phase ii trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (t4) pancreatic adenocarcinoma: correlation of smad4(dpc4) immunostaining with pattern of disease progression Phase II Trial of Cetuximab, Gemcitabine, and Oxaliplatin Followed by Chemoradiation With Cetuximab for Locally Advanced (T4) Pancreatic Adenocarcinoma: Correlation of Smad4(Dpc4) Immunostaining With Pattern of Disease Progression

Phase II Trial of Cetuximab, Gemcitabine, and Oxaliplatin Followed by Chemoradiation With Cetuximab for Locally Advanced (T4) Pancreatic Adenocarcinoma: Correlation of Smad4(Dpc4) Immunostaining With Pattern of Disease Progression

  1. Robert A. Wolff
  1. Christopher H. Crane, Gauri R. Varadhachary, John S. Yordy, Gregg A. Staerkel, Milind M. Javle, Bridgett D. Hobbs, Sunil Krishnan, Jason B. Fleming, Prajnan Das, Jeffrey E. Lee, James L. Abbruzzese, Robert A. Wolff, The University of Texas MD Anderson Cancer Center, Houston, TX; Howard Safran, Brown University Oncology Group, Providence, RI; Waqar Haque, Cleveland Clinic, Cleveland, OH.
  1. Corresponding author: Christopher H. Crane, MD, Dept of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: ccrane{at}mdanderson.org.

  1. Clinical data presented at the 2010 Gastrointestinal Symposium, January 23, 2010. Translational data presented at the 2011 Gastrointestinal Symposium, January 21, 2011.

 
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Abstract

Purpose This phase II trial was designed to assess the efficacy and safety of cetuximab, gemcitabine, and oxaliplatin followed by cetuximab, capecitabine, and radiation therapy in locally advanced pancreatic cancer (LAPC).

Patients and Methods Treatment-naive eligible patients (n = 69) received intravenous gemcitabine (1,000 mg/m2) and oxaliplatin (100 mg/m2) every 2 weeks for four doses, followed by radiation (50.4 Gy to the gross tumor only) with concurrent capecitabine (825 mg/m2 twice daily on radiation treatment days). Cetuximab (500 mg/m2) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression.

Conclusion This regimen appears effective and has acceptable toxicity. The primary end point (1-year overall survival rate > 45%) was met, with encouraging survival duration. Smad4(Dpc4) immunostaining correlated with the pattern of disease progression. Prospective validation of Smad4(Dpc4) expression in cytology specimens as a predictive biomarker is warranted and may lead to personalized treatment strategies for patients with localized pancreatic cancer.

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INTRODUCTION

Locally advanced pancreatic cancer is incurable with standard therapies, and the overall survival rate is typically less than 1 year. Although recent trials comparing gemcitabine alone to chemoradiotherapy followed by gemcitabine have produced discordant results,1,2 both chemotherapy and chemoradiotherapy are considered standard initial treatment options, although they have significant limitations. The sequencing of chemotherapy followed by chemoradiotherapy is thought to optimally incorporate standard therapies by selecting the most appropriate patients for consolidation with chemoradiotherapy.3,4

Cetuximab showed promising results in combination with gemcitabine in a phase II trial for patients with advanced pancreatic cancer5 and with radiation therapy in preclinical6 and clinical studies.7 The addition of oxaliplatin to gemcitabine was found to improve median survival in patients with advanced pancreatic cancer.8

Smad4(Dpc4) is a tumor suppressor gene that is inactivated in 53% of pancreatic cancers. It encodes a transcription factor that is involved in the regulation of expression of a broad set of genes; it has been implicated in the regulation of tumor microenvironment, and it has been correlated clinically with prognosis9 and the pattern of disease spread.10

We designed a phase II trial to evaluate the efficacy and safety of gemcitabine, oxaliplatin, and cetuximab followed by chemoradiotherapy with concurrent cetuximab in patients with locally advanced pancreatic cancer. We subsequently developed a correlative study hypothesis that Smad4(Dpc4) immunostaining of diagnostic cytology specimens was feasible and would correlate with the pattern of disease spread on the basis of a rapid autopsy study10 that was reported after the trial completed accrual.

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PATIENTS AND METHODS

Initial Evaluation

A medical oncologist and a radiation oncologist independently performed physical examinations and recorded the medical history of each patient before study enrollment. Serum hemoglobin, hematocrit, WBC, and platelet levels were measured, and serum chemistries were analyzed for each patient. A biopsy confirmed diagnosis of pancreatic adenocarcinoma was required. When necessary, biliary patency was established by using endobiliary stenting. Pancreatic protocol computed tomography (CT) and chest CT were performed in all patients. The baseline CA 19-9 level was measured, and treatment was initiated after bilirubin normalized.

Study Design and Treatment Plan

The study was designed to administer gemcitabine (1,000 mg/m2 given over 100 minutes) and oxaliplatin (100 mg/m2) every 2 weeks for four doses and cetuximab (400 mg/m2 loading dose) on day 1 of chemotherapy and then weekly (250 mg/m2). For patients without disease progression, chemotherapy was followed by chemoradiotherapy that consisted of 50.4 Gy and concurrent capecitabine (825 mg/m2 orally twice daily on days of radiation therapy). Weekly cetuximab was continued until restaging at 1 month after chemoradiotherapy. After the first 37 patients were accrued, the cetuximab dosage was changed to 500 mg/m2 every 2 weeks to make it possible for patients traveling a long distance to participate.

Radiation Therapy Technique

All patients underwent treatment simulation by using a CT simulator. Only the gross primary tumor and regional lymph nodes greater than 1 cm were targeted. The planning target volume margin was 1.5 cm in the radial direction and 2.5 cm in the cranial and caudal directions. The dose of 50.4 Gy in 28 fractions over 5.5 weeks was prescribed with 15- or 18-MV photons. A three- or four-field technique was used that had customization of beam angles and weighting.

Monitoring During Chemotherapy and Chemoradiotherapy

A medical oncologist recorded the history and performed a physical examination of each patient every 2 weeks during protocol therapy. A radiation oncologist independently performed the same evaluation weekly during chemoradiotherapy. Serum hemoglobin, hematocrit, WBC, platelet levels, and serum chemistries were evaluated every 2 weeks during chemotherapy and weekly during chemoradiotherapy. Capecitabine pill diaries were monitored weekly.

Follow-Up Imaging and Additional Therapy

Restaging with pancreatic protocol CT, chest radiography, and CA19-9 level was performed 1 week after the last dose of oxaliplatin, 5 weeks after the completion of chemoradiotherapy, and every 2 months during maintenance chemotherapy until progression. At the completion of protocol-based chemoradiotherapy, all patients with responding or stable disease were given the option of receiving any other available treatment or continuing on maintenance chemotherapy with cetuximab and gemcitabine. Surgery was considered in patients whose tumors were considered technically resectable at any time during follow-up.

Smad4(Dpc4) Immunostaining of Diagnostic Specimens

Specimens from 48 patients were examined, and 41 of those contained adequate tumor cellularity for analysis. Slides from each patient were then examined to determine which slides contained the highest number of tumor cells. Coverslips were removed. Slides then underwent destaining with 1% acid alcohol and subsequently were submitted for Smad4(Dpc4) staining. Smad4(Dpc4) immunostaining (Fig 1) was carried out with a Bond Max instrument (Leica Microsystems, Milton Keynes, United Kingdom) and with the Novocastra lyophilized mouse monoclonal antibody to Smad4(Dpc4) Locus 4 Protein (clone JM 56; Leica Microsystems). Each slide was labeled with a 1:5 dilution of the antibody (for 15 minutes). Slides then were counterstained with Bond 0.02% hematoxylin (for 8 minutes) and were coverslipped. Each specimen slide then was scored as Smad4(Dpc4) positive or Smad4(Dpc4) negative by a single board-certified cytopathologist.

Fig 1.
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Fig 1.

Median survival duration was 19.2 months (95% CI, 14.6 to 23.8 months) and 1-year, 2-year, and 4-year actuarial overall survival rates were 67.1%, 27.2%, and 12.4%, respectively. The survival duration was similar among the patients who did not undergo surgical resection.

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RESULTS

Patient Characteristics

The first patient was accrued on October 3, 2005. Full accrual of 69 patients was reached on June 24, 2009. Sixty patients were accrued at The M.D. Anderson Cancer Center, and nine were accrued by Brown University Oncology Group. Fifty-one (74%) had unresectable tumors; 16 (23%) had borderline resectable tumors on the basis of the involvement of less than 180 degrees of the superior mesenteric artery or involvement of the hepatic artery within 1 cm of the celiac axis; and two (3%) had borderline resectable tumors on the basis of advanced regional adenopathy. Median follow-up was 20.9 months (range, 5.2 to 51.5 months) for the 20 living patients and was 16.3 months (range, 2.7 to 49.7 months) for all patients. Patient characteristics are listed in Table 1.

View this table:
Table 1.

Patient Demographic and Clinical Tumor Characteristics

Dose Interruptions and Reductions

Overall, gemcitabine and oxaliplatin was reduced or held because of toxicity in 12 patients (17.4%). Four patients during induction chemotherapy and three patients during chemoradiotherapy had at least one dose of cetuximab held. Doses of capecitabine were reduced, missed, or held in nine patients (15.0%) for grade 2 or greater nonhematologic toxicity. There were no delays of radiation treatment as a result of toxicity.

Chemoradiotherapy Compliance

All patients completed the prescribed 28 fractions of radiation therapy. All 60 patients who underwent chemoradiotherapy completed capecitabine pill diaries. Forty-two patients (73%) completed all capecitabine doses exactly as prescribed. Of the 18 patients who missed doses, nine missed only one dose (ie, compliant with 98.7% of doses), eight missed between two and six doses, and one missed 36 doses.

Radiographic Response

Twelve patients (18%) had a partial response, 11 (16%) had a minor response, 29 (43%) had stable disease, 16 (24%) had progressive disease, 11 had distant progression, and one had local progression at 5 to 6 weeks after chemoradiotherapy. Two patients had local progression before chemoradiotherapy, two patients had distant progression before chemoradiotherapy, and one patient was not evaluable for response.

Maintenance Chemotherapy and Off-Protocol Therapy

Twenty-seven (58.7%) of the 46 patients who had stable or responding disease after initial restaging received maintenance cytotoxic chemotherapy for a median of 4 months (range, 1 to 20 months). Fifteen patients received gemcitabine and cetuximab, six received gemcitabine and erlotinib, five received other gemcitabine-based chemotherapy, and one received single-agent capecitabine. In addition, 28 (58.3%) of the 48 patients with progressive disease received cytotoxic chemotherapy after progression. Four patients received a boost dose to the primary tumor (one each of 10.8, 18.0, 19.8, or 20.0 Gy) at 1.8 or 2.0 Gy per fraction.

Overall Survival

The median survival duration was 19.2 months (95% CI, 14.2 to 24.2 months), and the 1-year, 2-year, and 4-year actuarial overall survival rates were 66.0%, 25.0%, and 11.3%, respectively (Fig 2). Survival duration was greater among the patients who developed any grade acneiform rash during cetuximab administration (P = .001; Fig 3). Initial CA 19-9 level less than 100 (P = .184), borderline resectable initial stage (P = .879), and surgical resection (P = .310; Fig 2) did not significantly influence survival. The median survival duration was 19.2 months (95% CI, 14.7 to 23.7 months) and the 1-year, 2-year, and 4-year actuarial overall survival rates were 67.2%, 22.2%, and 7.6% among the 60 patients who did not undergo surgical resection (Fig 2).

Fig 2.
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Fig 2.

There was a statistically significant prolongation in survival duration among the patients that developed any grade acneiform rash as a result of cetuximab.

Pattern of Progression

Forty-eight (69.6%) patients had progressive disease. The median progression-free survival duration was 12.5 months. The first site of progression was distant in 26 patients (54%), local in 14 patients (29%), and synchronous distant and local in eight patients (17%). Among the 15 patients with isolated local progression, seven occurred after 16 months, which resulted in a median progression time of 18.0 months and 1-year and 2-year actuarial local progression rates of 22.8%, and 61.0%, respectively (Fig 4). The median progression time was 14.3 months, and the 1-year, and 2-year distant progression rates were 41.0% and 67.7%, respectively. Patients developing acneiform rash had more durable freedom from local progression (P = .015) but not distant progression (P = .512).

Fig 4.
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Fig 4.

Representative diagnostic cytology specimens that were immunostained for Smad4(Dpc4) expression. Specimens were scored as (A) positive, (B) focal, (C) rare, and (D) negative. Positive and focal were considered to represent intact Smad4(Dpc4) expression, and rare and negative were considered to represent loss of Smad4(Dpc4) expression.

Correlation of Pattern of Progression With Smad4(Dpc4) Expression

Of the 41 patients with adequate tumor specimens for immunostaining, the dominant pattern of progression determined from clinical and radiographic data was local in 15, distant in 14, and indeterminate in eight. Four patients are alive without progression. Indeterminate was defined as progression-free at last follow-up before death. Eleven (73.3%) of 15 patients with intact Smad4(Dpc4) expression had a local dominant pattern of progression, and 10 (71.4%) of 14 patients with Smad4(Dpc4) loss had distant dominant pattern of spread (P = .016). Three patients with intact Smad4(Dpc4) are alive without disease progression at 22.0, 26.1, and 51.5 months; one patient with Smad4(Dpc4) loss is alive without disease progression at 25.5 months.

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DISCUSSION

Pancreatic cancer is generally treatment resistant and incurable without surgical resection. Few studies have demonstrated median survival durations longer than 12 months in patients with locally advanced disease. In this trial, the 1-year overall survival rate as the primary end point was met; the median survival duration was 19.2 months and the 4-year survival rate was 7.6% among the 60 patients who were treated without surgical resection. These results compare favorably to similar studies of patients with T4 pancreatic cancer.

The survival duration observed in the patients in this trial was not due to the inclusion of patients with borderline resectable tumors or to the subset of patients who underwent surgical resection. Nevertheless, some caution is appropriate in the interpretation of the impact of the study treatment on the survival duration we observed, because patient selection, aggressive endobiliary stent management, and the individualized use of maintenance and salvage chemotherapy could have contributed to the long survival duration. The median time to local tumor progression in chemoradiotherapy studies has been reported as between 7 and 10 months.13 The 18.4 month median time to local progression in our study suggests that improved local tumor control could have led to improved survival duration. Furthermore, patients who developed acneiform rash related to cetuximab had improved local tumor control and survival duration, as has been reported in other trials,7,14 suggesting a radiosensitizing effect of cetuximab.

The primary end point of this trial was met, which suggests that this regimen should be studied more. Subsequent to the activation of this study, separate phase III trials of oxaliplatin and15 of cetuximab in combination with gemcitabine,16 as well as a phase II trial of gemcitabine, oxaliplatin, and cetuximab,17 have had negative results in studies of patients with metastatic disease. Although these studies were negative, the phase III trials showed a suggestion of benefit of adding these agents to gemcitabine among the patients with ECOG 0 to 1 performance status in unplanned subset analyses. Nevertheless, the weight of the evidence does not support the additional study of this regimen as designed. However, the correlative study results may provide the rationale for future clinical investigation.

In this trial, the pattern of disease progression correlated with Smad4(Dpc4) expression in diagnostic cytology specimens. Patients with intact Smad4(Dpc4) more commonly had a local tumor dominant pattern of progression, and patients with Smad4(Dpc4) loss more commonly had distant disease progression (P = .016). Isolated local tumor progression leading to mortality was common. These observations are consistent with recent evidence from a rapid autopsy series from Johns Hopkins University. Thirty percent of patients in this series died as a result of complications related to their local tumor without metastatic disease, and there was a correlation between the extent of metastatic disease and loss Smad4(Dpc4) expression. For example, only 22% of patients with localized disease had loss of Smad4(Dpc4) expression, compared with 78% of patients with greater than 100 metastases.10 Together, these studies contradict the widespread perception that all patients with pancreatic cancer die as a result of distant metastatic disease, demonstrate that complications of local tumor progression are a significant source of disease-related mortality even after chemoradiotherapy, and these studies suggest the possibility that the a priori pattern of progression may be predictable on the basis of Smad4(Dpc4) expression.

In summary, this phase II clinical trial supports the additional study of epidermal growth factor receptor inhibition in combination with gemcitabine-based chemotherapy and consolidative chemoradiotherapy as a strategy to maximize survival in patients with locally advanced pancreatic cancer and good performance status. The pattern of disease progression (local v distant dominant) appears to correlate with Smad4(Dpc4) expression in cytology specimens. Prospective validation of Smad4(Dpc4) expression as a predictive biomarker is warranted and may lead to personalized treatment strategies.

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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Christopher H. Crane, Bristol Myers-Squibb, Varian Research Funding: Christopher H. Crane, Bristol Myers-Squibb; Prajnan Das, Genentech; Robert A. Wolff, Eli Lilly Expert Testimony: None Other Remuneration: None

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AUTHOR CONTRIBUTIONS

Conception and design: Christopher H. Crane, Gauri R. Varadhachary, Howard Safran, James L. Abbruzzese, Robert A. Wolff

Financial support: Christopher H. Crane

Administrative support: Christopher H. Crane

Provision of study materials or patients: Christopher H. Crane, Gauri R. Varadhachary, Sunil Krishnan, Jason B. Fleming, Jeffrey E. Lee, James L. Abbruzzese, Robert A. Wolff

Collection and assembly of data: Christopher H. Crane, John S. Yordy, Gregg A. Staerkel, Milind M. Javle, Howard Safran, Waqar Haque, Bridgett D. Hobbs

Data analysis and interpretation: Christopher H. Crane, John S. Yordy, Gregg A. Staerkel, Sunil Krishnan, Jason B. Fleming, Prajnan Das, Jeffrey E. Lee, James L. Abbruzzese, Robert A. Wolff

Manuscript writing: All authors

Final approval of manuscript: All authors

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Footnotes

  • Supported in part by a Cancer Center Support Grant No. CA16672 from the National Cancer Institute, Department of Health and Human Services, and by a grant from Bristol-Myers Squibb.

  • Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

  • Clinical trial information can be found for the following: NCT00338039.

  • Received November 17, 2010.
  • Accepted April 25, 2011.
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  1. Published online before print June 27, 2011, doi: 10.1200/JCO.2010.33.8038 JCO vol. 29 no. 22 3037-3043
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