Cetuximab-based neoadjuvant chemoradiation and surgical resection in patients with locally advanced esophageal and gastric cancer

Reviewer: Christine Hill, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 22 de enero del 2009

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Presenter: H.J. Wanebo, Brown University Oncology Group, Providence, Rhode Island

Background

  • Although surgical treatments remain a mainstay of definitive treatments for esophageal and gastric cancers, several groups have demonstrated benefit to multimodality treatments (Krasna, 2006). Although up-front surgical procedures are often performed when possible, pre-operative chemotherapy or chemoradiotherapy are also standard treatments.

    • Neoadjuvant chemoradiotherapy may improve survival over either surgery alone or neoadjuvant chemotherapy only (Tepper, 2008; Shah, 2009).
    • Specific chemotherapies utilized in treatment of esophageal and gastric cancer are variable, and may include 5-fluorouracil, platinum-based drugs, and taxane-based regimens. No randomized trial has demonstrated one regimen to be superior to others (Henry, 2006; Urba, 2003; Kelsey, 2007).
  • Cetuximab, an anti-EGFR monoclonal antibody, has been shown to improve outcomes when combined with conventional chemotherapy and/ or radiotherapy in the treatment of certain carcinomas.

    • Bonner and colleagues demonstrated improved locoregional control and overall survival for head and neck cancer patients treated with cetuximab and radiotherapy versus radiotherapy alone (Bonner JA, 2006).
    • Further studies have demonstrated improved outcomes for patients with recurrent and/ or metastatic head and neck cancer treated with cis/carboplatin, 5FU and cetuximab versus cis/carboplatin and 5FU alone (Vermorken, 2008).
    • Improved overall survival has also been demonstrated for patients receiving cetuximab as second- or third-line treatment for colorectal cancer (Jonker, 2007).
  • The study presented here was performed in order to evaluate the role of cetuximab-based chemoradiation for esophageal and gastric cancer in the role of a phase II clinical trial.

Methods

  • 60 patients total were enrolled in this IRB-approved phase II trial after endoscopic and radiologic staging.
    • 49 of 60 patients were male, and median patient age was 58 years.
    • All patients had locally advanced disease without known distant metastases (T2-4, N1-3, M0).

      • 55 patients had esophageal cancers, and 5 gastric cancers
      • 56 cancers were adenocarcinoma, and 4 squamous cell.
  • Patients received neoadjuvant chemoradiation as follows:

    • Cetuximab, 400 mg/ m2 during week 1, followed by 250 mg/ m2 weekly for 5 weeks.
    • Paclitaxel, 50 mg/ m2 weekly for 6 weeks
    • Carboplatin, AUC = 2, weekly for 6 weeks
    • 50.4 Gy in fractions of 180 cGy (28 total fractions).
  • Patients were then re-evaluated for surgical respectability.
  • Endpoints included 2-year overall survival, surgical resectability, and pathologic response to chemoradiotherapy with cetuximab.

Results

  • 54 of 60 patients (454 of 60 patients (47 male, 7 female) completed the planned neoadjuvant therapy.
    • Toxicities included the following:
      • Grade3/4 esophageal mucositis, n = 10 (20%)
      • Grade 3/4 dehydration, n = 5 (10%)
      • Drug hypersensitivity, n = 2 (< 5%)
  • Of these, 42 went had surgical resection

    • The remaining 12 patients had endoscopy only. Three of these were not felt to be operable, and 9 declined surgery.
    • Major surgical approaches included Ivor-Lewis esophagectomy (n = 28), transhiatal esophagectomy (n = 12), and gastrectomy (n = 2).
    • Two post-operative deaths occurred.
  • Complete endoscopic response was shown in 28 of 42 patients who went on to have surgery, and in 10 of 12 patients having endoscopy only.
  • Of patients who had surgery, pathologic complete response was observed for 10 (20%), and near complete response with microscopic residual disease for 10 (20%).
  • Overall survival at 2 years was 60% for patients who had surgery, versus 25% for those who had endoscopy only (p < 0.0001).
  • At median follow-up of 13 months (range 3 – 38 months), 56% of patient who had had surgery were alive without evidence of disease, 35% had died of disease, and 7% were alive with disease.

Authors' Conclusions

  • The authors conclude that cetuximab-based neoadjuvant chemoradiation is tolerable for patients with esophageal and gastric cancers.
  • They note that addition of cetuximab is associated with significant downstaging that facilitates surgical resection, and may enhance survival for this group of patients.

Comments

  • This trial represents an interesting contribution to the literature regarding optimal multimodality treatment for esophageal and gastric cancers.
  • Certainly, the demonstration of overall survival benefit with use of cetuximab in the setting of other cancers has been very exciting as an advancement in patient care, particularly as cetuximab is one of the first successful targeted agents to be used successfully clinically.
  • The regimen of chemotherapy, radiotherapy, and cetuximab utilized in this study appears to be tolerable, with acceptable toxicity.
  • The authors comment on improved respectability following use of cetuximab; however, they do not comment in detail on the respectability of patients’ disease prior to receiving neoadjuvant treatment; additionally, since this is a phase II trial, no control or comparison group is available. For these reasons, the conclusion that addition of cetuximab improves chance of respectability may be somewhat inaccurate; having said this, patients in this trial appeared to fare well after surgical treatments, and the majority of patients went on to have surgery or the option of surgery.
  • The conclusions of the study carried out here are also limited by the relatively limited follow-up time (median 13 months).
  • Despite these factors, the results presented here are interesting and hypothesis generating. As recent trials have demonstrated a potential benefit to use of neoadjuvant chemoradiation in treatment of esophageal cancer (Tepper, 2008; Shah, 2009), further investigation of optimal regimens is of utmost importance. The results of this trial are certainly promising enough to warrant investigation of cetuximab in combination with chemotherapy and radiation prior to surgery for esophageal cancer in the setting of a randomized phase III clinical trial.

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