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Clinical Cancer Research 13, 234-240, January 1, 2007. doi: 10.1158/1078-0432.CCR-06-1618
© 2007 American Association for Cancer Research
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Cancer Therapy: Clinical

Clinical and In vitro Studies of Imatinib in Advanced Carcinoid Tumors

James C. Yao, Jun X. Zhang, Asif Rashid, Sai-Ching J. Yeung, Janio Szklaruk, Kenneth Hess, Keping Xie, Lee Ellis, James L. Abbruzzese and Jaffer A. Ajani

Authors' Affiliation: Departments of Gastrointestinal Medical Oncology, Pathology, Internal Medicine, Diagnostic Imaging, Biostatistics and Applied Mathematics, and Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: James C. Yao, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M.D. Anderson Cancer, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-2828; Fax: 713-563-0539; E-mail: jyao{at}mdanderson.org.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Effective systemic therapy options for carcinoid tumors are lacking. We conducted in vitro studies and a phase II clinical trial to explore the activity of imatinib in carcinoid tumors.

Experimental Design: Cells of the human bronchial carcinoid cell line NCI-H727 and the human pancreatic carcinoid cell line BON-1 were treated with increasing concentrations of imatinib using standard procedures to assess in vitro growth-inhibitory activity. A clinical trial using a two-stage phase II design to assess the response rate and safety profile of imatinib at a dose of 400 mg given twice daily in patients with advanced carcinoid tumors was completed.

Results: In both cell lines, there was a dose- and time-dependent cytotoxic effect. The clinical trial enrolled 27 evaluable patients. Median duration on trial was 16 weeks. One patient had a partial response, 17 had stable disease, and 9 had progressive disease by the Response Evaluation Criteria in Solid Tumors criteria. Median progression-free survival time was 24 weeks. Median overall survival is 36 months. Seven patients who achieved a biochemical response had a superior progression-free survival time compared with patients without biochemical response (115 weeks compared with 24 weeks; P = 0.003). An increase in plasma basic fibroblast growth factor was associated with a shorter progression-free survival duration (P = 0.02).

Conclusions: Our data suggest that imatinib is active in vitro and has a modest clinical activity in carcinoid patients. Changes in tumor markers may help select patients who are likely to benefit from therapy.

Carcinoid tumors originate from neuroendocrine cells distributed throughout the body. They can produce bioactive amines and peptides that cause flushing, diarrhea, asthma, and carcinoid heart disease. Although the introduction of somatostatin analogues has significantly decreased the morbidity and mortality associated with carcinoid syndrome, clinical management in the setting of advanced disease remains suboptimal. Despite several chemotherapy trials, no treatment has shown a tumor response rate greater than 15% to 16% (1, 2). Biological therapy with IFN has also been explored. A recently reported clinical trial with patients randomly assigned to lanreotide, IFN, and lanreotide plus IFN reported disappointing response rates of 4%, 4%, and 7% (3). Novel therapeutic strategies are clearly needed to improve the outcome of carcinoid patients.

Imatinib mesylate (Gleevec) is a phenylaminopyrimidine derivative and inhibits protein tyrosine kinases, abl, platelet-derived growth factor (PDGF) receptor (PDGFR), and c-kit. Inhibition of abl and c-kit in chronic myelogenous leukemia (4) and gastrointestinal stromal tumor (5), respectively, has led to significant advances in therapy in these diseases. In dermatofibrosarcoma protuberans, characterized by overexpression of PDGFß due to a translocation, imatinib also showed significant clinical activity through the inhibition of PDGFRß. PDGF and PDGFR are also expressed in carcinoid tumors. Expression of PDGF has been found in 70% of carcinoid tumors (6). Additionally, PDGFR{alpha} has been found on both carcinoid tumor cells and stroma of carcinoid tumors, supporting a possible autocrine loop supporting tumor growth. PDGFRß has been found in the stroma of carcinoid tumors (6). PDGFRß expression seems to be more intense in the stroma and small capillaries around tumor clusters, suggesting that carcinoid cells may simultaneously produce PDGF and up-regulate PDGFRß in a paracrine fashion (7).

We conducted in vitro laboratory studies as well as a phase II clinical study to investigate the efficacy and safety of imatinib among patients with advanced carcinoid tumors.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
In vitro studies
Carcinoid cancer cell lines. The human bronchial carcinoid cancer cell line NCI-H727 (CRL-5815) was purchased from the American Type Culture Collection (Manassas, VA). Human pancreatic carcinoid cell line BON-1 (8) was provided by Dr. Kjell Oberg (Uppsala University, Uppsala, Sweden). Adherent monolayer cultures were maintained in 75-cm2 flasks and incubated in a humid atmosphere with 5% CO2 at 37°C. The culture medium was changed every 2 to 3 days and subculture monolayer cells almost once a week, with a subcultivation ratio of 1:4. The cells in log-phase growth were used for the following study.

In vitro cytotoxicity assay. BON-1 cells (7,500 per well) and NCI-H727 cells (5,000 per well) were seeded into flat-bottomed 96-well plates in triplicate and allowed to adhere overnight in 10% fetal bovine serum–supplemented DMEM or RPMI 1640 complete medium, respectively; the medium was then exchanged for serum-free medium (negative control) or serum-free medium containing serial dilutions of imatinib. After 48 h (control cultures did not reach confluence), the number of metabolically active cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and absorbance was measured in a Packard Spectra microplate reader at 540 nm. Growth inhibition was calculated using the following formula: inhibition rate = (1 – a / b) x 100%, where a and b are the absorbance values of the treated and control groups, respectively (9). Experiments were done in triplicates.

Clinical trial
Study population. The study population consisted of patients with histologically confirmed metastatic carcinoid tumor. Other neuroendocrine neoplasms were excluded. Prior therapies, including chemotherapy, immunotherapy, somatostatin analogues, hepatic artery embolization, radiofrequency ablation, and cryoablation, were allowed provided measurable disease remained. Further eligibility criteria included performance status of ≤2 on the Zubrod scale, absolute granulocyte count >1,500/mm3, hemoglobin >8 g/dL, platelet count >100,000/mm3, serum bilirubin <1.5 times the upper limit of the laboratory normal, serum creatinine ≤1.5 mg/dL, and aspartate aminotransferase and alanine aminotransferase ≤2.5 times the upper limit of the laboratory reference range. Patients with clinically apparent brain metastases and pregnant or lactating women were excluded. Concurrent use of octreotide was allowed.

This study was approved by the Institutional Review Board of M.D. Anderson Cancer Center. All patients provided written informed consent.

Treatment plan and evaluations. After confirmation of pathologic diagnoses at M.D. Anderson Cancer Center, pretreatment evaluations were obtained, including history, physical examination, measurement of serum chemistry, complete blood count, and baseline tumor markers (serum chromogranin A, pancreatic polypeptide, gastrin, glucagon, and urinary 5-hydroxyindoleacetic acid). Baseline tumor measurements were made by computed tomography or magnetic resonance imaging.

Treatment with imatinib was given orally at a starting dose of 400 mg twice daily (800 mg total daily dose). Treatment was delivered continuously. Dose reductions to 600 and 400 mg total daily dose were allowed for grade 3 and 4 toxicities or recurrent grade 2 nonhematologic toxicities.

Response and progression were evaluated in this study using the criteria proposed by the Response Evaluation Criteria in Solid Tumors Committee (10). Progression-free survival and overall survival durations were measured from the date of study entry. Biochemical response was evaluated among patients with elevated markers at baseline and defined by either a ≥50% reduction in tumor markers or a reduction in elevated tumor marker into the laboratory reference range. Imaging studies to assess response were obtained every 12 weeks.

Safety was monitored using a self-administered patient diary that was evaluated according to the Common Toxicity Criteria version 2. In this study, dose reductions were permitted for Common Toxicity Criteria grade 3 or 4 toxicities and recurrent grade 2 toxicities. As an optional procedure, patients had collection of blood at baseline, week 3, week 6, and week 12. Also as an optional procedure, patients had serial assessments of tumor blood flow variables by perfusion computed tomography, which was done at baseline, week 6, and week 12.

Statistical considerations. The primary objective of the study was to assess the objective response rate of imatinib among patients with advanced carcinoid tumors. A two-stage statistical design was used. In the first stage, 27 evaluable patients were enrolled. If three or more partial or complete responses were observed, then an additional 13 patients were to be added. If fewer than three objective responses occurred, then the study was to be terminated. This design assured a <10% chance of accepting imatinib for further testing if the true response rate was <10% and a >90% chance (power) of accepting imatinib for further testing if the true response rate was at least 25%. The probability of early termination was 48%. Progression-free survival and overall survival durations were computed using the Kaplan-Meier method.

Immunohistochemical analyses. As part of the phase II trial, where available, archival tissue from participants in the clinical trial was collected for immunohistochemical analyses of PDGF, PDGFR, c-kit, and abl. Sections (5 µm thick) of formalin-fixed, paraffin-embedded cancer specimens were deparaffinized in xylene and rehydrated in graded alcohol. Antigen retrieval was done with microwave for 8 min in citric acid buffer solution. Endogenous peroxidase was blocked by using 3% hydrogen peroxide in PBS for 12 min. The specimens were incubated with a protein-blocking solution consisting of PBS (pH 7.5) containing 5% normal donkey serum and 5% bovine serum albumin for 20 min at room temperature and then incubated at 4°C in a 1:100 dilution of a rabbit polyclonal antibody against human PDGF-A, PDGFR-{alpha}, and PDGFR-ß or 1:50 dilution of a rabbit polyclonal antibody against human PDGF-ß. The specimens were then rinsed and incubated with peroxidase-conjugated anti-rabbit IgG for 1 h at room temperature. Next, slides were rinsed with PBS and incubated for 5 min with diaminobenzidine (Research Genetics, Huntsville, AL). The sections were washed thrice with distilled water, counterstained with Mayer's hematoxylin (BioGenex Laboratories, San Ramon, CA), and washed once each with distilled water and PBS. Afterward, the slides were mounted by using Universal mount (Research Genetics) and examined under a bright-field microscope.

Analysis of plasma concentrations of basic fibroblast growth factor and vascular endothelial growth factor. Plasma samples were obtained from patients who consented to have optional blood drawn for analyses of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) before and following treatment. After complete protease inhibitors cocktail (one tablet per 50 mL final volume; Roche Diagnostics, Inc., Indianapolis, IN) was added, the plasma samples were snap frozen in liquid nitrogen and stored at –80°C until the assays. No samples underwent more than three freeze-thaw cycles. ELISA-Kine Plus kits for bFGF and VEGF were purchased from MP Biomedicals (Irvine, CA; formerly ICN Biomedical, Inc.), and the assays were done according to the protocols provided by the vendors. Each plasma sample was assayed in triplicate.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
In vitro studies
The H727 and BON-1 carcinoid cell lines were used for the in vitro studies. H727 is a well-differentiated carcinoid line derived from a bronchial carcinoid. BON-1 is a serotonin-producing cell line derived from peripancreatic lymph node metastasis of a pancreatic neuroendocrine carcinoma (8). Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, we observed a cytotoxic effect of imatinib on both H727 and BON-1 carcinoid cells. This effect was dose dependent. Values for the IC50 of imatinib on BON-1 and H727 cells after exposure for 48 h were 32.4 and 32.8 µmol/L, respectively (Fig. 1 ).


Figure 1
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  		Fig. 1. IC50 calculation of imatinib on the carcinoid cancer cell lines BON-1 and H727 after exposure to different concentrations of imatinib for 48 h.

 
Phase II clinical trial
Patient population. Between May 2002 and May 2003, a total of 31 patients gave informed consent and was screened for study entry. Of these, one patient did not receive imatinib. Three additional patients did not complete the first course of therapy and did not return to M. D. Anderson Cancer Center for follow-up. Therefore, 27 patients were evaluable for response. Three patients had foregut carcinoid, 12 had midgut carcinoid, and 3 had hindgut carcinoid. One patient had a renal primary. In eight patients, the primary site was not known. Details of the patient and tumor characteristics are included in Tables 1 and 2 , respectively.


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  		Table 1. Patient characteristics for the 27 evaluable patients enrolled in the trial

 

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  		Table 2. Disease characteristics by primary site at study entry

 
Clinical activity. We observed a single confirmed partial response among the 27 patients evaluable for response (Fig. 2 ). Seventeen patients (83%) had stable disease, including 7 of the 14 patients who had previously known progressive disease. Nine patients (33%) had progressive disease. The median progression-free survival duration was 5.9 months (95% confidence interval, 2.1-9.7 months; Fig. 3 ). The median overall survival is 36 months (95% confidence interval, 18–54 months; Fig. 4 ).


Figure 2
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  		Fig. 2. Partial response observed in one patient—computed tomographic images.

 

Figure 3
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  		Fig. 3. Progression-free survival. The median progression-free survival was 25.7 wks (95% confidence interval, 9.1–42.3 wks).

 

Figure 4
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  		Fig. 4. Overall survival of evaluable patients. The survival rates were 89% after 1 yr and 70.69% after 2 yrs. Median survival has not been reached. Median survival duration is 36 mo (95% confidence interval, 18–54 mo).

 
After treatment, either a normalization or a ≥50% reduction in values was observed in 5 of 14 (36%) patients with elevated 24-h urinary 5-hydroxyindoleacetic acid, in 3 of 13 (23%) patients with elevated chromogranin A, and in the single patient with elevated pancreatic polypeptide. The seven patients who achieved a biochemical response had a significantly better progression-free survival duration (P = 0.003; Fig. 5 ). The median progression-free survival durations of patients with and without biochemical response were 115 and 24 weeks, respectively. Patients receiving concurrent octreotide therapy during the study also had a significantly improved progression-free survival duration compared with those not on octreotide therapy (49 weeks compared with 14 weeks; P = 0.03). However, patients with midgut carcinoid (67%) were more likely to receive concurrent octreotide than those with foregut (0%) or hindgut (33%) carcinoid.


Figure 5
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  		Fig. 5. Comparison of progression-free survival between patients who achieved a biochemical response and those who did not. Patients who achieved a biochemical response had a significantly longer progression-free survival duration (P = 0.003) than did those with no biochemical response (24 wks compared with 115 wks, respectively).

 
In the single patient with a partial response, a significant reduction in chromogranin A was observed within 3 weeks of treatment initiation. The patient achieved a radiologic partial response after 6 months of therapy. Tumor bulk remained stable with continued therapy for the next 15 months. Imatinib was then stopped, and the patient received depot octreotide only with stable disease for the next 4 months. This patient then developed evidence of disease progression with increasing pain and elevated liver enzyme and chromogranin A levels. Imatinib was reinitiated at 500 mg per day. An evaluation 3 months later showed improvement in symptoms, liver function, and chromogranin A. The patient currently remains on imatinib with stable disease.

Safety. In general, imatinib therapy was well tolerated. The most common grade 3/4 toxicity associated with high-dose imatinib (800 mg per day) was fatigue, which occurred in seven patients (26%). Grade 3 asymptomatic hypophosphatemia was observed in five patients. Hypophosphatemia was easily corrected with oral replacement. Grade 3 diarrhea and edema were each observed in three patients; granulocytopenia, nausea, and hypokalemia were each observed in two patients. Both patients having granulocytopenia were previously treated with chemotherapy. Although grade 1 or 2 rash was common, only one patient experienced grade 3 rash.

In our study, dose reduction was allowed for either grade 3/4 toxicities or recurrent grade 2 toxicities, which were common among patients receiving prolonged therapy. Seventeen (63%) patients had dose reductions. Among these 17 patients, 8, 7, and 2 patients had their doses reduced to final doses of 600, 400, and 300 mg per day, respectively. No patient had to be removed from the study because of toxicities.

Plasma bFGF and VEGF. Mean baseline plasma bFGF and VEGF concentrations were 65.5 and 6.4 ng/mL, respectively. Following 12 weeks of treatment, mean plasma bFGF was 31.6 ng/mL. This represents a 52% reduction, which is statistically significant by the paired sample t test (P = 0.027). Twelve patients had ≥50% reductions in bFGF, whereas three patients had a significant increase (doubling) in bFGF. Median progression-free survival durations for patients with a decreased plasma bFGF concentration (5.6 months) and patients with a stable plasma bFGF concentration (6.1 months) were longer than the duration for patients with an increased bFGF (3.2 months; P = 0.02).

No significant change in the mean plasma VEGF level was detected following 12 weeks of therapy (5.9 ng/mL). Decreases, stable levels, and increases in plasma VEGF were observed in 6, 17, and 3 patients, respectively. No significant differences in progression-free survival were observed.

Immunohistochemical analyses. Immunohistochemical analyses for targets of imatinib were done on tumor tissue if available. c-kit was not expressed in any of the 13 cases evaluated, including the sole patient with the radiologic response. c-abl was assessed in 12 patients. All cases had intense staining in 100% of cells. PDGF{alpha} and PDGFß were expressed in 62% and 100% of cases, respectively. PDGFR{alpha} and PDGFß were expressed in all cases examined. We observed no significant correlation between these markers and clinical response, progression-free survival, or overall survival.

Functional computed tomography. As an optional procedure, serial functional computed tomography was done at baseline and week 12. A total of seven patients with 13 lesions had serial scans done. No significant changes in tumor blood flow, blood volume, or permeability surface area were detected (Table 3 ). However, the small number of patients having serial scans may have limited our ability to detect changes in tumor perfusion.


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  		Table 3. Effect of imatinib on tumor perfusion as measured by functional computed tomography among seven carcinoid patients

 

   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Introduction of imatinib has led to significant improvements in the outcome of patients with diseases associated with activating mutations in abl, c-kit, and PDGFß. Although there have been no reported mutations in abl, kit, and PDGF in carcinoid tumors, carcinoid tumors simultaneously express PDGF ligand and receptors (7, 11). We conducted preclinical and clinical studies to examine the role of high-dose imatinib in carcinoid tumors. Although preclinical studies suggested growth-inhibitory activity, our phase II clinical trial showed only modest biological activity. One patient had a significant reduction in tumor burden associated with symptomatic improvement. When the patient stopped receiving imatinib, disease progression was observed. Clinical improvement was again noted when imatinib was reintroduced. Evidence of cytostatic activity was also observed in our trial. Several patients with disease progression achieved disease stabilization associated with significant decreases in tumor marker levels.

With the introduction of imatinib, immunohistochemical analyses have at times been done to screen for expression of imatinib targets on tumors. Our studies showed that most carcinoid tumors expressed abl, PDGF, and PDGFR. However, expression did not predict outcome. Previous studies have reported expression of c-kit in 3% to 17% of carcinoid tumors and in 26% of islet cell carcinoid tumors (12, 13). Our study did not find c-kit expression in any of the cases tested. One explanation could be that the rates of c-kit expression may vary by primary location of the carcinoid tumor. A study examining lung neuroendocrine tumors found c-kit expression in 17% pulmonary carcinoids (13). A separate study examining islet cell carcinoma found c-kit expression in 26% of cases (12). Our current study and the study from Mayo Clinic examining c-kit expression in carcinoid found expression in 0% and 3% of cases, respectively (12). Further, the lack of c-kit expression in our patient who responded to imatinib suggests that c-kit expression may not be a good marker for clinical benefit.

Several factors may have affected the observed differences in the in vitro, xenograft, and clinical studies. Current carcinoid cell lines available for in vitro studies may not be representative of typical bowel carcinoid. Both the BON-1 and H727 cell lines used in our trial were derived from foregut neuroendocrine tumors (8). In addition to the rate of kit expression described above, foregut neuroendocrine tumors are more likely to have chromosome 11q deletion (14–16). The more common classic midgut carcinoids, on the other hand, are more likely to have chromosome 18q loss (17, 18).

In our study, patients receiving concurrent octreotide had significantly better progression-free survival than those who did not. Several potential reasons may explain this difference. Patients with midgut carcinoid tumors, which are more indolent, are more likely to have carcinoid syndrome and therefore receive concurrent octreotide (1). Octreotide may also have significant cytostatic activity. In two studies, 50% to 55% of patients with progressive disease at study entry experienced disease stabilization after starting therapy with octreotide (19–21). The cytostatic activity may mediated through somatostatin receptors present on tumor cells. Alternatively, octreotide has also been reported to decrease plasma VEGF and insulin-like growth factor-I levels among cancer patients, suggesting a possible antiangiogenic mechanism (22–26).

Carcinoid is a disease lacking systemic therapy options. Imatinib seems to have important clinical activity in a limited number of patients. Although immunohistochemical analyses for expression of abl, kit, PDGF, and PDGFR did not predict outcome, analyses of tumor markers and plasma bFGF seemed more promising as surrogate markers of clinical benefit. In our study, increase in bFGF was a predictor of early disease progression, whereas significant decreases in tumor markers correlated with a longer progression-free survival interval. However, the number of patients included in our study is limited, and evaluation of early changes bFGF and tumor markers as surrogate markers of clinical benefit in future studies would be of interest.


   Acknowledgments
 
We thank Samidha Worah for expert support with data management and Cindi Tomlin for help in the preparation of this manuscript.


   Footnotes
 
Grant support: Novartis Cooperation and American Society of Clinical Oncology.

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.

Note: Presented in part at the Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, Louisiana.

Received 7/ 5/06; revised 10/ 9/06; accepted 10/18/06.


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 Materials and Methods
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 Discussion
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Cancer Research Clinical Cancer Research
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