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AVACROSS Study: Locally Advanced Rectal Cancer
Addition of Bevacizumab to XELOX Induction Therapy Plus Concomitant Capecitabine-Based Chemoradiotherapy in Magnetic Resonance Imaging-Defined Poor-Prognosis Locally Advanced Rectal Cancer: The AVACROSS Study

Introduction

Patients diagnosed with locally advanced rectal cancer commonly receive concomitant chemoradiotherapy followed by surgical resection as standard therapy for this disease.  The principles of surgery include removal of primary tumor with adequate margins, restoration of organ integrity if able, and lymph node dissection.Surgery follows within 5-10 weeks following neoadjuvant chemoradiation. After mesorectal excision, adjuvant chemotherapy is usually recommended for six months using a combination of 5-fluorouracil/leucovorin, FOLFOX or capecitabine with oxaliplatin.1  The authors of a study published in The Oncologist note that the previously mentioned approach to locally advanced rectal cancer is aimed at local disease control, delaying systemic therapy treatment.2  The delay in systemic therapy can be significant, and some patients may receive their treatment up to 4 months post their original diagnosis, depending on the postoperative recovery period.  Nogue and colleagues aimed to study the efficacy and toxicity of adding bevacizumab to induction chemotherapy followed by preoperative bevacizumab-based chemoradiotherapy in patients with locally advanced rectal cancer.2 Participating patients (n = 47) with high-risk adenocarcinoma as determined by magnetic resonance imaging criteria were entered in a multicenter, phase II trial.  Study treatment consisted of four 21-day cycles of bevacizumab (7.5 mg/kg) and XELOX (capecitabine plus oxaliplatin), followed by concomitant radiotherapy (50.4 Gy) plus bevacizumab (5 mg/kg every 2 weeks) and capecitabine (825 mg/m2 twice daily on days 1-15).2 Patients received surgery 6-8 weeks post chemoradiotherapy; the primary endpoint of the study was pathologic complete response (pCR).

Results

  • Of the 45 patients who underwent surgery, pCR was obtained in 16 patients (36%; 95% confidence interval [CI]: 22.29%-51.27%)
  • 17 patients (38%) had Dworak tumor regression grade 3
  • R0 resection was performed in 44 patients (98%); one patient who had received only one induction CT cycle had microscopic residual disease (R1)
  • Most grade 3/4 adverse events occurred during the induction phase; patients reported diarrhea (11%), asthenia (4%), neutropenia (6%) and thrombocytopenia (4%)
  • 11 patients (24%) required surgical reintervention
  • One patient suffered a sudden death during induction phase
  • After a mean follow-up of 32 months, 38 patients continued to be free of any sign of disease; 5 patients had metastatic progression. Three patients had died (two from metastatic disease and another from a second neoplasm)

The authors of the study concluded that the addition of bevacizumab to induction chemotherapy and chemoradiotherapy is feasible, with significant activity and manageable toxicity.  Nogue and colleagues also note that caution is recommended regarding surgical complications; bevacizumab can also interfere with wound healing.2

ManageCRC Commentary

Efforts to improve treatment approaches for patients with locally advanced rectal cancer have usually included the addition of new drugs to the chemotherapy regimens; targeted therapies such as cetuximab, panitumumab and bevacizumab are part of the recommended treatment for advanced or metastatic disease per the current National Comprehensive Cancer Network’s (NCCN) guidelines for rectal cancer.1 Because patients with rectal cancer often have a relatively high risk of locoregional recurrence, neoadjuvant/adjuvant therapy includes locoregional treatment.  The use of bevacizumab in combination with standard chemotherapy approaches given after a 6-8 week delay is interesting but needs further study.  The current NCCN guidelines call for a delay of 5-10 weeks after induction therapy in order to reduce complications from combined chemo/RT treatment.1 The optimal time of surgery following chemoradiation for advanced rectal cancer has not definitively been reached; a recent study noted that the delay of surgery following intense neoadjuvant therapy followed by the addition of chemotherapy with mFOLFOX6 produced modest increases in pCR rates without increased complications.3 Bevacizumab, although usually well-tolerated by patients, does carry a unique side effect profile.  The single death of the patient undergoing induction therapy is concerning; the death was thought to be cardiac-related and capecitabine and bevacizumab can cause cardiac adverse events.  Cost of bevacizumab therapy is also a potential concern; the risks and benefits of new combinations of therapies must be balanced as well.  The data from this phase II study is intriguing, but larger phase III studies must be performed before this approach can be considered standard in the treatment of patients with locally advanced rectal cancer.

References

  1. National Comprehensive Cancer Network.NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer. Version 4.2011. Available at: http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf Free registration required.
  2. Nogue, M, Salud, A, Vicente, P et al.  Addition of bevacizumab to XELOX induction therapy plus concomitant capecitabine-based chemoradiotherapy in magnetic resonance imaging-defined poor-prognosis locally advanced rectal cancer: The AVACROSS Study. Oncologist, 2011; 16 [epub ahead of print]. Link to abstract at: http://www.ncbi.nlm.nih.gov/pubmed?term=the%20AVACROSS%20study doi: 10.1634/theoncologist.2010-0285
  3. Garcia-Aguilar, J, Smith, DD, Avila, K et al. Optimal timing of surgery after chemoradiation for advanced rectal cancer: Preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg, 2011; [epub ahead of print]. Link to abstract at: http://www.ncbi.nlm.nih.gov/pubmed/21494121 doi: 10.1097/SLA.0b013e3182196e1f


Article Created On : 4/26/2011 11:42:28 AM             Article Updated On : 4/26/2011 11:42:28 AM