogenesis [10]. Pancreatic cancers contain high levels of EGFR overexpression [11, 12]. Erlotinib, also known as OSI-774 (TarcevaTM®) is an orally bioavailable EGFR tyrosine inhibitor. Additive effects have been observed with gemcitabine and erlotinib in animal models [13]. A recent randomized phase III trial of 569 patients with untreated inoperable pancreatic cancer demonstrated a small but significant survival benefit for the combination of gemcitabine and erlotinib versus gemcitabine alone [14]. This was the first trial to show a survival benefit for any combination therapy in pancreas cancer and led to Food and Drug Administration (FDA) approval of this combination in the front-line therapy of pancreas cancer in 2005.
The aim of this phase I study was 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 (OS).
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patients and methods |
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eligilibility criteria
Patients with histologically confirmed, newly diagnosed, locally advanced nonmetastatic adenocarcinoma of the pancreas were eligible for entry onto this study. Metastases were required to be excluded by diagnostic laparoscopy or exploratory laparotomy in all patients. Additional inclusion criteria were as follows: No prior chemotherapy or radiation for pancreas cancer; Age >18 years; ECOG performance status (PS) zero to two; Life expectancy of >12 weeks; Adequate organ and marrow function; Patients of child-bearing potential were required to use adequate contraception (hormonal or barrier method of birth control) before study entry and for the duration of study participation; Ability to understand and willingness to sign a written informed consent document; Measurable or assessable disease was required. Patients were excluded if they had received prior chemotherapy or radiotherapy for pancreas cancer, had an active intercurrent illness or gastrointestinal disease or pathology that limited absorption of oral medication. This study was reviewed and monitored by the Memorial Sloan-Kettering Cancer Center (MSKCC) Institutional Review Board and MSKCC's Data and Safety Monitoring Committee.
screening evaluations/pretreatment assessment
All patients signed an informed consent document before study enrollment. Patients underwent a complete history and physical examination. A complete blood count, including differential and platelet count, chemistry panel, including, electrolytes, blood urea nitrogen, creatinine, glucose, bilirubin, asparate aminotransferase (AST), alkaline phosphatase, albumin, total protein, calcium, phosphorus and lactate dehydrogenase, carcinoembryonic antigen, Ca19-9, coagulation profile including International Normalised Ratio, were obtained. A baseline urinalysis was carried out. For females of child-bearing potential, a serum or urine pregnancy test was carried out . All the above tests were conducted within 7 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 initiation of therapy).
A chest X-ray and either a computed tomography scan (CT) abdomen/pelvis with oral/IV contrast (5 mm cuts through the pancreas) or an magnetic resonance imaging of the abdomen and pelvis with gadolinium, were required within 21 days of study enrollment. Tumor paraffin block was collected and assayed for confirmation of diagnosis and for correlative immunohistochemical studies, where available. Additional tissue, if available, was snap frozen for additional biologic correlates.
agent administration
All treatment was administered on an outpatient basis. There were two parts to this study: (i) Combination chemotherapy, radiation and erlotinib; (ii) Maintenance chemotherapy and erlotinib. Once the MTD was determined for erlotinib in combination with gemcitabine and radiation, an additional 11 patients were treated at the MTD to better define toxicity and response.
combined chemoradiation
Patients began treatment on day 1 with radiation and erlotinib. Gemcitabine was dosed at 40 mg/m2/30 min on a twice weekly either Monday/Thursday or Tuesday/Friday schedule beginning on day 1 or day 2 at the treating physician's discretion.
radiation technical details
The intent of the treatment was to deliver 50.4 Gy to the tumor and the primary draining lymph nodes. Patients were placed supine, immobilized and underwent simulation with a CT simulator. In general the field borders were the following (whichever field was the largest):
- AP/PA Fields: (i) superior: inlet of the diaphragm or 2 cm above the celiac axis or 2 cm above the gross tumor volume (GTV); (ii) inferior: L3/4 interspace or 2 cm below the GTV; (iii) lateral: the edge of the transverse processes to include the paraaortic nodes or 2 cm beyond the GTV.
- Lateral Fields: (i) superior and inferior: same as AP/PA; (ii) anterior: included the paraaortic nodes and 2 cm beyond the GTV; (iii) posterior: include at least half of the vertebral bodies while blocking the spinal cord.
- Lateral Fields: (i) superior and inferior: same as AP/PA; (ii) anterior: included the paraaortic nodes and 2 cm beyond the GTV; (iii) posterior: include at least half of the vertebral bodies while blocking the spinal cord.
CT based treatment planning was carried out and the dose was prescribed to the isodose line which covered the GTV with a 1 cm margin. Dose-limiting structures included spinal cord (45 Gy), kidney (at least 50% of the total volume received <18 Gy) and liver (at lease 40% of the total volume received <30 Gy). Treatment was delivered with a 15 MV linear accelerator with multileaf collimators. Patients received 1.8 Gy/day, 5 days/week and had weekly port films for field verification.
Erlotinib was self-administered orally daily continuously throughout the radiation period. Erlotinib was dose-escalated in successive patient cohorts starting at 100 mg/day (see study design section and also Table 3).
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maintenance chemotherapy
For patients who did not demonstrate any evidence of extra-pancreatic tumor progression maintenance therapy was administered with gemcitabine and erlotinib commencing
4 weeks, but not later than 7 weeks, after completion of radiation. Patients received gemcitabine administered by i.v. infusion at a dose of 1000 mg/m2 >30 minutes, on days 1 and 8 of each 21 day cycle for a total of four cycles. Starting on day 1, erlotinib was given orally at a fixed dose of 100 mg/day daily for four cycles. Radiologic restaging was carried out at week 6 and 12. For patients who tolerated maintenance therapy well and in whom no evidence of disease progression was evident at 12 weeks, the option to continue protocol therapy was allowed with the same protocol maintenance treatment criteria and assessment scan intervals observed.
study design/end points
This is a phase I clinical trial studying the effect of adding erlotinib to gemcitabine and radiation in patients with locally advanced unresectable pancreatic adenocarcinoma. The principal objective of the study was to determine the MTD of erlotinib that can be added to a gemcitabine–radiation combination. The secondary objectives were to assess toxicity, response rate, time to tumor progression and OS in this patient population. The tertiary objective was to study a panel of markers before treatment in both normal and tumor tissues. The correlative study results (including kras and EGFR status, mutation analysis and gene copy number, with correlation to clinical outcome) will be reported in a later publication. For the primary tumor end points, descriptive statistics were employed to document the toxic effects and/or side-effects at each dose level. For tumor response measurements, response data for each patient were recorded. Response rate was estimated using the binomial probability and exact 95% confidence intervals (CIs) were provided. Time to progression and OS curves were estimated using Kaplan–Meier methodology. Time to progression was determined as being the time elapsed from the date of study enrollment to documentation of clear-cut progression of disease. OS was dated from the time of study enrollment to the date of death.
Three dose levels were considered: 100 mg/day, 125 mg/day and 150 mg/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 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 dose of 150 mg/day or one dose level below the cohort in which we observed DLT in 2 of 3 or 2 of 6 patients. Once the MTD was determined an expanded cohort of patients were treated at the MTD to better assess tolerability and preliminarily to assess efficacy of the regimen.
At the completion of combined modality therapy, patients underwent a 4-week break during which no gemcitabine, erlotinib or radiation was administered. Patients were radiologically restaged between 3 and 4 weeks following completion of radiation. Those with stable or responsive disease and acceptable treatment tolerance continued on the maintenance phase of the study.
The MTD of erlotinib was based on the development of DLTs. DLT's were evaluated according to the National Cancer Institute Common Toxicity Criteria, version 3.0 (http://ctep.info.nih.gov/reporting/ctc_v30.html), and were defined as any of the following: grade 4 thrombocytopenia (platelets < 25 000/µl), grade 3 neutropenia [absolute neutrophil count (ANC) < 1000/µl] lasting 
4 days, neutropenic fever (fever > 38.1°C and ANC < 1000/µl), grade 3 or 4 diarrhea or 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 radiation. Grade IV fatigue was dose limiting if lasting >7 days. Any toxicity-related treatment interruptions that resulted in a 2 week or greater delay in completing chemoradiation was also adjudicated as dose limiting. This was a phase I open label, nonrandomized, Cancer Therapy Evaluation Program-supported study.
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patient characteristics
Patient demographics are shown in Table 2. Twenty-one patients were enrolled from 3 June 2003 to 24 March 2005. The cut-off point for data analysis was 15 January 2007. Of these 21, 17 were assessable for having completed all protocol therapy, three were assessable for toxicity alone due to incomplete treatment and one patient was withdrawn before receiving treatment due to an elevated alanine aminotransferase (ALT). This latter patient was not included in any of the study end point analyses.
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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 further cohort of three patients was enrolled at dose level 2 (125 mg erlotinib). One of these three patients experienced DLT (platelets and neutropenia). This cohort was therefore expanded to six patients. One patient from the expanded cohort experienced grade 3 elevation's in AST and ALT which were possibly related to therapy and therefore adjudicated as DLT. All of the six patients treated at erlotinib 125 mg experienced delays in treatment because of toxicity and four required a dose reduction of gemcitabine. One of these patients 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 150 mg. The MTD was therefore defined as erlotinib 100 mg/day, along with gemcitabine 40 mg/m2/twice weekly and 180 cGy/day radiation.
Once the MTD was determined, a further 11 patients were enrolled at this dose as part of an expanded cohort to further define toxicity and assess response. Five of these patients experienced treatment delays and two were removed from protocol due to excessive toxicity, one patient because of persistent thrombocytopenia and the other for diarrhea with weight loss and electrolyte abnormalities. In total, four patients 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.
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toxic effects during maintenance therapy
In total, 17 patients completed chemoradiotherapy. Fourteen of these patients proceeded to the maintenance portion of the study. Two patients had developed evidence of progressive disease and were removed from protocol. One patient, upon completion of chemoradiotherapy, was deemed potentially resectable after a restaging CT scan. This patient was removed from protocol (but included in the analysis) and proceeded to have an R0 pancreaticoduodenectomy for T3, N1, M0 and American Joint Committee on Cancer stage II-B disease.
There was one grade 5 toxicity occurrence during this 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 response (PR) to treatment. On the day before his third cycle of maintenance therapy the patient was hospitalized with an acute gastrointestinal bleed. An esophagoduodenoscopy revealed gastric and duodenal ulceration secondary to invasion of tumor. The patient died shortly afterwards. An attribution to treatment cannot be excluded.
There were no grade 4 toxic effects in the maintenance portion of the study (see table 5). Four patients required a dose reduction of gemcitabine and one required a dose reduction of erlotinib. Eleven patients completed the maintenance portion. Four of these opted to continue extra treatment per protocol option, and the number of extra cycles ranged from 1 to 22.
efficacy
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 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 progression of disease on protocol therapy and two had subsequent progression after initially having stable disease as a best response. The median survival duration for the seventeen patients was 18.7 months (95% CI 13.3–24.8) (Figure 2). The median time to tumor progression was 13 months (95% CI 4.8–17.8) (Figure 1).
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discussion |
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Combination concurrent chemotherapy and RT for locally advanced unresectable pancreas cancer is a widely employed standard approach. Gemcitabine has superceded 5-FU as the standard therapy for metastatic pancreatic cancer and is FDA approved for first-line treatment of patients with locally advanced (nonresectable stage II or stage III) or metastatic (stage IV) adenocarcinoma of the pancreas. Gemcitabine has been shown to be a potent radiosensitizer in human colorectal, pancreatic and other solid tumor cell lines [15–17]. A phase I study has shown that a twice-weekly dosing schedule of gemcitabine 40 mg/m2 with concurrent radiation is feasible and well tolerated [18]. This dose was adopted by the Cancer and Leukaemia Group B for a phase II study [19] in which patients received maintenance gemcitabine upon completion of the chemoradiotherapy with a median OS of 8.2 months. Some studies have also attempted to incorporate even higher doses of gemcitabine into a combined chemoradiation approach with success [8, 20, 21].
Pancreatic cancers contain high levels of EGFR overexpression [12]. EGFR and its ligands EGF and TGF-alpha are important in cell proliferation, as well as motility, adhesion, invasion, survival and angiogenesis [10]. In non-small-cell lung cancer (NSCLC) a specific subpopulation exists that harbour somatic mutations in the EGFR. This appears to account for 10% of NSCLC cases although the proportion varies according to the population studied [22–24]. The occurrence of these mutations correlates with an exquisite sensitivity to inhibition of the EGFR tyrosine kinase with gefitinib or erlotinib in the majority of cases [25–27]. Erlotinib has been shown by Shepherd et al. [28] to prolong survival in patients with NSCLC who have been previously treated with chemotherapy. In that study, higher response rates were found in patients who had amplification of the EGFR gene (but not mutations of the EGFR gene). In multivariate analysis, however, survival was not significantly associated with the number of EGFR copies or EGFR mutational status [29].
A similar degree of responsiveness has not been observed in other cancers, and this phenomenon of ‘oncogene addiction’ [30], interrupted so exquisitely by gefitinib or erlotinib, appears to be limited to NSCLC. There is some activity for EGFR inhibitors in pancreas cancer, albeit more modest. In the study by Moore et al. [14] 569 patients with, untreated locally advanced or metastatic pancreas cancer were randomized to receive gemcitabine with either erlotinib or placebo. Patients who received the gemcitabine/erlotinib combination had improved progression-free survival (HR 0.77, 95% CI, 0.64–0.92; P = 0.004), one-year survival (23% versus 17%; P = 0.023) and median OS (6.24 months versus 5.91 months, HR 0.82, 95% CI, 0.69–0.99; P = 0.038) compared with the gemcitabine/placebo group. The proportion of patients with EGFR mutations has not been published. Kwak et al. [31], analyzed 55 cases of pancreatic cancer for EGFR mutations. Five of these specimens were from patients who had been enrolled on a study of erlotinib and capecitabine as second-line therapy and who had sufficient clinical response to remain on study for at least 100 days. Two of 55 (3.6%) were found to have EGFR mutations, both from the five patients who had demonstrated nonprogression of disease on erlotinib and capecitabine. While none of the 50 unselected pancreas cancer patients’ specimens were found to have EGFR mutations, the authors state that technical factors relating to an excessive stromal component to, and lack of microdissection of, the specimens may have resulted in lower sensitivity for detection of mutations.
A common criticism of clinical trials in pancreatic cancer is that patients with stage III and stage IV disease are often grouped together, rendering interpretation of survival data more difficult and potentially obscuring a survival advantage in genuine stage III patients. A strength of our study is that all the patients were surgically staged and therefore the population is homogenous. Although the primary end point was not survival and recognizing the limitations of interpreting survival data in selected good PS patients conducted in single-institution phase I studies, the median OS of 18.7 months, is nonetheless, striking.
This phase I study investigated the combination of erlotinib, an EGFR inhibitor with gemcitabine-based chemoradiation. This is one of the first studies reporting on this combination in pancreas cancer. Ianniti et al. [32] conducted a phase I study of erlotinib in combination with gemcitabine, paclitaxel and radiation, followed by maintenance erlotinib in locally advanced pancreatic cancer. The majority of the patients on that study (14 of 17) were surgically staged. The MTD determined was erlotinib 50 mg/day and the median survival was 14 months.
In conclusion, in association with fixed dose gemcitabine at 40 mg/m2 twice-weekly and radiation at 180 cGy/day, respectively, the MTD of erlotinib was found to be 100 mg/day. The results of the correlative studies should provide some further insights into the mechanistic understanding of the role of EGFR therapy in pancreas adenocarcinoma.
This is a relatively well tolerated, biologically active combination in a poor prognostic cancer. The encouraging results are worthy of further development in pancreas cancer, in an adjuvant or neo-adjuvant setting and provide a further building block for treatment of locoregionally advanced disease.
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Received for publication June 8, 2007. Revision received August 6, 2007. Accepted for publication August 9, 2007.
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